StudyFinder
Search Results Within Category "Cancer - Brain and Spinal Tumors - Other Brain and Spinal Tumors"
11 Study Matches
CBL0137 for the Treatment of Relapsed or Refractory Solid Tumors, Including CNS Tumors and Lymphoma
- cancer@cchmc.org
ALL
12 months to 21 years old
PHASE1
NCT04870944
Inclusion Criteria:
* Parts A and B: Patients must be \>= 12 months and =\< 21 years of age at the time of study enrollment
* Patients must have had histologic verification of malignancy at original diagnosis or relapse, except in patients with diffuse intrinsic brain stem tumors, or patients with pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers, including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG)
* Part A: Patients with relapsed or refractory solid tumors or lymphoma, including patients with CNS tumors or known CNS metastases (including untreated or progressive) are eligible
* Part B: Patients with progressive or recurrent DIPG (diagnosed by biopsy or imaging characteristics) and other H3 K27-altered DMG previously treated with radiation therapy
* Part A: Patients must have either measurable or evaluable disease
* Part B: Patients must have measurable disease
* Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
* Patients must have a performance status corresponding to Easter Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients \> 16 years of age and Lansky for patients =\< 16 years of age. Patients must have a Karnofsky or Lansky score \>= 50%
* Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g., blood count criteria, the patient is considered to have recovered adequately
* Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive
* Solid tumor patients: \>= 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)
* Anti-cancer agents not known to be myelosuppressive (eg, not associated with reduced platelet or absolute neutrophil count \[ANC\] counts): \>= 7 days after the last dose of agent
* Antibodies: \>= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =\< 1
* Corticosteroids: If used to modify immune adverse events related to prior therapy, \>= 14 days must have elapsed since last dose of corticosteroid. Patients with CNS tumors receiving corticosteroids must have been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment
* Hematopoietic growth factors: \>= 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or 7 days for short acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
* Interleukins, interferons and cytokines (other than hematopoietic growth factors): \>= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
* Stem cell Infusions (with or without total body irradiation \[TBI\]):
* Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: \>= 84 days after infusion and no evidence of graft versus host disease (GVHD)
* Autologous stem cell infusion including boost infusion: \>= 30 days
* Cellular therapy: \>= 42 days after the completion of any type of cellular therapy (e.g., modified T cells, natural killer \[NK\] cells, dendritic cells, etc.)
* Radiation therapy \[XRT\]/external beam irradiation including protons: \>= 14 days after local XRT; \>= 150 days after TBI, craniospinal XRT or if radiation to \>= 50% of the pelvis; \>= 42 days if other substantial bone marrow (BM) radiation
* Radiopharmaceutical therapy (e.g., radiolabeled antibody, I-131 metaiodobenzylguanidine \[131I MIBG\]): \>= 42 days after systemically administered radiopharmaceutical therapy
* Patients must not have received prior exposure to CBL0137
* For patients with solid tumors without known bone marrow involvement:
* Peripheral absolute neutrophil count (ANC) \>= 1000/uL (performed within 7 days prior to enrollment unless otherwise indicated)
* Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions). These patients will not be evaluable for hematologic toxicity. At least 5 of every cohort of 6 patients must be evaluable for hematologic toxicity for the dose-escalation part of the study. If dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity
* For patients with solid tumors without known bone marrow involvement:
* Platelet count \>= 100,000/uL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) (performed within 7 days prior to enrollment unless otherwise indicated)
* Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions). These patients will not be evaluable for hematologic toxicity. At least 5 of every cohort of 6 patients must be evaluable for hematologic toxicity for the dose-escalation part of the study. If dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity
* Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 or a creatinine based on age/sex as follows (performed within 7 days prior to enrollment unless otherwise indicated):
* Age: Maximum serum creatinine (mg/dL)
* 1 to \< 2 years: 0.6 (male); 0.6 (female)
* 2 to \< 6 years: 0.8 (male); 0.8 (female)
* 6 to \< 10 years: 1 (male); 1 (female)
* 10 to \< 13 years: 1.2 (male); 1.2 (female)
* 13 to \< 16 years: 1.5 (male); 1.4 (female)
* \>= 16 years: 1.7 (male); 1.4 (female)
* Patients with solid tumors:
* Bilirubin (sum of conjugated + unconjugated or total) =\< 1.5 x upper limit of normal (ULN) for age (performed within 7 days prior to enrollment unless otherwise indicated)
* Patients with solid tumors:
* Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L (performed within 7 days prior to enrollment unless otherwise indicated)
* Shortening fraction of \>= 27% by echocardiogram (performed within 7 days prior to enrollment unless otherwise indicated) or
* Ejection fraction of \>= 50% by gated radionuclide study (performed within 7 days prior to enrollment unless otherwise indicated)
* Corrected QT (QTC) \< 480 msec (performed within 7 days prior to enrollment unless otherwise indicated)
* Patients with seizure disorder may be enrolled if seizures well controlled without the use of enzyme-inducing anti-convulsant agents. Well controlled is defined by no increase in seizure frequency in the prior 7 days
* Nervous system disorders (Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\]5) resulting from prior therapy must be =\< grade 2, with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible
* Patients have consented to receive a central venous catheter prior to the administration of CBL0137. A central line is required for CBL0137 administration
Exclusion Criteria:
* Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, OR because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (e.g., male or female condom) for the duration of the study. Abstinence is an acceptable method of birth control
* Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. If used to modify immune adverse events related to prior therapy, \>= 14 days must have elapsed since last dose of corticosteroid
* Patients who are currently receiving another investigational drug are not eligible
* Patients who are currently receiving other anti-cancer agents are not eligible (except leukemia patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy)
* Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
* Patients who are receiving drugs that are strong inducers or inhibitors of CYP3A4, CYP2B6 (e.g., carbamazepine) and CYP1A2 (e.g., ciprofloxacin, enoxacin, fluvoxamine, smoking) are not eligible. These agents are to be avoided for 7 days prior to the start of CBL0137 and for the duration of the protocol therapy. Sensitive substrates of CYP2D6 (e.g., atomoxetine, desipramine, dextromethorphan, eliglustat, nebivolol, nortriptyline, perphenazine, tolterodine, R-venlafaxine) should also be avoided for the duration protocol therapy
* Patients who are receiving drugs associated with a known risk of Torsades de Pointes (TdP) are not eligible. Drugs associated with known risk of Torsades de Pointes (TdP) are to be avoided for 7 days prior to the start of CBL0137 and for duration of the protocol therapy
* Patients with known peripheral vascular disease are excluded
* Patients with a history of pro-thrombotic disorder are not eligible
* Patients who have an uncontrolled infection are not eligible
* Patients who have received a prior solid organ transplantation are not eligible
* Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible PROCEDURE: Biospecimen Collection, PROCEDURE: Bone Marrow Aspirate, PROCEDURE: Bone Marrow Biopsy, PROCEDURE: Echocardiography Test, DRUG: FACT Complex-targeting Curaxin CBL0137
Diffuse Midline Glioma, H3 K27-Altered, Metastatic Malignant Neoplasm in the Central Nervous System, Recurrent Diffuse Intrinsic Pontine Glioma, Recurrent Diffuse Midline Glioma, H3 K27-Altered, Recurrent Lymphoma, Recurrent Malignant Solid Neoplasm, Recurrent Primary Malignant Central Nervous System Neoplasm, Refractory Lymphoma, Refractory Malignant Solid Neoplasm, Refractory Primary Malignant Central Nervous System Neoplasm
Lutathera for Treatment of Recurrent or Progressive High-Grade CNS Tumors
- cancer@cchmc.org
ALL
4 years to 39 years old
PHASE1
NCT05278208
All participants must meet the following inclusion and exclusion criteria. No exceptions will be given. Imaging studies to establish eligibility must be done within three weeks prior to enrollment. All other clinical evaluations to establish eligibility (except for \[68Ga\]Ga-DOTATATE PET) must be done within 7 days prior to enrollment.
• Screening Criteria
• 1 Diagnosis Patient must have a diagnosis of primary high-grade CNS tumor (any histopathologic diagnosis that is WHO grade III-IV) or meningioma (any histologic grade) that is recurrent, progressive, or refractory. Note that patients with DIPG (based on radiographic/clinical diagnosis) who have undergone biopsy will be eligible with histologic diagnosis of grade II-IV infiltrating glioma. All tumors must have histologic verification either at the time of diagnosis or recurrence, except for patients meningioma who have not previously undergone biopsy or resection. Note: Refractory disease is defined as the presence of persistent abnormality on conventional MRI that is further distinguished by histology (biopsy or sample of lesion) or advanced imaging, OR as determined by the treating physician and discussed with the primary investigator prior to enrollment.
• 2 Prior Therapy Patients must have recurred/progressed following prior standard therapy for their tumor. Note: Patients with meningioma, atypical meningioma, or anaplastic meningioma must have received at least surgical resection or radiation.
• 3 Screening Consent Participant/legal guardian is willing to sign a screening consent for \[68Ga\]Ga-DOTATATE PET imaging. The screening consent is to be obtained according to institutional guidelines. Assent, when appropriate, will be obtained according to institutional guidelines.
• Eligibility Criteria * Phase I Age Patient must be ≥ 4 and \<12 years of age at the time of enrollment. Disease Status: Patients who participate in the efficacy expansion cohort must have bi-dimensionally measurable disease, defined as at least one lesion that can be accurately measured in at least two dimensions Patients with measurable extraneural disease only are also eligible. * Phase II Age Patient must be 12 to \ • Inclusion Criteria
• 1 Uptake on \[68Ga\]Ga-DOTATATE PET Patients must have uptake on DOTATATE PET/CT in at least one tumor lesion (corresponding to known disease) equivalent to a Krenning score ≥2 (confirmed by central radiology review).
• 2 Prior Therapy Patients must have recovered from the acute treatment related toxicities (defined as ≤ grade 1 if not defined in eligibility criteria) of all prior chemotherapy, immunotherapy, radiotherapy, or any other treatment modality prior to entering this study.
• 3 Chemotherapy Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if nitrosourea.
• 4 Investigational/Biologic Agent ●Biologic or investigational agent (anti-neoplastic): Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent ≥ 7 days prior to study enrollment. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. ●Monoclonal Antibodies and agents with known prolonged half-lives: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent ≥ 28 days prior to study enrollment.
• 5 Radiation Patients must have had their last fraction of: * Craniospinal irradiation or total body irradiation or radiation to \> 50% of pelvis \> 3 months prior to enrollment. * Focal irradiation \> 4 weeks prior to enrollment
• 6 Stem Cell Transplant Patient must be: * ≥ 6 months since allogeneic stem cell transplant prior to enrollment with no evidence of active graft vs. host disease * ≥ 3 months since autologous stem cell transplant prior to enrollment
• 7 Growth Factors Patients must be off all colony-forming growth factor(s) for at least 1 week prior to enrollment (e.g. filgrastim, sargramostim or erythropoietin). Two weeks must have elapsed if patients received long-acting formulations.
