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

NCT05106296 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: GCC2020
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

Brief 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. The GCC2020 trial is a prospective open-label phase 1 trial to determine the best safe dose of the BTK-inhibitor ibrutinib to use in combination with previously studied chemo-immunotherapy regimens comprised of the investigational IDO-inhibitor indoximod plus oral palliative chemotherapy for participants, age 6 to 25 years, with relapsed or refractory primary brain cancer. Those previously treated with indoximod-based therapy 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. Ibrutinib will be combined with either indoximod plus oral cyclophosphamide and etoposide (Regimen A) or indoximod plus oral temozolomide (Regimen B). No cross-over between these two regimens will be allowed. Dose-escalation cohorts will determine the best safe dose of ibrutinib for each of these regimens. This will be followed by expansion cohorts, using ibrutinib at the best safe dose for each regimen, to allow assessment of preliminary evidence of efficacy.

Conditions

Ependymoma; Medulloblastoma; Glioblastoma; Primary Brain Tumor

Keywords

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; temozolomide

Outcome Measures

Primary Outcomes (4)

• Incidence of regimen-limiting toxicity (RLT) for Regimen A

  To determine the pediatric recommended phase 2 dose (RP2D) of ibrutinib, when combined with indoximod-based chemo-immunotherapy (Regimen A)

  First 90 days of treatment

• Objective Response Rate (ORR) for Regimen A

  Defined as the proportion of patients with a best objective response of either complete response (CR) or partial response (PR), using "immunotherapy Response Assessment for Neuro-Oncology" (iRANO) criteria

  Up to 5 years

• Incidence of regimen-limiting toxicity (RLT) for Regimen B

  To determine the pediatric recommended phase 2 dose (RP2D) of ibrutinib, when combined with indoximod-based chemo-immunotherapy (Regimen B)

  First 90 days of treatment

• Objective Response Rate (ORR) for Regimen B

  Defined as the proportion of patients with a best objective response of either complete response (CR) or partial response (PR), using "immunotherapy Response Assessment for Neuro-Oncology" (iRANO) criteria

  Up to 5 years

Secondary Outcomes (8)

• Adverse events (AEs)

  Up to 19 months

• Frequency of cycle delays for toxicity

  Up to 18 months

• Frequency of dose-reductions of the chemotherapy regimen

  Up to 18 months

• Complete Response Rate (CRR)

  Up to 5 years

• Partial Response Rate (PRR)

  Up to 5 years

Study Arms (2)

Regimen A

EXPERIMENTAL

Patients will be treated with ibrutinib plus indoximod, cyclophosphamide, and etoposide. Cycles are a minimum of 28 days.

Drug: Indoximod; Drug: Ibrutinib; Drug: Cyclophosphamide; Drug: Etoposide

Regimen B

EXPERIMENTAL

Patients will be treated with ibrutinib plus indoximod and temozolomide. Cycles are a minimum of 28 days.

Drug: Indoximod; Drug: Ibrutinib; Drug: Temozolomide

Interventions

Indoximod DRUG

Indoximod will be taken by mouth twice daily, throughout each treatment cycle.

Regimen A; Regimen B

Cyclophosphamide DRUG

Cyclophosphamide will be taken by mouth once daily, on days 1-21 of each treatment cycle.

Regimen A

Etoposide DRUG

Etoposide will be taken by mouth once daily, on days 1-21 of each treatment cycle.

Regimen A

Ibrutinib DRUG

For Regimen A, Ibrutinib will be taken by mouth once daily, on days 1-21 of each treatment cycle.

Regimen A

Temozolomide DRUG

Temozolomide will be taken by mouth once daily, on days 1-5 of each treatment cycle.

Regimen B

Eligibility Criteria

• Age: 3 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Theodore S. Johnson: lead
• Augusta University: collaborator
• CureSearch for Children's Cancer: collaborator
• Rally Foundation for Childhood Cancer Research: collaborator

Study Sites (1)

Augusta University, Georgia Cancer Center

Augusta, Georgia, 30912, United States

RECRUITING

Related 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 I trial. Neuro Oncol. 2024 Feb 2;26(2):348-361. doi: 10.1093/neuonc/noad174.

  PMID: 37715730 BACKGROUND

• 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.

  PMID: 34614413 BACKGROUND

MeSH Terms

Conditions

Ependymoma; Medulloblastoma; Glioblastoma; Brain Neoplasms; Neuroectodermal Tumors, Primitive

Interventions

1-methyltryptophan; ibrutinib; Cyclophosphamide; Etoposide; Temozolomide

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Astrocytoma; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Dacarbazine; Triazenes; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Theodore S. Johnson, MD, PhD

  Augusta University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Theodore S. Johnson, MD, PhD

CONTACT

706-721-4962; thjohnson@augusta.edu

Robin Dobbins, RN

CONTACT

706-721-2154; rdobbins@augusta.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Pediatrics and Co-Director of the Pediatric Immunotherapy Program

Study Record Dates

• First Submitted: October 22, 2021
• First Posted: November 3, 2021
• Study Start: February 8, 2022
• Primary Completion (Estimated): March 30, 2028
• Study Completion (Estimated): September 30, 2028
• Last Updated: January 9, 2026

Record last verified: 2026-01

Locations

US (1)