Chemo-immunotherapy Using Ibrutinib Plus Indoximod for Patients With Pediatric Brain Cancer

Study Overview
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Brief Summary
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Recent lab-based discoveries suggest that IDO (indoleamine 2,3-dioxygenase) and BTK (Bruton's tyrosine Kinase) form a closely linked metabolic checkpoint in tumor-associated antigen-presenting cells. The central clinical hypothesis for the GCC2020 study is that combining ibrutinib (BTK-inhibitor) with indoximod (IDO-inhibitor) during chemotherapy will synergistically enhance anti-tumor immune responses, leading to improvement in clinical response with manageable overlapping toxicity. GCC2020 is a prospective open-label phase 1 trial to determine the best safe dose of ibrutinib to use in combination with a previously studied chemo-immunotherapy regimen, comprised of the IDO-inhibitor indoximod plus oral metronomic cyclophosphamide and etoposide (4-drug combination) for participants, age 12 to 25 years, with relapsed or refractory primary brain cancer. Those previously treated with indoximod plus temozolomide may be eligible, including prior treatment via the phase 2 indoximod study (GCC1949, NCT04049669), the now closed phase 1 study (NLG2105, NCT02502708), or any expanded access (compassionate use) protocols. A dose-escalation cohort will determine the best safe dose of ibrutinib for the 4-drug combination. This will be followed by an expansion cohort, using ibrutinib at the best safe dose in the 4-drug combination, to allow assessment of preliminary evidence of efficacy.

Official Title
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Repurposing Ibrutinib for Chemo-Immunotherapy in a Phase 1b Study of Ibrutinib With Indoximod Plus Metronomic Cyclophosphamide and Etoposide for Pediatric Patients With Brain Cancer

Conditions
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Ependymoma, Medulloblastoma, Glioblastoma, Primary Brain Tumor