• 8 Thrombopoietin receptor agonist * Phase I: Patients must be off thrombopoietin receptor agonists for at least 1 week prior to enrollment (e.g. romiplostim, eltrombopag) * Phase II: Patients can receive concurrent thrombopoietin receptor agonists
• 9 Somatostatin analogs Patients must be off long-acting somatostatin analogs for at least 4 weeks and off short-acting somastatin analogs (i.e., octreotide) for at least 24 hours.
• 10 Neurologic Status * Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment, documented by a detailed neurological exam. * Patients with seizure disorders may be enrolled if seizures are well controlled.
• 11 Performance Status Karnofsky Performance Scale (KPS for \> 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) assessed within two weeks of enrollment must be ≥ 50. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• 12 Organ Function Patients must have adequate organ and marrow function, for eligibility and enrollment, as defined below: * Adequate Bone Marrow Function as defined as: * Absolute neutrophil count ≥ 1.0 x 109 cells/ L * Platelets ≥100 x 109 cells/ L (unsupported, defined as no platelet transfusion within 7 days) * Hemoglobin ≥8 g/dl (may receive transfusions) * Adequate Renal Function as defined as: * Creatinine clearance or radioisotope GFR \>70mL/min/1.73m2 OR * A serum creatinine based on (Schwartz et al. J. Peds, 106:522, 1985) age/gender as follows: 1 to \< 2 years: maximum serum creatinine 0.6 mg/dL for males and females. 2 to \< 6 years: maximum serum creatinine 0.8 mg/dL for males and females. 6 to \< 10 years: maximum serum creatinine 1.0 mg/dL for males and females. 10 to \< 13 years: maximum serum creatinine 1.2 mg/dL for males and females. 13 to \< 16 years: maximum serum creatinine 1.5 mg/dL for males and 1.4 mg/dL for females. ≥ 16 years: maximum serum creatinine 1.7 mg/dL for males and 1.4 mg/dL for females. * Adequate Liver Function as defined as: * Total bilirubin ≤ 3 times institutional upper limit of normal (ULN) for age * AST(SGOT)/ALT(SGPT) ≤ 3 times institutional ULN * Serum albumin ≥ 2g/dL * Coagulation parameters: INR \<1.5 times ULN and aPTT \<1.5 times ULN unless patients are receiving therapeutic anticoagulation which affects these parameters * Adequate Cardiac Function as defined as: * Ejection fraction of ≥ 55% by echocardiogram * Serum electrolytes (Sodium, Potassium, Chloride) within institutional limits of normal (patients can be on enteral supplementation)
• 13 Corticosteroids Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment, with a maximum dexamethasone dose of 2.5mg/m2/day.
• 14 Pregnancy Status Female patients of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• 15 Pregnancy Prevention Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study and for at least 7 months after drug cessation in females of childbearing potential and for at least 4 months after drug cessation in males of child fathering potential.
• 16 Informed Consent The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines.
• Exclusion Criteria
• 1 Confirmed bone marrow metastatic disease Patients with confirmed metastatic disease to bone marrow are ineligible.
• 2 Presence of bulky disease Patients with bulky disease on imaging as described below are ineligible. Treating physicians are encouraged to request a rapid central imaging review to confirm fulfillment of these criteria if there are questions or concerns. Bulky disease is defined as: * Tumor with evidence of clinically significant uncal herniation or midline shift. * Tumor with diameter of \>5cm in one dimension on T2/FLAIR. * Tumor that in the opinion of the site investigator shows significant mass effect in either the brain or spine. Note that patients with metastatic or multi-focal disease (with exception of bone marrow) are eligible as long as no sites of disease meet above criteria for bulky disease.
• 3 Breast-feeding Nursing mothers are excluded from this study. There is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Lutathera.
• 4 Concurrent Illness * Patients with a history of any other malignancy, except patients with a secondary brain tumor if the patient's prior malignancy has been in remission for at least 5 years from the end of treatment. * Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results. * Patients with type I diabetes.
• 5 Concomitant Medications * Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible. * Prior or current treatment with 177Lu-DOTATATE/TOC or 90Y-DOTATATE/TOC.
• 6 Prisoners will be excluded from this study.
• 7 Inability to participate: Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits, obtain follow-up studies required to assess toxicity to therapy, or adhere to drug administration plan, other study procedures, and study restrictions.
• Inclusion of Women and Minorities Both males and females of all races and ethnic groups are eligible for this study.
• Screening Criteria
• 1 Diagnosis Patient must have a diagnosis of primary high-grade CNS tumor (any histopathologic diagnosis that is WHO grade III-IV) or meningioma (any histologic grade) that is recurrent, progressive, or refractory. Note that patients with DIPG (based on radiographic/clinical diagnosis) who have undergone biopsy will be eligible with histologic diagnosis of grade II-IV infiltrating glioma. All tumors must have histologic verification either at the time of diagnosis or recurrence, except for patients meningioma who have not previously undergone biopsy or resection. Note: Refractory disease is defined as the presence of persistent abnormality on conventional MRI that is further distinguished by histology (biopsy or sample of lesion) or advanced imaging, OR as determined by the treating physician and discussed with the primary investigator prior to enrollment.
• 2 Prior Therapy Patients must have recurred/progressed following prior standard therapy for their tumor. Note: Patients with meningioma, atypical meningioma, or anaplastic meningioma must have received at least surgical resection or radiation.
• 3 Screening Consent Participant/legal guardian is willing to sign a screening consent for \[68Ga\]Ga-DOTATATE PET imaging. The screening consent is to be obtained according to institutional guidelines. Assent, when appropriate, will be obtained according to institutional guidelines.
• Eligibility Criteria * Phase I Age Patient must be ≥ 4 and \<12 years of age at the time of enrollment. Disease Status: Patients who participate in the efficacy expansion cohort must have bi-dimensionally measurable disease, defined as at least one lesion that can be accurately measured in at least two dimensions Patients with measurable extraneural disease only are also eligible. * Phase II Age Patient must be 12 to \ • Inclusion Criteria
• 1 Uptake on \[68Ga\]Ga-DOTATATE PET Patients must have uptake on DOTATATE PET/CT in at least one tumor lesion (corresponding to known disease) equivalent to a Krenning score ≥2 (confirmed by central radiology review).
• 2 Prior Therapy Patients must have recovered from the acute treatment related toxicities (defined as ≤ grade 1 if not defined in eligibility criteria) of all prior chemotherapy, immunotherapy, radiotherapy, or any other treatment modality prior to entering this study.
• 3 Chemotherapy Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if nitrosourea.
• 4 Investigational/Biologic Agent ●Biologic or investigational agent (anti-neoplastic): Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent ≥ 7 days prior to study enrollment. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. ●Monoclonal Antibodies and agents with known prolonged half-lives: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent ≥ 28 days prior to study enrollment.
• 5 Radiation Patients must have had their last fraction of: * Craniospinal irradiation or total body irradiation or radiation to \> 50% of pelvis \> 3 months prior to enrollment. * Focal irradiation \> 4 weeks prior to enrollment
• 6 Stem Cell Transplant Patient must be: * ≥ 6 months since allogeneic stem cell transplant prior to enrollment with no evidence of active graft vs. host disease * ≥ 3 months since autologous stem cell transplant prior to enrollment
• 7 Growth Factors Patients must be off all colony-forming growth factor(s) for at least 1 week prior to enrollment (e.g. filgrastim, sargramostim or erythropoietin). Two weeks must have elapsed if patients received long-acting formulations.
• 8 Thrombopoietin receptor agonist * Phase I: Patients must be off thrombopoietin receptor agonists for at least 1 week prior to enrollment (e.g. romiplostim, eltrombopag) * Phase II: Patients can receive concurrent thrombopoietin receptor agonists
• 9 Somatostatin analogs Patients must be off long-acting somatostatin analogs for at least 4 weeks and off short-acting somastatin analogs (i.e., octreotide) for at least 24 hours.
• 10 Neurologic Status * Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment, documented by a detailed neurological exam. * Patients with seizure disorders may be enrolled if seizures are well controlled.
• 11 Performance Status Karnofsky Performance Scale (KPS for \> 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) assessed within two weeks of enrollment must be ≥ 50. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• 12 Organ Function Patients must have adequate organ and marrow function, for eligibility and enrollment, as defined below: * Adequate Bone Marrow Function as defined as: * Absolute neutrophil count ≥ 1.0 x 109 cells/ L * Platelets ≥100 x 109 cells/ L (unsupported, defined as no platelet transfusion within 7 days) * Hemoglobin ≥8 g/dl (may receive transfusions) * Adequate Renal Function as defined as: * Creatinine clearance or radioisotope GFR \>70mL/min/1.73m2 OR * A serum creatinine based on (Schwartz et al. J. Peds, 106:522, 1985) age/gender as follows: 1 to \< 2 years: maximum serum creatinine 0.6 mg/dL for males and females. 2 to \< 6 years: maximum serum creatinine 0.8 mg/dL for males and females. 6 to \< 10 years: maximum serum creatinine 1.0 mg/dL for males and females. 10 to \< 13 years: maximum serum creatinine 1.2 mg/dL for males and females. 13 to \< 16 years: maximum serum creatinine 1.5 mg/dL for males and 1.4 mg/dL for females. ≥ 16 years: maximum serum creatinine 1.7 mg/dL for males and 1.4 mg/dL for females. * Adequate Liver Function as defined as: * Total bilirubin ≤ 3 times institutional upper limit of normal (ULN) for age * AST(SGOT)/ALT(SGPT) ≤ 3 times institutional ULN * Serum albumin ≥ 2g/dL * Coagulation parameters: INR \<1.5 times ULN and aPTT \<1.5 times ULN unless patients are receiving therapeutic anticoagulation which affects these parameters * Adequate Cardiac Function as defined as: * Ejection fraction of ≥ 55% by echocardiogram * Serum electrolytes (Sodium, Potassium, Chloride) within institutional limits of normal (patients can be on enteral supplementation)
• 13 Corticosteroids Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment, with a maximum dexamethasone dose of 2.5mg/m2/day.
• 14 Pregnancy Status Female patients of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• 15 Pregnancy Prevention Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study and for at least 7 months after drug cessation in females of childbearing potential and for at least 4 months after drug cessation in males of child fathering potential.
• 16 Informed Consent The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines.
• Exclusion Criteria
• 1 Confirmed bone marrow metastatic disease Patients with confirmed metastatic disease to bone marrow are ineligible.
• 2 Presence of bulky disease Patients with bulky disease on imaging as described below are ineligible. Treating physicians are encouraged to request a rapid central imaging review to confirm fulfillment of these criteria if there are questions or concerns. Bulky disease is defined as: * Tumor with evidence of clinically significant uncal herniation or midline shift. * Tumor with diameter of \>5cm in one dimension on T2/FLAIR. * Tumor that in the opinion of the site investigator shows significant mass effect in either the brain or spine. Note that patients with metastatic or multi-focal disease (with exception of bone marrow) are eligible as long as no sites of disease meet above criteria for bulky disease.
• 3 Breast-feeding Nursing mothers are excluded from this study. There is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Lutathera.
