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

Glioblastoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05106296
• Other study ID #: GCC2020
• Status: Recruiting
• Phase: Phase 1
• Start date: February 8, 2022
• Est. completion date: September 2026

Study information

• Verified date: December 2023
• Source: Augusta University
• Contact: Theodore S. Johnson, MD, PhD
• Phone: 706-721-4962
• Email: thjohnson[@]augusta.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 37
• Est. completion date: September 2026
• Est. primary completion date: August 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 25 Years

Eligibility

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.

Related Conditions & MeSH terms

• Brain Neoplasms
• Ependymoma
• Glioblastoma
• Medulloblastoma
• Primary Brain Tumor

Intervention

Drug:
• Ibrutinib
Ibrutinib will be taken by mouth once daily, on days 1-21 of each treatment cycle.
• Indoximod
Indoximod will be taken by mouth twice daily, throughout each treatment cycle.
• Cyclophosphamide
Cyclophosphamide will be taken by mouth once daily, on days 1-21 of each treatment cycle.
• Etoposide
Etoposide will be taken by mouth once daily, on days 1-21 of each treatment cycle.

Locations

Country	Name	City	State
United States	Augusta University, Georgia Cancer Center	Augusta	Georgia

Sponsors (2)

Lead Sponsor	Collaborator
Theodore S. Johnson	Augusta University

Country where clinical trial is conducted

United States, 

References & Publications (2)

Johnson TS, MacDonald TJ, Pacholczyk R, Aguilera D, Al-Basheer A, Bajaj M, Bandopadhayay P, Berrong Z, Bouffet E, Castellino RC, Dorris K, Eaton BR, Esiashvili N, Fangusaro JR, Foreman N, Fridlyand D, Giller C, Heger IM, Huang C, Kadom N, Kennedy EP, Manoharan N, Martin W, McDonough C, Parker RS, Ramaswamy V, Ring E, Rojiani A, Sadek RF, Satpathy S, Schniederjan M, Smith A, Smith C, Thomas BE, Vaizer R, Yeo KK, Bhasin MK, Munn DH. Indoximod-based chemo-immunotherapy for pediatric brain tumors: a first-in-children phase 1 trial. Neuro Oncol. 2023 Sep 16:noad174. doi: 10.1093/neuonc/noad174. Online ahead of print. — View Citation

Sharma MD, Pacholczyk R, Shi H, Berrong ZJ, Zakharia Y, Greco A, Chang CS, Eathiraj S, Kennedy E, Cash T, Bollag RJ, Kolhe R, Sadek R, McGaha TL, Rodriguez P, Mandula J, Blazar BR, Johnson TS, Munn DH. Inhibition of the BTK-IDO-mTOR axis promotes differentiation of monocyte-lineage dendritic cells and enhances anti-tumor T cell immunity. Immunity. 2021 Oct 12;54(10):2354-2371.e8. doi: 10.1016/j.immuni.2021.09.005. Epub 2021 Oct 5. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Adverse events (AEs)	To assess frequency, severity, and recoverability of AEs for the treatment regimen	Up to 19 months
Secondary	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
Secondary	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
Secondary	Complete Response Rate (CRR)	Defined as the proportion of patients with a best objective response of CR using iRANO criteria	Up to 5 years
Secondary	Partial Response Rate (PRR)	Defined as the proportion of patients with a best objective response of PR using iRANO criteria	Up to 5 years
Secondary	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
Secondary	iRANO-PFS	Time of Progression-Free Survival (PFS), defined as time from study entry to progression using iRANO criteria	Up to 5 years
Secondary	Overall Survival (OS)	Time from study entry to death	Up to 5 years