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: Indoximod
* Drug: Cyclophosphamide
* Drug: Etoposide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis: Patients must have prior documented progressive or refractory disease with histologically proven initial diagnosis of ependymoma, medulloblastoma, glioblastoma, or another type of primary cancer of the central nervous system with no curative conventional therapy options available. Metastatic disease is acceptable. Patients must have MRI confirmation (with and without gadolinium contrast) of current active disease. Patients must be able to swallow pills. Lansky or Karnofsky performance status score must be ≥ 50%. Adequate renal function: Creatinine clearance (CLcr) > 25 mL/min (by calculated methods) AND Creatinine ≤ 1.5-times upper limit of age-adjusted normal for age of patient. Adequate liver function: Alanine aminotransferase (ALT) ≤ 3-times upper limit of normal. Aspartate aminotransferase (AST) ≤ 3-times upper limit of normal. Total bilirubin ≤ 1.5-times upper limit of normal unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin. Adequate bone marrow function: Absolute neutrophil count (ANC) ≥ 1000/mm3 (independent of growth factor support). Platelets ≥ 100,000/mm3 (independent of transfusion support). Hemoglobin ≥ 8 g/dL (independent of transfusion support). Seizure disorders must be well controlled on antiepileptic medication. Prior therapy: Patients previously treated with chemotherapy drugs included in this protocol are eligible for enrollment. At the time of Screening, patients must be at least 21 days from the administration of any investigational agent (other than indoximod) or prior cytotoxic therapy (including chemotherapy). At the time of Screening, patients must be at least 28 days from administration of antibody-based therapies (e.g., bevacizumab), tumor-directed vaccines, or cellular immune therapies (e.g., T cells, NK cells, etc.). At the time of Screening, patients must be at least 56 days from administration of tumor-directed therapies using infectious agents (e.g., viruses, bacteria, etc.). At the time of Screening, patients must be at least 90 days from any radiation or proton therapy (all modalities, including radiosurgery) that targeted all sites of known disease. There is no lock-out window for patients who were treated with focal radiation or focal proton therapy (all modalities, including radiosurgery) that did not target all disease sites, if at least one site of active tumor is expected to persist and/or grow. Concurrent anti-neoplastic therapy: No investigational or commercial agents, including intrathecal drugs, other than that described by this clinical study protocol (GCC2020) may be administered with the intent to treat the patient's malignancy while they remain enrolled on this study. Contraception, pregnancy, and breastfeeding: Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study. Men must agree to not donate sperm during and for 3 months after the study. Women who are pregnant or breastfeeding are ineligible for this study. Patients who become pregnant while participating in this study will have to stop Study Therapy. Patients, or their parent for patients less than 18 years of age, must sign an Informed Consent Document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study. . Exclusion Criteria: Patients who are unable to swallow pills. Patients with known hypersensitivity to any drugs in the treatment plan. Patients with active autoimmune disease that requires systemic therapy. Allergies, allergic conditions, and reactive inflammatory conditions that are not autoimmune in nature would not exclude patients (e.g., eczema, asthma, etc.). Pregnant or breastfeeding women. Major surgery or a wound that has not fully healed within 4 weeks of Screening. Known central nervous system lymphoma. Patients with active bleeding or history of thrombotic or hemorrhagic stroke, or intracranial hemorrhage, within 6 months prior to Screening; with the exception of retained blood products from recent prior uncomplicated surgery (e.g., tumor biopsy, debulking, or resection; VP shunt placement, etc.). Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon). Requires chronic treatment with strong CYP3A inhibitor drugs. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification. Patients with baseline QTc interval of more than 470 msec at the time of Screening, and patients with congenital long QT syndrome. Vaccinated with live, attenuated vaccines within 4 weeks of Screening. Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled active systemic infection. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety, interfere with the absorption or metabolism of ibrutinib, indoximod, or chemotherapy, or put the study outcomes at undue risk.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Regimen<br>Patients will be treated with the 4-drug chemo-immunotherapy regimen. Cycles are a minimum of 28 days, and maximum treatment duration is 12 cycles. | Drug: Ibrutinib<br>* Ibrutinib will be taken by mouth once daily, on days 1-21 of each treatment cycle.<br>Drug: Indoximod<br>* Indoximod will be taken by mouth twice daily, throughout each treatment cycle.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be taken by mouth once daily, on days 1-21 of each treatment cycle.<br>Drug: Etoposide<br>* Etoposide will be taken by mouth once daily, on days 1-21 of each treatment cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of regimen-limiting toxicity (RLT) | To determine the pediatric recommended phase 2 dose (RP2D) of ibrutinib, when combined with indoximod-based chemo-immunotherapy (4-drug combination therapy) | First 90 days of treatment | 
| Objective Response Rate (ORR) | Defined as the proportion of patients with a best objective response of either complete response (CR) or partial response (PR) to evaluate preliminary evidence of efficacy of ibrutinib, when combined with indoximod-based chemo-immunotherapy (4-drug combination therapy), using immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events (AEs) | To assess frequency, severity, and recoverability of AEs for the treatment regimen | Up to 19 months | 
| Frequency of cycle delays for toxicity | To assess whether the immunotherapy contributes to delays in starting subsequent cycles of the chemotherapy drugs | Up to 18 months | 
| Frequency of dose-reductions of the chemotherapy regimen | To assess whether the immunotherapy contributes to reductions in the doses of the chemotherapy drugs | Up to 18 months | 
| Complete Response Rate (CRR) | Defined as the proportion of patients with a best objective response of CR using iRANO criteria | Up to 5 years | 
| Partial Response Rate (PRR) | Defined as the proportion of patients with a best objective response of PR using iRANO criteria | Up to 5 years | 
| Modified Objective Response Rate (mORR) | Defined as the proportion of patients with best objective response of complete response (CR), partial response (PR), or stable disease (SD, on at least 2 sequential study-timed MRIs) using iRANO criteria | Up to 5 years | 
| iRANO-PFS | Time of Progression-Free Survival (PFS), defined as time from study entry to progression using iRANO criteria | Up to 5 years | 
| Overall Survival (OS) | Time from study entry to death | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IDO, indoleamine 2,3-dioxygenase, indoximod, BTK, Bruton's Tyrosine Kinase, ibrutinib, immunotherapy, pediatric, childhood, brain tumor, brain cancer, glioblastoma, medulloblastoma, ependymoma, PNET, cyclophosphamide, etoposide, immune, central nervous system, CNS