• 4 Concurrent Illness * Patients with a history of any other malignancy, except patients with a secondary brain tumor if the patient's prior malignancy has been in remission for at least 5 years from the end of treatment. * Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results. * Patients with type I diabetes.
• 5 Concomitant Medications * Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible. * Prior or current treatment with 177Lu-DOTATATE/TOC or 90Y-DOTATATE/TOC.
• 6 Prisoners will be excluded from this study.
• 7 Inability to participate: Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits, obtain follow-up studies required to assess toxicity to therapy, or adhere to drug administration plan, other study procedures, and study restrictions.
• Inclusion of Women and Minorities Both males and females of all races and ethnic groups are eligible for this study.
DRUG: LUTATHERA® (Lutetium Lu 177 dotatate)
High Grade Glioma, Meningioma, Embryonal Tumor, Medulloblastoma, Anaplastic Ependymoma, Recurrent Diffuse Intrinsic Pontine Glioma, Recurrent Malignant Glioma, Recurrent Medulloblastoma, Recurrent Primary Central Nervous System Neoplasm, Refractory Diffuse Intrinsic Pontine Glioma, Refractory Malignant Glioma, Refractory Medulloblastoma, Refractory Primary Central Nervous System Neoplasm
Somatostatin Receptor, DOTATATE, Lutathera
ONC201 in H3 K27M-mutant Diffuse Glioma Following Radiotherapy (the ACTION Study) (ACTION)
Lori Backus - Lori.Backus@cchmc.org
ALL
PHASE3
NCT05580562
Inclusion Criteria:
• Able to understand the study procedures and agree to participate in the study by providing written informed consent (by participant or legally authorized representative), and assent when applicable.
• Body weight ≥ 10 kg at time of randomization.
• Histologically diagnosed H3 K27M-mutant diffuse glioma (new diagnosis). Detection of a missense K27M mutation in any histone H3-encoding gene detected by testing of tumor tissue (immunohistochemistry \[IHC\] or next-generation sequencing \[NGS\] in a Clinical Laboratory Improvement Amendments \[CLIA\]-certified or equivalent laboratory). \[Site to provide (as available): ≥ 11 unstained formalin-fixed paraffin-embedded (FFPE) slides from tumor tissue.\]
• At least one, high-quality, contrast-enhanced MRI of the brain obtained prior to starting radiotherapy for submission to sponsor's imaging vendor for central read. For participants who had a surgical resection, this scan must be post-resection; for participants who did not have a resection, this scan may be pre- or post-biopsy.
• At least one, high-quality, contrast-enhanced MRI of the brain obtained 2 to 6 weeks after completion of frontline radiotherapy. If unable to obtain contrast-enhanced imaging due to lack of venous access after multiple attempts, a patient may still be eligible after collection of a nonenhanced MRI of the brain. \[Site to also provide all available MRIs completed prior to initiating treatment with study intervention.\]
• Received frontline radiotherapy
• Initiated radiotherapy within 12 weeks from the initial diagnosis of H3 K27M-mutant diffuse glioma.
• Completed radiotherapy within 2 to 6 weeks prior to randomization
• Completed standard fractionated radiotherapy (eg. 54 to 60 Gy in 28 to 33 fractions given over approximately 6 weeks or hypofractionated radiotherapy (eg. 40 Gy in 15 fractions given over approximately 3 weeks).
• Karnofsky Performance Status or Lansky Performance Status ≥ 70 at time of randomization.
• Stable or decreasing dose of corticosteroids and anti-seizure medications for 7 days prior to randomization, if applicable. Stable steroid dose is defined as ≤ 2 mg/day increase (based on dexamethasone dose or equivalent dose of an alternative steroid).
Exclusion Criteria:
• Primary spinal tumor.
• Diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons.
• Evidence of leptomeningeal spread of disease or cerebrospinal fluid dissemination.
• Any known concurrent malignancy.
• New lesion(s) outside of the radiation field.
• Received whole-brain radiotherapy.
• Received proton therapy for glioma.
• Use of any of the following treatments within the specified time periods prior to randomization:
• Dordaviprone (ONC201) or ONC206 at any time.
• Systemic bevacizumab (includes biosimilars) at any time since the initial diagnosis of H3 K27M-mutant diffuse glioma.
• Temozolomide within past 3 weeks.
• Tumor treating fields at any time.
• DRD2 antagonist within past 2 weeks.
• Any investigational therapy within past 4 weeks.
• Strong CYP3A4 inhibitors within 3 days.
• Strong CYP3A4 inducers (includes enzyme-inducing antiepileptic drugs) within 2 weeks.
• Laboratory test results meeting any of the following parameters within 2 weeks prior to randomization:
• Absolute neutrophil count \< 1.0 × 109/L or platelets \< 75 × 109/L.
• Total bilirubin \> 1.5 × upper limit of normal (ULN) (participants with Gilbert's syndrome may be included with total bilirubin \> 1.5 × ULN if direct bilirubin is ≤ 1.5 × ULN).
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2.5 × ULN.
• Creatinine clearance ≤ 60 mL/min as calculated by the Cockcroft Gault equation (or estimated glomerular filtration rate \< 60 mL/min/1.73 m2).
• QTc \> 480 msec (based on mean from triplicate electrocardiograms) during screening.
• Known hypersensitivity to any excipients used in the study intervention formulation.
• Pregnant, breastfeeding, or planning to become pregnant while receiving study intervention or within 3 months after the last dose. Participants of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study intervention.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring systemic therapy or psychiatric illness/social situations that would limit compliance with study requirements.
• Any other condition (eg, medical, psychiatric, or social) that, in the opinion of the investigator, may interfere with participant safety or the ability to complete the study according to the protocol.
DRUG: Dordaviprone (ONC201), DRUG: Dordaviprone (ONC201) + Placebo, OTHER: Placebo
H3 K27M, Glioma
H3 K27M, H3 K28M, H3 K27-altered, histone, H3F3A, HIST1H3B, HIST1H3C, H3.1, H3.3, DMG, thalamus, thalamic, midline
MEKTOVI® for the Treatment of Pediatric Adamantinomatous Craniopharyngioma
- cancer@cchmc.org
ALL
1 year to 39 years old
PHASE2
NCT05286788
Inclusion Criteria:
• Age: Patients must be ≥ 12 months and ≤ 39 years of age at the time of study enrollment.
• Diagnosis: Patients with histologically-confirmed adamantinomatous craniopharyngioma (ACP) Histologic confirmation of ACP may be made on solid tumor or, if no solid tumor can be safely obtained, cyst fluid with classic ACP characteristics of thick, cholesterol-rich, greenish-brown liquid in the context of imaging features consistent with craniopharyngioma, including lobulated, cystic/solid mass with calcifications that originates in the sellar/suprasellar region.
• Disease Status: Patients must have measurable disease. * Stratum 1: Patients with progressive or recurrent ACP who demonstrate cystic and/or solid recurrence or progression at least 6 months post completion of radiation therapy * Stratum 2 (NOT CURRENTLY ENROLLING): Patients with measurable ACP who have undergone surgery but have NOT previously undergone irradiation (but may have received prior systemic or intracystic therapy). Progressive disease is allowed but not required.
• Performance Level: Karnofsky ≥ 50% for patients \> 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age (See Appendix I). Note: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Prior Therapy: Patients must have recovered or stabilized from the acute toxic effects of prior treatments * Biologic (anti-neoplastic agent): At least 7 days must have elapsed after the last (systemic or intracystic) dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair * Immunotherapy: At least 42 days after the completion of any type of systemic immunotherapy, e.g. tumor vaccines. * Monoclonal antibodies: At least 21 days after the last dose of a monoclonal antibody. * Radiation therapy: Patients must have had their last (conventional or hypofractionated) fraction of: a) Focal irradiation \> 6 months prior to enrollment and b) No prior craniospinal irradiation is permitted. * Corticosteroids: Patients receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment * Myelosuppressive systemic therapy: At least 21 days must have elapsed after the last systemic myelosuppressive therapy. * Surgery: At least 6 weeks must have elapsed since major or intermediate surgery. Major surgery includes major craniotomy for tumor resection of cyst fenestration, organ resection, and exploratory laparotomy. Intermediate procedures include ventriculoperitoneal shunt placement, stereotactic brain biopsy, and intraventricular catheter placement. Minor procedures that are not excluded include skin biopsy/incision and drainage, bone marrow aspirate, and central venous catheter placement, ommaya aspirations, lumbar punctures, and nasal endoscopy to remove packing.
• Organ Function Requirements Adequate Bone Marrow Function Defined as: * Peripheral absolute neutrophil count (ANC) ≥1000/mm3 * Platelet count ≥100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) * Hemoglobin \>8 g/dL (may be transfused) Adequate Renal Function Defined as: * Creatinine clearance or radioisotope GFR \> 70ml/min/1.73 m2 or * A serum creatinine based on (Schwartz et al. J. Peds, 106:522, 1985) age/gender as follows:
• to \< 2 years: maximum serum creatinine 0.6 mg/dL for males and females. 2 to \< 6 years: maximum serum creatinine 0.8 mg/dL for males and females. 6 to \< 10 years: maximum serum creatinine 1.0 mg/dL for males and females. 10 to \< 13 years: maximum serum creatinine 1.2 mg/dL for males and females. 13 to \< 16 years: maximum serum creatinine 1.5 mg/dL for males and 1.4 mg/dL for females. ≥ 16 years: maximum serum creatinine 1.7 mg/dL for males and 1.4 mg/dL for females. Adequate Liver Function Defined as: * Total bilirubin ≤ 1.5 × institutional upper limit of normal * AST (SGOT) ≤ 2.5 × institutional upper limit of normal * ALT (SGPT) ≤ 2.5 × institutional upper limit of normal Adequate Cardiac Function Defined as: * Left Ventricular Ejection Fraction greater than the institutional lower limit of normal by echocardiogram * QTc ≤ 480 msec (by Bazett formula) Adequate Neurologic Function Defined as: * Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment. * Patients with current seizure disorders may be enrolled if seizures are well-controlled on antiepileptic therapies.
• Informed Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines
Exclusion Criteria:
• Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on this study due to unknown risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for at least 90 days after discontinuation of drug for females and at least 60 days for males. For females of childbearing potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods (bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices; hormonal contraceptive methods must be supplemented by a barrier method) and agreement to refrain from donating eggs are required. For males of reproductive potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm.
• Gastrointestinal Disease: * Patients with a history of serious gastrointestinal disease, including inflammatory bowel disease or gastrointestinal perforation * Patients who are unable to absorb enteral medications * Administration via NG/NJ/G-tube is allowed
• Concomitant Medications * Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. * Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible. * Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible.
• Study Specific: * Patients who have an uncontrolled infection are not eligible. * Patients who have received any live or attenuated vaccinations within three months prior to start of therapy are not eligible. * Any significant concurrent medical or surgical condition that would jeopardize the patient's safety or ability to complete the study, including, but not limited to, disease of the nervous, renal, hepatic, cardiac (such as symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia), pulmonary, or endocrine system * Patients who have a history of Human Immunodeficiency Virus, Hepatitis B Virus, Hepatitis C Virus or Tuberculosis infection are not eligible. * Patients who have received a prior solid organ transplantation are not eligible. * Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible. * Patients who have a history of alcohol, drug, or chemical abuse within 6 months of screening. * Patients who have had surgery within the last 6 weeks or who have concerns for poor postsurgical wound healing. * Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to tocilizumab and its excipients are not eligible.
DRUG: Binimetinib Oral Tablet [Mektovi]
Adamantinous Craniopharyngioma, Recurrent Adamantinomatous Craniopharyngioma
Study of Ribociclib and Everolimus in HGG and DIPG or Ribociclib and Temozolomide in DHG, H3G34-mutant
- cancer@cchmc.org
ALL
12 months to 39 years old
PHASE2
NCT05843253
TarGeT-A study strata definitions Part1: Initial Feasibility Study for the combination of ribociclib PfOS formulation with everolimus: Enrollment on this cohort will be limited to patients aged \<21 years with primary intracranial localized HGG and DIPG
Part 2
* Stratum A: Patients with localized, intracranial, non-pontine, and non-thalamic HGG (who do not meet criteria for strata C-D)
* Stratum B: Patients with DIPG
* Stratum C: Patients with primary thalamic, spinal cord, and/or secondary/radiation-related HGG.
* Stratum D: Patients with metastatic/disseminated HGG, multifocal HGG, and/or gliomatosis cerebri who received CSI.
Stratum E
* Stratum E: Patients with localized DHG, H3G34-mutant.
• Inclusion criteria already met to enroll on TarGeT-SCR (central molecular and histopathologic screening) based on:
• 1) Age: patients must be ≥12 months and ≤39 years of age at the time of enrollment on TarGeT-SCR. For the Part 1 Initial Feasibility Cohort (receiving ribociclib and everolimus) only: patients must be \<21 years of age at the time of enrollment on this protocol.
• 2) Diagnosis: patients with newly-diagnosed HGG, including DIPG are eligible. All patients must have histologic confirmation tumor tissue from diagnostic biopsy or resection, without exceptions. The diagnosis of HGG, including DIPG, must have been confirmed through TarGeT-SCR: * For the diagnosis of DIPG, patients must have a tumor with pontine epicenter and diffuse involvement of at least 2/3 of the pons, with histopathology, consistent with diffuse WHO grade 2-4 glioma * All other HGGs must be WHO grade 3 or 4.
• 3) Disease status: There are no disease status requirements for enrollment * Patients without measurable disease are eligible. * Patients with metastatic or multifocal disease or gliomatosis cerebri who received upfront CSI are eligible * Patients with a primary spinal HGG are eligible * Patients with secondary, radiation-related HGG are eligible.
• Inclusion criteria for assignment to TarGeT-A, for all strata:
• 1) Presence of at least one relevant actionable somatic alteration, detailed here: * Pathogenic alterations presumed to cause activation of cell cycle: * Amplification of CDK4 or CDK6 * Deletion of CDKN2A, CDKN2B, or CDKN2C * Amplification of CCND1 or CCND2 * Pathogenic alterations presumed to cause activation of the PI3K/mTOR pathway: * Deletion or mutation of PTEN * Mutation or amplification of PIK3CA * Mutation of PIK3R1 * Deletion or mutation of TSC1 or TSC2 * Patients with evidence of homozygous (biallelic) RB1 loss by sequencing are excluded from TarGeT-A * Patients whose tumors harbor other alterations suspected to activate the cell cycle and/or PI3K/mTOR pathway could potentially also be eligible, but only following consensus recommendation by the international multidisciplinary molecular screening committee. * For Stratum E: H3G34 (R/V) mutation
• 2) Performance Level: Karnofsky ≥ 50% for patients \> 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of ag. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• 3) Prior Therapy for HGG: * Surgery, RT, dexamethasone are permissible. Temozolomide administered concurrently with RT is permissible. Avastin/bevacizumab use is permitted given the last dose was administered \> 21 days prior to enrollment. No other prior anticancer therapy for HGG will be allowed. * Patients must have received photon or proton RT. * Patients must have started RT \< 42 calendar days from initial diagnosis defined as the date of diagnostic biopsy or resection. If a patient underwent 2 upfront surgeries (e.g., biopsy then resection or debulking), this is the date of the second surgery. * RT delivered via photon or proton beam, must have been administered at a standard dose including (54 Gy in 30 fractions for DIPG, 54-59.4 Gy in 30-33 fractions), 45 Gy-54 Gy for primary spinal disease, and/or 36 Gy-39.6 Gy craniospinal for patients with spinal or leptomeningeal metastatic disease with supplemental boost to 45-54 Gy for metastasis within the thecal sac and 54 Gy-60 Gy for intracranial metastasis. Any variances in the radiotherapy dose within 10% of the standard doses outlined above will be discussed with the Sponsor-Investigator to confirm eligibility prior to study enrollment. * Patients must enroll and start treatment No later than 35 calendar days post-completion of RT. The earliest patients can begin protocol treatment is 28 calendar days post-completion of RT.
• 4) Organ Function Requirements
• 4.1) Adequate Bone Marrow Function Defined as: * Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 * Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) * Hemoglobin \>8 g/dL (may be transfused)
• 4.2) Adequate Renal Function Defined as: * Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 OR * Maximum serum creatinine based on (Schwartz et al. J. Peds, 106:522, 1985) age/gender as follows: 1 to \< 2 years=0.6 mg/dL for males and females; 2 to \< 6 years=0.8 mg/dL for males and females; 6 to \< 10 years= 1.0 mg/dL for males and females; 10 to \< 13 years=1.2 mg/dL for males and females. 13 to \< 16 years=1.5 mg/dL for males and 1.4 mg/dL for females.
• 4.3) Adequate Liver Function Defined as: * Total bilirubin must be ≤ 1.5 times institutional upper limit of normal for age * AST(SGOT)/ALT(SGPT) ≤ 3 times institutional upper limit of normal * Serum albumin ≥ 2g/dL
• 4.4) Adequate Cardiac Function Defined as: * Ejection fraction of ≥ 50% by echocardiogram * QTc ≤ 450 msec (by Bazett formula)
• 4.5) Adequate Neurologic Function Defined as: Patients with seizure disorder may be enrolled if well-controlled on anticonvulsants that are not strong inducers or inhibitors of CYP3A4/5.
• 4.6) Adequate Pulmonary Function Defined as: No evidence of dyspnea at rest, and a pulse oximetry \>94% on room air if there is clinical indication for determination.
• 5) Ability to take medications by mouth: For ribociclib and everolimus strata, patients must be able to take study medications by mouth as administration via NG/NJ/G tube is not allowed.
• 6) Informed Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines
• 7) Contraception: Male and female patients of childbearing potential must be willing to use a highly effective contraception method. Exclusion Criteria
• Pregnant or Breast-Feeding Pregnant or breast-feeding women will not be entered on this study due to known potential risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Patients of childbearing or child fathering potential must agree to use at least one highly effective method of contraception while being treated on this study and for 3 months after completing therapy. A woman is considered of childbearing potential if she is fertile, following menarche and until becoming post-menopausal unless permanently sterile. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. Male participants should refrain from sperm donation throughout the duration of treatment and for 3 months after completion of therapy A highly effective contraception method is defined as one that results in a low failure rate (\<1% per year) when used consistently and correctly. The following are considered highly effective contraception methods: * Combined estrogen and progesterone containing hormonal contraception associated with inhibition of ovulation. * Progesterone-only hormonal contraception associated with inhibition of ovulation. * Intra Uterine Device (IUD) * Intra Uterine hormone releasing system * Bilateral tubal occlusion * Vasectomized partner * Sexual abstinence (avoiding having heterosexual intercourse) The following contraceptive measures are NOT considered effective * Progesterone-only hormonal contraception (birth control pill) that that does NOT stop ovulation * Male or female condom with or without spermicide * Cap, diaphragm or sponge with spermicide
• Concomitant Medications * Patients receiving corticosteroids are eligible. The use of corticosteroids must be reported. * Patients who are currently receiving another investigational drug are not eligible. * Patients who are currently receiving other anti-cancer agents are not eligible, with the exception of temozolomide given concurrently with RT only. * Patients who are receiving enzyme inducing anticonvulsants that are strong inducers or inhibitors of CYP3A4/5 are not eligible. * Patients who are receiving strong inducers or inhibitors of CYP3A4/5 are not eligible and should be avoided from 14 days prior to enrollment to the end of the study. * Patients who are receiving medications known to prolong QTc interval are not eligible. * Patients who are receiving therapeutic anticoagulation with warfarin or other coumadin-derived anticoagulants are not eligible. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed as long as the patient has adequate coagulation defined as aPTT \< 1.5Xs ULN and INR \< 1.5.
• Patients who have an uncontrolled infection are not eligible.
• Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study are not eligible.
• Patients with known clinically significant active malabsorption syndrome or other condition that could affect absorption are not eligible.
• Patients with prior or ongoing clinically significant medical or psychiatric condition that, in the investigator's opinion, could affect the safety of the subject, or could impair the assessment of study results are not eligible.
Inclusion Criteria:
• Inclusion criteria already met to enroll on TarGeT-SCR (central molecular and histopathologic screening) based on:
• 1) Age: patients must be ≥12 months and ≤39 years of age at the time of enrollment on TarGeT-SCR. For the Part 1 Initial Feasibility Cohort (receiving ribociclib and everolimus) only: patients must be \<21 years of age at the time of enrollment on this protocol.
• 2) Diagnosis: patients with newly-diagnosed HGG, including DIPG are eligible. All patients must have histologic confirmation tumor tissue from diagnostic biopsy or resection, without exceptions. The diagnosis of HGG, including DIPG, must have been confirmed through TarGeT-SCR: * For the diagnosis of DIPG, patients must have a tumor with pontine epicenter and diffuse involvement of at least 2/3 of the pons, with histopathology, consistent with diffuse WHO grade 2-4 glioma * All other HGGs must be WHO grade 3 or 4.
• 3) Disease status: There are no disease status requirements for enrollment * Patients without measurable disease are eligible. * Patients with metastatic or multifocal disease or gliomatosis cerebri who received upfront CSI are eligible * Patients with a primary spinal HGG are eligible * Patients with secondary, radiation-related HGG are eligible.
• Inclusion criteria for assignment to TarGeT-A, for all strata:
• 1) Presence of at least one relevant actionable somatic alteration, detailed here: * Pathogenic alterations presumed to cause activation of cell cycle: * Amplification of CDK4 or CDK6 * Deletion of CDKN2A, CDKN2B, or CDKN2C * Amplification of CCND1 or CCND2 * Pathogenic alterations presumed to cause activation of the PI3K/mTOR pathway: * Deletion or mutation of PTEN * Mutation or amplification of PIK3CA * Mutation of PIK3R1 * Deletion or mutation of TSC1 or TSC2 * Patients with evidence of homozygous (biallelic) RB1 loss by sequencing are excluded from TarGeT-A * Patients whose tumors harbor other alterations suspected to activate the cell cycle and/or PI3K/mTOR pathway could potentially also be eligible, but only following consensus recommendation by the international multidisciplinary molecular screening committee. * For Stratum E: H3G34 (R/V) mutation
• 2) Performance Level: Karnofsky ≥ 50% for patients \> 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of ag. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• 3) Prior Therapy for HGG: * Surgery, RT, dexamethasone are permissible. Temozolomide administered concurrently with RT is permissible. Avastin/bevacizumab use is permitted given the last dose was administered \> 21 days prior to enrollment. No other prior anticancer therapy for HGG will be allowed. * Patients must have received photon or proton RT. * Patients must have started RT \< 42 calendar days from initial diagnosis defined as the date of diagnostic biopsy or resection. If a patient underwent 2 upfront surgeries (e.g., biopsy then resection or debulking), this is the date of the second surgery. * RT delivered via photon or proton beam, must have been administered at a standard dose including (54 Gy in 30 fractions for DIPG, 54-59.4 Gy in 30-33 fractions), 45 Gy-54 Gy for primary spinal disease, and/or 36 Gy-39.6 Gy craniospinal for patients with spinal or leptomeningeal metastatic disease with supplemental boost to 45-54 Gy for metastasis within the thecal sac and 54 Gy-60 Gy for intracranial metastasis. Any variances in the radiotherapy dose within 10% of the standard doses outlined above will be discussed with the Sponsor-Investigator to confirm eligibility prior to study enrollment. * Patients must enroll and start treatment No later than 35 calendar days post-completion of RT. The earliest patients can begin protocol treatment is 28 calendar days post-completion of RT.
• 4) Organ Function Requirements
• 4.1) Adequate Bone Marrow Function Defined as: * Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 * Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) * Hemoglobin \>8 g/dL (may be transfused)
• 4.2) Adequate Renal Function Defined as: * Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 OR * Maximum serum creatinine based on (Schwartz et al. J. Peds, 106:522, 1985) age/gender as follows: 1 to \< 2 years=0.6 mg/dL for males and females; 2 to \< 6 years=0.8 mg/dL for males and females; 6 to \< 10 years= 1.0 mg/dL for males and females; 10 to \< 13 years=1.2 mg/dL for males and females. 13 to \< 16 years=1.5 mg/dL for males and 1.4 mg/dL for females.
• 4.3) Adequate Liver Function Defined as: * Total bilirubin must be ≤ 1.5 times institutional upper limit of normal for age * AST(SGOT)/ALT(SGPT) ≤ 3 times institutional upper limit of normal * Serum albumin ≥ 2g/dL
• 4.4) Adequate Cardiac Function Defined as: * Ejection fraction of ≥ 50% by echocardiogram * QTc ≤ 450 msec (by Bazett formula)
• 4.5) Adequate Neurologic Function Defined as: Patients with seizure disorder may be enrolled if well-controlled on anticonvulsants that are not strong inducers or inhibitors of CYP3A4/5.
• 4.6) Adequate Pulmonary Function Defined as: No evidence of dyspnea at rest, and a pulse oximetry \>94% on room air if there is clinical indication for determination.
• 5) Ability to take medications by mouth: For ribociclib and everolimus strata, patients must be able to take study medications by mouth as administration via NG/NJ/G tube is not allowed.
• 6) Informed Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines
• 7) Contraception: Male and female patients of childbearing potential must be willing to use a highly effective contraception method. Exclusion Criteria
• Pregnant or Breast-Feeding Pregnant or breast-feeding women will not be entered on this study due to known potential risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Patients of childbearing or child fathering potential must agree to use at least one highly effective method of contraception while being treated on this study and for 3 months after completing therapy. A woman is considered of childbearing potential if she is fertile, following menarche and until becoming post-menopausal unless permanently sterile. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. Male participants should refrain from sperm donation throughout the duration of treatment and for 3 months after completion of therapy A highly effective contraception method is defined as one that results in a low failure rate (\<1% per year) when used consistently and correctly. The following are considered highly effective contraception methods: * Combined estrogen and progesterone containing hormonal contraception associated with inhibition of ovulation. * Progesterone-only hormonal contraception associated with inhibition of ovulation. * Intra Uterine Device (IUD) * Intra Uterine hormone releasing system * Bilateral tubal occlusion * Vasectomized partner * Sexual abstinence (avoiding having heterosexual intercourse) The following contraceptive measures are NOT considered effective * Progesterone-only hormonal contraception (birth control pill) that that does NOT stop ovulation * Male or female condom with or without spermicide * Cap, diaphragm or sponge with spermicide
• Concomitant Medications * Patients receiving corticosteroids are eligible. The use of corticosteroids must be reported. * Patients who are currently receiving another investigational drug are not eligible. * Patients who are currently receiving other anti-cancer agents are not eligible, with the exception of temozolomide given concurrently with RT only. * Patients who are receiving enzyme inducing anticonvulsants that are strong inducers or inhibitors of CYP3A4/5 are not eligible. * Patients who are receiving strong inducers or inhibitors of CYP3A4/5 are not eligible and should be avoided from 14 days prior to enrollment to the end of the study. * Patients who are receiving medications known to prolong QTc interval are not eligible. * Patients who are receiving therapeutic anticoagulation with warfarin or other coumadin-derived anticoagulants are not eligible. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed as long as the patient has adequate coagulation defined as aPTT \< 1.5Xs ULN and INR \< 1.5.
• Patients who have an uncontrolled infection are not eligible.
• Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study are not eligible.
• Patients with known clinically significant active malabsorption syndrome or other condition that could affect absorption are not eligible.
• Patients with prior or ongoing clinically significant medical or psychiatric condition that, in the investigator's opinion, could affect the safety of the subject, or could impair the assessment of study results are not eligible.
DRUG: Ribociclib, DRUG: Everolimus, DRUG: Temozolomide (TMZ)
High Grade Glioma, Diffuse Intrinsic Pontine Glioma, Anaplastic Astrocytoma, Glioblastoma, Glioblastoma Multiforme, Diffuse Midline Glioma, H3 K27M-Mutant, Metastatic Brain Tumor, WHO Grade III Glioma, WHO Grade IV Glioma, Diffuse Hemispheric Glioma, H3 G34-Mutant
Project: Every Child for Younger Patients With Cancer
- cancer@cchmc.org
ALL
Up to 25 years old
NCT02402244
Inclusion Criteria:
* Enrollment must occur within 6 months of initial disease presentation OR within 6 months of refractory disease, disease progression, disease recurrence, second or secondary malignancy, or post-mortem
* Patients previously enrolled on ACCRN07 are eligible to enroll on Tracking Outcome, Registry and Future Contact components of APEC14B1 any time after they reach age of majority
* Patients with a known or suspected neoplasm that occurs in the pediatric, adolescent or young adult populations are eligible for enrollment as follows:
* All cancer cases with an International Classification of Diseases for Oncology (ICD-O) histologic behavior code of one "1" (borderline), two "2" (carcinoma in situ) or three "3" (malignant)
* All neoplastic lesions of the central nervous system regardless of behavior, i.e., benign, borderline or malignant
* All neoplastic lesions of the kidney regardless of behavior, i.e., benign, borderline or malignant
* The following other benign/borderline conditions:
* Mesoblastic nephroma
* Teratomas (mature and immature types)
* Myeloproliferative diseases including transient myeloproliferative disease
* Langerhans cell histiocytosis
* Lymphoproliferative diseases
* Desmoid tumors
* Gonadal stromal cell tumors
* Neuroendocrine tumors including pheochromocytoma
* Melanocytic tumors, except clearly benign nevi
* Ganglioneuromas
* Subjects must be =\< 25 years of age at time of original diagnosis, except for patients who are being screened specifically for eligibility onto a COG (or COG participating National Clinical Trials Network \[NCTN\]) therapeutic study, for which there is a higher upper age limit
* All patients or their parents or legally authorized representatives must sign a written informed consent and agree to participate in at least one component of the study; parents will be asked to sign a separate consent for their own biospecimen submission
* If patients or their parents or legally authorized representatives have not signed the Part A subject consent form at the time of a diagnostic bone marrow procedure, it is recommended that they initially provide consent for drawing extra bone marrow using the Consent for Collection of Additional Bone Marrow; consent using the Part A subject consent form must be provided prior to any other procedures for eligibility screening or banking under APEC14B1 OTHER: Cytology Specimen Collection Procedure, OTHER: Medical Chart Review
Adrenal Gland Pheochromocytoma, Carcinoma In Situ, Central Nervous System Neoplasm, Childhood Immature Teratoma, Childhood Kidney Neoplasm, Childhood Langerhans Cell Histiocytosis, Childhood Mature Teratoma, Congenital Mesoblastic Nephroma, Desmoid Fibromatosis, Ganglioneuroma, Lymphoproliferative Disorder, Malignant Neoplasm, Malignant Solid Neoplasm, Melanocytic Neoplasm, Myeloproliferative Neoplasm, Neoplasm of Uncertain Malignant Potential, Neuroendocrine Neoplasm, Stromal Neoplasm
ACTEMRA® for the Treatment of Pediatric Adamantinomatous Craniopharyngioma
- cancer@cchmc.org
ALL
1 year to 39 years old
PHASE2
NCT05233397
Inclusion Criteria:
• Age: Patients must be ≥ 12 months and ≤ 39 years of age at the time of study enrollment.
• Diagnosis: Patients with histologically-confirmed adamantinomatous craniopharyngioma (ACP) Histologic confirmation of ACP may be made on solid tumor or, if no solid tumor can be safely obtained, cyst fluid with classic ACP characteristics of thick, cholesterol-rich, greenish-brown liquid in the context of imaging features consistent with craniopharyngioma, including lobulated, cystic/solid mass with calcifications that originates in the sellar/suprasellar region.
• Disease Status: Patients must have measurable disease. * Stratum 1: Patients with progressive or recurrent ACP who demonstrate cystic and/or solid recurrence or progression at least 6 months post completion of radiation therapy * Stratum 2 (CLOSED): Patients with measurable ACP who have undergone surgery but have NOT previously undergone irradiation (but may have received prior systemic or intracystic therapy). Progressive disease is allowed but not required.
• Performance Level: Karnofsky ≥ 50% for patients \> 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age (See Appendix I). Note: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Prior Therapy: Patients must have recovered or stabilized from the acute toxic effects of prior treatments * Biologic (anti-neoplastic agent): At least 7 days must have elapsed after the last (systemic or intracystic) dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair * Immunotherapy: At least 42 days after the completion of any type of systemic immunotherapy, e.g. tumor vaccines. * Monoclonal antibodies: At least 21 days after the last dose of a monoclonal antibody. * Radiation therapy: Patients must have had their last (conventional or hypofractionated) fraction of: a) Focal irradiation \> 6 months prior to enrollment and b) No prior craniospinal irradiation is permitted. * Corticosteroids: Patients receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment * Myelosuppressive systemic therapy: At least 21 days must have elapsed after the last systemic myelosuppressive therapy. * Surgery: At least 6 weeks must have elapsed since major or intermediate surgery. Major surgery includes major craniotomy for tumor resection or cyst fenestration, organ resection, exploratory laparotomy. Intermediate procedures include ventriculoperitoneal shunt placement, stereotactic brain biopsy and intraventricular catheter placement. Minor procedures that are not excluded include skin biopsy/incision and drainage, bone marrow aspirate, and central venous catheter placement. Ommaya aspirations and Lumbar Punctures are considered minor procedures..
• Organ Function Requirements Adequate Bone Marrow Function Defined as: * Peripheral absolute neutrophil count (ANC) ≥1000/mm3 * Platelet count ≥100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) * Hemoglobin \>8 g/dL (may be transfused) Adequate Renal Function Defined as: * Creatinine clearance or radioisotope GFR \> 70ml/min/1.73 m2 or * A serum creatinine based on (Schwartz et al. J. Peds, 106:522, 1985) age/gender as follows: 1 to \< 2 years: maximum serum creatinine 0.6 mg/dL for males and females. 2 to \< 6 years: maximum serum creatinine 0.8 mg/dL for males and females. 6 to \< 10 years: maximum serum creatinine 1.0 mg/dL for males and females. 10 to \< 13 years: maximum serum creatinine 1.2 mg/dL for males and females. 13 to \< 16 years: maximum serum creatinine 1.5 mg/dL for males and 1.4 mg/dL for females. ≥ 16 years: maximum serum creatinine 1.7 mg/dL for males and 1.4 mg/dL for females. Adequate Liver Function Defined as: * Total bilirubin within normal institutional limits * AST (SGOT) ≤ 2.5 × institutional upper limit of normal * ALT (SGPT) ≤ 2.5 × institutional upper limit of normal Adequate Neurologic Function Defined as: * Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment. * Patients with current seizure disorders may be enrolled if seizures are well-controlled on antiepileptic therapies.
• Informed Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
Exclusion Criteria:
• Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on this study due to unknown risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for at least 90 days after discontinuation of drug for females and at least 60 days for males. For females of childbearing potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods (bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices; hormonal contraceptive methods must be supplemented by a barrier method) and agreement to refrain from donating eggs are required. For males of reproductive potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm.
• Gastrointestinal Disease: Patients with a history of serious gastrointestinal disease, including inflammatory bowel disease or gastrointestinal perforation
• Concomitant Medications * Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. * Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible. * Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible.
• Study Specific: * Patients who have an uncontrolled infection are not eligible. * Patients who have received any live or attenuated vaccinations within three months prior to start of therapy are not eligible. * Any significant concurrent medical or surgical condition that would jeopardize the patient's safety or ability to complete the study, including, but not limited to, disease of the nervous, renal, hepatic, cardiac (such as symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia), pulmonary, or endocrine system * Patients who have a history of Human Immunodeficiency Virus, Hepatitis B Virus, Hepatitis C Virus or Tuberculosis infection are not eligible. * Patients who have received a prior solid organ transplantation are not eligible. * Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible. * Patients who have a history of alcohol, drug, or chemical abuse within 6 months of screening. * Patients who have had major or intermediate surgery within the last 6 weeks or who have concerns for poor postsurgical wound healing. * Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to tocilizumab and its excipients are not eligible.
DRUG: Tocilizumab
Adamantinomatous Craniopharyngioma, Recurrent Adamantinomatous Craniopharyngioma
Targeted Pediatric High-Grade Glioma Therapy
- cancer@cchmc.org
ALL
12 months to 39 years old
NCT05839379
Inclusion Criteria:
• Age: Patients must be ≥12 months and ≤39 years of age at the time of enrollment onto this screening protocol.
• Diagnosis: Patients with newly diagnosed HGG, including DIPG are eligible. Diagnosis must have histologic confirmation from biopsy or resection. The diagnosis of HGG must have been confirmed by pathology review at the local site. For the diagnosis of DIPG, patients must have a tumor with pontine epicenter and diffuse involvement of at least 2/3 of the pons, with histopathology consistent with diffuse WHO grade 2-4 glioma (eg, diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, H3K27-altered diffuse midline glioma). For all other tumors, histologic grade must be WHO grade 3-4.
• Disease Status: There are no disease status requirements for enrollment. * Measurable disease is not required. Patients without measurable disease are eligible. * Patients with metastatic/disseminated or multifocal disease or gliomatosis cerebri are eligible. * Patients with a primary spinal tumor are eligible. * Patients with secondary, radiation related HGG are eligible.
• Prior Therapy for HGG: Surgery, radiation, and/or dexamethasone are permissible. Temozolomide concurrent with radiation is permissible. Prior administration of avastin/bevacizumab is allowed (individual treatment arms have different washout period requirements, check individual arm eligibility). No other prior anticancer therapy for HGG will be allowed. * Participants screening for assignment to TarGeT-L may not have received radiation. Timing from surgery to start of RT: For patients who have started RT, radiation must have started \<42 days from definitive surgery or biopsy, however it is strongly recommended patients start RT within 31 days from definitive surgery (if patient had two surgeries, radiation must have started within 31 days from second surgery).
• Tumor Sample Availability OR results from previous molecular profiling/targeted sequencing * If a patient screens through OPTION #1, tumor sample in addition to normal comparator tissue (peripheral blood, saliva, or buccal swab) must be submitted for comprehensive molecular screening at the time of screening enrollment. * If a patient screens through OPTIONS #2 or #3, results from previously performed molecular profiling must be submitted following enrollment. It is highly recommended that results be uploaded within 7 days of enrollment (if results are available at time of enrollment) or within 7 days of results becoming available (if pending at time of enrollment) to allow adequate time for central review.
• Informed Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
• Enrollment timeline: Patients are eligible to enroll on the TarGeT-SCR anytime between diagnosis and the following specific timepoints post completion of RT (if relevant) * Patients screening through OPTION #1 are eligible to enroll anytime between diagnosis and 10 days post RT (if completing RT). * Patients screening through OPTIONS #2 or #3 are eligible to enroll anytime between diagnosis and 21 days post RT (if completing RT). * Participants screening for TarGeT-L (lorlatinib) are eligible to enroll on TarGeT-SCR anytime between diagnosis and 31 days post definitive surgery (to allow time for molecular review). However, it is important to note the following: * For treatment protocols that include targeted therapy administered concurrently with RT, patients must start treatment within 10 calendar days of starting RT. * For treatment protocols that only include maintenance/adjuvant therapy (no systemic therapy given concurrently with radiation), patients must start treatment by 35 days post RT #SCREENING OPTIONS * OPTION1: Molecular screening through CONNECT TarGeT Clinical Testing Laboratories * OPTION2: Molecular screening through a national comprehensive tumor profiling program * OPTION3: Clinically validated targeted sequencing or focused profiling
Exclusion Criteria:
-Tumors that do not meet HGG and DIPG diagnoses specified above High Grade Glioma, Diffuse Intrinsic Pontine Glioma, Anaplastic Astrocytoma, Glioblastoma, Glioblastoma Multiforme, Diffuse Midline Glioma, H3 K27M-Mutant, Metastatic Brain Tumor, WHO Grade III Glioma, WHO Grade IV Glioma
A Study of a New Way to Treat Children and Young Adults With a Brain Tumor Called NGGCT
- cancer@cchmc.org
ALL
3 years to 29 years old
PHASE2
NCT04684368
Inclusion Criteria:
* Patients must be \>= 3 years and \< 30 years at the time of study enrollment
* Patients must be newly diagnosed with localized primary CNS NGGCT of the suprasellar and/or pineal region by pathology and/or serum or cerebrospinal fluid (CSF) elevation of AFP above institutional normal or \> 10 ng/mL or human chorionic gonadotropin (hCG) beta \> 100 mIU/mL as confirmed by Rapid Central Marker Screening Review on APEC14B1-CNS. Suprasellar, pineal and bifocal tumors are included. (CSF tumor markers and cytology must be within 31 days prior to enrollment and start of protocol therapy \[repeat if necessary\]. Serum tumor markers, AFP and hCGbeta must be within 7 days prior to enrollment and start of protocol therapy \[repeat if necessary\]). Basal ganglia or other primary sites are excluded
* Patients with any of the following pathological elements are eligible: endodermal sinus (yolk sac), embryonal carcinoma, choriocarcinoma, malignant/immature teratoma and mixed germ cell tumor (GCT) (i.e., may include some pure germinoma) if malignant elements listed above are present. Patients with only mature teratoma are excluded. Patients with pure germinoma admixed with mature teratoma are excluded (would be eligible for pure germinoma protocols)
* Patients must have a cranial MRI with and without gadolinium at diagnosis/prior to enrollment. If surgical resection is performed, patients must have pre-operative and post operative brain MRI with and without gadolinium. The post operative brain MRI should be obtained within 72 hours of surgery. If patient has a biopsy only, post-operative brain MRI is recommended but not required (within 31 days prior to study enrollment and start of protocol therapy )
* Patients must have a spine MRI with gadolinium obtained at diagnosis/prior to enrollment. Spine MRI with and without gadolinium is recommended (within 31 days prior to study enrollment and start of protocol therapy)
* Lumbar CSF must be obtained prior to study enrollment unless medically contraindicated. If a patient undergoes surgery and lumbar CSF cytology cannot be obtained at the time of surgery, then it should be performed at least 10 days following surgery and prior to study enrollment. False positive cytology can occur within 10 days of surgery
* Patients must have RAPID CENTRAL TUMOR MARKER REVIEW CSF tumor markers obtained prior to enrollment unless medically contraindicated. Ventricular CSF obtained at the time of CSF diversion procedure (if performed) is acceptable for tumor markers but lumbar CSF is preferred. In case CSF diversion and biopsy/surgery are combined, CSF tumor markers should be collected first
* Peripheral absolute neutrophil count (ANC) \>= 1000/uL (within 7 days prior to enrollment)
* Platelet count \>= 100,000/uL (transfusion independent) (within 7 days prior to enrollment)
* Hemoglobin \>= 8.0 g/dL (may receive red blood cell \[RBC\] transfusions) (within 7 days prior to enrollment)
* Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 or a serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
* Age: Maximum serum creatinine (mg/dL)
* 3 to \< 6 years: 0.8 (male), 0.8 (female)
* 6 to \< 10 years: 1 (male), 1 (female)
* 10 to \< 13 years: 1.2 (male), 1.2 (female)
* 13 to \< 16 years: 1.5 (male), 1.4 (female)
* \>= 16 years: male (1.7), 1.4 (female)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
* Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 135 U/L (within 7 days prior to enrollment)
* Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
* Central nervous system function defined as:
* Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
* Patients must not be in status epilepticus, coma or assisted ventilation prior to study enrollment
* Protocol therapy must begin within 31 calendar days of definitive surgery or clinical diagnosis, whichever is later. If a biopsy only was performed, the biopsy date will be considered the date of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery.
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
* NEUROCOGNITIVE FUNCTION AND QUALITY OF LIFE ASSESSMENT:
* English-, Spanish-, or French- speaking
* Note: Patients who speak a language other than English, Spanish, or French will be allowed to participate in ACNS2021 but will not complete the neurocognitive and quality of life assessments
* No known history of neurodevelopmental disorder prior to diagnosis of NGGCT (e.g., Down syndrome, fragile X, William syndrome, intellectual disability). Patients with NF1 will be allowed to participate
* Additional eligibility criteria for the COG Standardized Neuropsychological Battery only: must be at a site that has a psychologist to administer the battery
* Note: If not eligible for the COG Standardized Battery, patients should still complete the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2), Pediatric Quality of Life Inventory (PedsQL), Adaptive Behavior Assessment System Third Edition (ABAS-3), and Behavior Assessment System for Children, Third Edition (BASC-3) questionnaires
Exclusion Criteria:
* Patients with tumors located outside the ventricles (i.e., basal ganglia, thalamus)
* Patients with only mature teratoma and non-elevated markers upon tumor sampling at diagnosis
* Patients who have received any prior tumor-directed therapy for their diagnosis of NGGCT other than surgical intervention and corticosteroids
* Patients with metastatic disease (i.e., MRI evaluation, lumbar CSF cytology or intraoperative evidence of dissemination)
* Female patients who are pregnant, since fetal toxicities and teratogenic effects have been noted for several of the study drugs
* Note: Serum and urine pregnancy tests may be falsely positive due to HCGbeta-secreting germ cell tumors. Ensure the patient is not pregnant by institutional standards
* Lactating females who plan to breastfeed their infants
* Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation PROCEDURE: Biospecimen Collection, DRUG: Carboplatin, DRUG: Etoposide, BIOLOGICAL: Filgrastim, DRUG: Ifosfamide, PROCEDURE: Magnetic Resonance Imaging, DRUG: Mesna, BIOLOGICAL: Pegfilgrastim, PROCEDURE: Peripheral Blood Stem Cell Transplantation, OTHER: Questionnaire Administration, RADIATION: Radiation Therapy, RADIATION: Radiation Therapy, PROCEDURE: Second-Look Surgery, DRUG: Thiotepa
Central Nervous System Nongerminomatous Germ Cell Tumor, Choriocarcinoma, Embryonal Carcinoma, Immature Teratoma, Malignant Teratoma, Mixed Germ Cell Tumor, Pineal Region Germ Cell Tumor, Pineal Region Immature Teratoma, Pineal Region Yolk Sac Tumor, Suprasellar Germ Cell Tumor
Study of Olutasidenib and Temozolomide in HGG
Peter M de Blank, MD - Peter.deBlank@cchmc.org
ALL
12 years to 39 years old
PHASE2
NCT06161974
Criteria TarGeT-D study strata definitions
* Stratum A: Patients with localized, intracranial, non-pontine, and non-thalamic IDH 1 mutant Astrocytoma, CNS WHO Grade 3.
* Stratum B: Patients with localized, intracranial, non-pontine, and non-thalamic IDH 1 mutant Astrocytoma, CNS WHO Grade 4.
* Stratum C: Patients with IDH-1 mutant DIPG, primary thalamic and spinal cord IDH-1 mutant HGG.
• Inclusion criteria already met to enroll on TarGeT-SCR (central molecular and histopathologic screening) based on:
• 1) Age: patients must be ≥12 years and ≤39 years of age at the time of enrollment on TarGeT-SCR 1.2) Diagnosis: * Patients with a newly-diagnosed IDH1-mutant HGG including DIPG are eligible. All patients must have tumor tissue from diagnostic biopsy or resection, without exceptions. The diagnosis of HGG, including DIPG, must have been confirmed through TarGeT-SCR. * For the diagnosis of DIPG, patients must have a tumor with pontine epicenter and diffuse involvement of at least 2/3 of the pons, and histopathology consistent with diffuse WHO Grade 2-4 glioma. * All other HGG must be WHO Grade 3 or 4.
• 3) Disease status: There are no disease status requirements for enrollment * Measurable disease is not required. Patients without measurable disease are eligible. * Primary spinal tumor: Patients with a primary spinal HGG are eligible. * Patient must not have metastatic disease.
• Inclusion criteria for assignment to TarGeT-D, for all strata:
• 1 Presence of at Least One Relevant Actionable Somatic Mutation in IDH1 Gene, Detailed Here: * R132H, R132C, R132S, R132G or R132L. * Patients whose tumors harbor other alterations in addition to IDH1 mutation will potentially be eligible following consensus recommendation by the international multidisciplinary molecular screening committee. * Patients with IDH2 mutations are not eligible. * Patients with oligodendroglioma, IDH-mutant and 1p/19q-codeleted are not eligible.
• 2 Weight: Patients must weigh ≥35 Kg (77 lbs) at the time of enrollment on TarGeT-D.
• 3 Performance Level: Karnofsky ≥ 50% for patients \> 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• 4 Prior Therapy 2.4.1 Surgery, radiation, and/or dexamethasone are permissible. Temozolomide administered concurrently with radiotherapy is permissible. Prior administration of bevacizumab is allowed, given at least 42-day washout period is completed prior to beginning treatment on TarGeT-D. No other prior anticancer therapy for HGG will be allowed.
• 4.2 Radiation therapy requirements: RT, delivered via photon or proton beam, must have been administered at a standard dose including 54 Gy in 30 fractions for DIPG, 55-59.4 Gy in 30-33 fractions for other HGG or 45-54 Gy for primary spinal cord HGG. Any variances in the radiotherapy dose within 10% of the standard doses outlined above will be discussed with the Study Chair to confirm eligibility prior to study enrollment.
• 4.3 Timing between diagnosis and start of RT: Patients must have started RT \< 42 calendar days of initial diagnosis defined as the date of diagnostic biopsy or resection; if a patient underwent two upfront surgeries (e.g., biopsy then resection or debulking), this is the date of the second surgery. * Patients in pre-maintenance phase must enroll and start treatment no later than 21 calendar days post-completion of RT. * Patients not in pre-maintenance phase must enroll and start treatment no later than 35 calendar days post-completion of RT.
• 5 Organ Function Requirements 2.5.1 Adequate Bone Marrow Function Defined as: * Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3. * Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment). * Hemoglobin \> 8 g/dL (may be transfused). 2.5.2 Adequate Renal Function Defined as * Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 OR * Maximum serum creatinine based on age/gender as follows: 10 to \< 13 yrs=1.2 mg/dL for males and females. 13 to \< 16 yrs=1.5 mg/dL for males and 1.4 mg/dL for females.
• 5.3 Adequate Liver Function Defined as: * Total bilirubin must be ≤ 1.5 × institutional ULN. * AST(SGOT)/ALT(SGPT) \< 3 × institutional ULN. * Alkaline Phosphatase \< 3 × institutional ULN. 2.5.4 Adequate Neurologic Function Defined as: * Patients with seizure disorder may be enrolled if well-controlled on anticonvulsants that are not a strong inducer or inhibitor of CYP3A4/5. * Patients must be able to swallow oral medications to be eligible for study enrollment.
• 6. Informed consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
• Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on this study due to unknown potential risks of fetal and teratogenic adverse events as seen in animal studies. Pregnancy tests must be obtained in girls who are post-menarchal. Patients of childbearing or child fathering potential must agree to use one highly effective method of contraception while being treated on this study and for 3 months after completing therapy. A woman is considered of childbearing potential if she is fertile, following menarche and until becoming post-menopausal unless permanently sterile. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. Male participants should refrain from sperm donation throughout the duration of treatment and for 3 months after completion of therapy. A highly effective contraception method is defined as one that results in a low failure rate (\<1% per year) when used consistently and correctly. The following are considered highly effective contraception methods: * Combined estrogen and progesterone containing hormonal contraception associated with inhibition of ovulation. * Progesterone-only hormonal contraception associated with inhibition of ovulation. * Intra Uterine Device (IUD). * Intra uterine hormone releasing system. * Bilateral tubal occlusion. * Vasectomized partner. * Sexual abstinence (avoiding heterosexual intercourse). * The following contraceptive measures are NOT considered effective: * Progesterone-only hormonal contraception (birth control pill) that that does NOT stop ovulation. * Male or female condom with or without spermicide. * Cap, diaphragm, or sponge with spermicide.
• Using the following types of concomitant medications: * Corticosteroids: Patients receiving corticosteroids are eligible. The use of corticosteroids must be reported. * Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible. * Anti-cancer Agents: Concurrent anti-cancer agents are not allowed with the exception of temozolomide given concurrently with RT and as protocol-instructed post RT maintenance therapy after enrollment on TarGeT-D. * Anticonvulsants: Patients who are receiving enzyme inducing anticonvulsants that are strong inducers of CYP3A4/5 are not eligible. * Strong CYP3A4/5 inducers: Patients who are receiving strong inducers of CYP3A4/5 are not eligible. Strong inducers of CYP3A4/5 should be avoided from 14 days prior to or 5 half-lives (whichever is longer) enrollment to the end of the study. * Patients who are receiving medications known to prolong QTc interval are not eligible * Selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft) should be used with caution but are not contraindicated.
• Other Criteria * Infection: Patients who have an uncontrolled infection are not eligible. * Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study are not eligible. * Patients with known clinically significant active malabsorption syndrome or other condition that could affect absorption are not eligible. * Patients with malignancy related to HIV or solid organ transplant: known history of HIV, HBV surface antigen positivity or positive HCV antibody are not eligible. Viral testing is not required unless clinically indicated in patients without a known history. * Patients with prior or ongoing clinically significant illness, medical or psychiatric condition, that, in the investigator's opinion, could affect the safety of the participant, or could impair the assessment of study results are not eligible. * Patients with any prior solid organ transplant are not eligible. * Patients with secondary/radiation-related HGG are not eligible. * Patients with metastatic/disseminated HGG who have received CSI are not eligible.
Inclusion Criteria:
• Inclusion criteria already met to enroll on TarGeT-SCR (central molecular and histopathologic screening) based on:
• 1) Age: patients must be ≥12 years and ≤39 years of age at the time of enrollment on TarGeT-SCR 1.2) Diagnosis: * Patients with a newly-diagnosed IDH1-mutant HGG including DIPG are eligible. All patients must have tumor tissue from diagnostic biopsy or resection, without exceptions. The diagnosis of HGG, including DIPG, must have been confirmed through TarGeT-SCR. * For the diagnosis of DIPG, patients must have a tumor with pontine epicenter and diffuse involvement of at least 2/3 of the pons, and histopathology consistent with diffuse WHO Grade 2-4 glioma. * All other HGG must be WHO Grade 3 or 4.
• 3) Disease status: There are no disease status requirements for enrollment * Measurable disease is not required. Patients without measurable disease are eligible. * Primary spinal tumor: Patients with a primary spinal HGG are eligible. * Patient must not have metastatic disease.
• Inclusion criteria for assignment to TarGeT-D, for all strata:
• 1 Presence of at Least One Relevant Actionable Somatic Mutation in IDH1 Gene, Detailed Here: * R132H, R132C, R132S, R132G or R132L. * Patients whose tumors harbor other alterations in addition to IDH1 mutation will potentially be eligible following consensus recommendation by the international multidisciplinary molecular screening committee. * Patients with IDH2 mutations are not eligible. * Patients with oligodendroglioma, IDH-mutant and 1p/19q-codeleted are not eligible.
• 2 Weight: Patients must weigh ≥35 Kg (77 lbs) at the time of enrollment on TarGeT-D.
• 3 Performance Level: Karnofsky ≥ 50% for patients \> 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• 4 Prior Therapy 2.4.1 Surgery, radiation, and/or dexamethasone are permissible. Temozolomide administered concurrently with radiotherapy is permissible. Prior administration of bevacizumab is allowed, given at least 42-day washout period is completed prior to beginning treatment on TarGeT-D. No other prior anticancer therapy for HGG will be allowed.
• 4.2 Radiation therapy requirements: RT, delivered via photon or proton beam, must have been administered at a standard dose including 54 Gy in 30 fractions for DIPG, 55-59.4 Gy in 30-33 fractions for other HGG or 45-54 Gy for primary spinal cord HGG. Any variances in the radiotherapy dose within 10% of the standard doses outlined above will be discussed with the Study Chair to confirm eligibility prior to study enrollment.
• 4.3 Timing between diagnosis and start of RT: Patients must have started RT \< 42 calendar days of initial diagnosis defined as the date of diagnostic biopsy or resection; if a patient underwent two upfront surgeries (e.g., biopsy then resection or debulking), this is the date of the second surgery. * Patients in pre-maintenance phase must enroll and start treatment no later than 21 calendar days post-completion of RT. * Patients not in pre-maintenance phase must enroll and start treatment no later than 35 calendar days post-completion of RT.
• 5 Organ Function Requirements 2.5.1 Adequate Bone Marrow Function Defined as: * Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3. * Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment). * Hemoglobin \> 8 g/dL (may be transfused). 2.5.2 Adequate Renal Function Defined as * Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 OR * Maximum serum creatinine based on age/gender as follows: 10 to \< 13 yrs=1.2 mg/dL for males and females. 13 to \< 16 yrs=1.5 mg/dL for males and 1.4 mg/dL for females.
• 5.3 Adequate Liver Function Defined as: * Total bilirubin must be ≤ 1.5 × institutional ULN. * AST(SGOT)/ALT(SGPT) \< 3 × institutional ULN. * Alkaline Phosphatase \< 3 × institutional ULN. 2.5.4 Adequate Neurologic Function Defined as: * Patients with seizure disorder may be enrolled if well-controlled on anticonvulsants that are not a strong inducer or inhibitor of CYP3A4/5. * Patients must be able to swallow oral medications to be eligible for study enrollment.
• 6. Informed consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
Exclusion Criteria:
• Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on this study due to unknown potential risks of fetal and teratogenic adverse events as seen in animal studies. Pregnancy tests must be obtained in girls who are post-menarchal. Patients of childbearing or child fathering potential must agree to use one highly effective method of contraception while being treated on this study and for 3 months after completing therapy. A woman is considered of childbearing potential if she is fertile, following menarche and until becoming post-menopausal unless permanently sterile. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. Male participants should refrain from sperm donation throughout the duration of treatment and for 3 months after completion of therapy. A highly effective contraception method is defined as one that results in a low failure rate (\<1% per year) when used consistently and correctly. The following are considered highly effective contraception methods: * Combined estrogen and progesterone containing hormonal contraception associated with inhibition of ovulation. * Progesterone-only hormonal contraception associated with inhibition of ovulation. * Intra Uterine Device (IUD). * Intra uterine hormone releasing system. * Bilateral tubal occlusion. * Vasectomized partner. * Sexual abstinence (avoiding heterosexual intercourse). * The following contraceptive measures are NOT considered effective: * Progesterone-only hormonal contraception (birth control pill) that that does NOT stop ovulation. * Male or female condom with or without spermicide. * Cap, diaphragm, or sponge with spermicide.
• Using the following types of concomitant medications: * Corticosteroids: Patients receiving corticosteroids are eligible. The use of corticosteroids must be reported. * Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible. * Anti-cancer Agents: Concurrent anti-cancer agents are not allowed with the exception of temozolomide given concurrently with RT and as protocol-instructed post RT maintenance therapy after enrollment on TarGeT-D. * Anticonvulsants: Patients who are receiving enzyme inducing anticonvulsants that are strong inducers of CYP3A4/5 are not eligible. * Strong CYP3A4/5 inducers: Patients who are receiving strong inducers of CYP3A4/5 are not eligible. Strong inducers of CYP3A4/5 should be avoided from 14 days prior to or 5 half-lives (whichever is longer) enrollment to the end of the study. * Patients who are receiving medications known to prolong QTc interval are not eligible * Selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft) should be used with caution but are not contraindicated.
• Other Criteria * Infection: Patients who have an uncontrolled infection are not eligible. * Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study are not eligible. * Patients with known clinically significant active malabsorption syndrome or other condition that could affect absorption are not eligible. * Patients with malignancy related to HIV or solid organ transplant: known history of HIV, HBV surface antigen positivity or positive HCV antibody are not eligible. Viral testing is not required unless clinically indicated in patients without a known history. * Patients with prior or ongoing clinically significant illness, medical or psychiatric condition, that, in the investigator's opinion, could affect the safety of the participant, or could impair the assessment of study results are not eligible. * Patients with any prior solid organ transplant are not eligible. * Patients with secondary/radiation-related HGG are not eligible. * Patients with metastatic/disseminated HGG who have received CSI are not eligible.
DRUG: Olutasidenib + TMZ
High Grade Glioma, Astrocytoma, Astrocytoma, Grade III, Astrocytoma, Grade IV, Diffuse Intrinsic Pontine Glioma, WHO Grade III Glioma, WHO Grade IV Glioma, Metastatic Brain Tumor, Diffuse Midline Glioma, H3 K27M-Mutant, Thalamus Tumor, Spinal Tumor, IDH1 Mutation, IDH1 R132, IDH1 R132C, IDH1 R132H, IDH1 R132S, IDH1 R132G, IDH1 R132L, Oligodendroglioma
Lorlatinib for Newly-Diagnosed High-Grade Glioma With ROS or ALK Fusion
Diarra Diop - diarra.diop@cchmc.org
ALL
1 year to 21 years old
EARLY_PHASE1
NCT06333899
Inclusion Criteria:
• Patients must be ≥ 12 months and ≤ 21 years of age at the time of study enrollment on TarGeT-SCR.
• Diagnosis: Patients with newly diagnosed high-grade glioma (HGG), including diffuse intrinsic pontine gliomas (DIPG), whose tumors harbor an ALK or ROS-1 fusion alteration are eligible. Patients must have had histologically verified high-grade glioma from diagnostic biopsy or resection. For the diagnosis of DIPG, patients must have a tumor with pontine epicenter and diffuse involvement of at least 2/3 of the pons, with histopathology consistent with diffuse WHO Grade 2-4. All other HGGs must be Grade 3 or 4.
• Disease Status: Patients with disseminated DIPG or HGG are eligible only if the patient is to receive chemotherapy only, i.e. no craniospinal RT is intended to be given. MRI of spine must be performed if disseminated disease is suspected clinically by the treating physicians. Patients with primary spinal tumors are eligible only if the patient is to receive either chemotherapy or focal radiation therapy, i.e., no craniospinal RT is intended to be given. Patients with leptomeningeal disease only, with no definitive identifiable primary tumor, and documented ALK or ROS-1 fusion, must be discussed with the Study Chair on a case-by-case basis.
• Performance Level: Karnofsky ≥ 50% for patients \> 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age (See Appendix I). Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Prior Therapy: * Patients must not have received any prior anti-cancer chemotherapy. * Prior use of corticosteroids is allowed (see below Exclusion Criteria)
• Organ Function Requirements 6.1 Adequate Bone Marrow Function Defined as: * Peripheral absolute neutrophil count (ANC) ≥ 1000/μL * Platelet count ≥ 100,000/μL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) * Hemoglobin \>8 g/dL (may receive transfusions) 6.2 Adequate Renal Function Defined as: * Serum creatinine within normal institutional limits OR Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 6.3 Adequate Liver Function Defined as: * Total bilirubin ≤ 2 × institutional upper limit of normal * AST(aspartate aminotransferase)/ALT(alanine transaminase) ≤ 2.5 × institutional upper limit of normal 6.4 Adequate Pulmonary Function Defined as: Pulse oximetry \> 94% on room air if there is clinical indication for determination (e.g. dyspnea at rest).
• 5Adequate Cardiac Function Defined as: QTc ≤ 470 msec (by Bazett formula) 6.6 Adequate Neurologic Function Defined as: Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.
• 7 Informed Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines
Exclusion Criteria:
• Pregnant or breast-feeding women will not be entered on this study due to unknown risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. Females of reproductive potential must use an effective non-hormonal method of contraception, since lorlatinib can render hormonal contraceptives ineffective, during study treatment and for at least 6 months after the final dose. Males with female partners of reproductive potential must use effective contraception during treatment with lorlatinib and for 3 months after the final dose.
• Concomitant Medications * Investigational Agents/Drugs: Patients who have previously received or are currently receiving another investigational drug are not eligible. * Anti-cancer Agents: Patients who have previously received or are currently receiving other anti-cancer agents, including chemotherapy, immunotherapy, monoclonal antibodies, biologic or targeted therapy, are not eligible
• Infection: Patients must not have any active, uncontrolled systemic bacterial, viral or fungal infection.
• Patients who have received prior solid organ transplantation are not eligible.
• Patients must not have malabsorption syndrome or other condition affecting oral absorption.
• Patients must not be receiving any treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or inducer. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to treatment with loraltinib. Moderate inducers of CYP3A4 should be avoided
• Avoid concomitant use of lorlatinib with certain CYP3A substrates, for which minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the CYP3A substrate dosage in accordance with approved product labeling.
• P-glycoprotein (P-gp) substrates: Lorlatinib is considered a moderate P-gp inducer. Co-administration of lorlatinib with P-gp substrates including but not limited to digoxin should be avoided as the concentration of these drugs may be reduced by lorlatinib.
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
• Patients with a known personal history of acute or chronic severe psychiatric disorders or current history of suicidal ideation and history of suicide attempt.
DRUG: Lorlatinib, DRUG: Lorlatinib with chemotherapy1, DRUG: Lorlatinib with chemotherapy 2, DRUG: Lorlatinib post Radiation
High Grade Glioma, Diffuse Intrinsic Pontine Glioma, Anaplastic Astrocytoma, Infant Type Hemispheric Glioma, Glioblastoma, Glioblastoma Multiforme, WHO Grade III Glioma, WHO Grade IV Glioma, Diffuse Midline Glioma, H3K27-altered
ALK fusion, ROS fusion, High Grade Glioma, Diffuse Intrinsic Pontine Glioma