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

Primary Purpose

Ependymoma, Medulloblastoma, Glioblastoma

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Ibrutinib
Indoximod
Cyclophosphamide
Etoposide
Sponsored by
Theodore S. Johnson
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ependymoma focused on measuring 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

Eligibility Criteria

12 Years - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Augusta University, Georgia Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment Regimen

Arm Description

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.

Outcomes

Primary Outcome Measures

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)
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

Secondary Outcome Measures

Adverse events (AEs)
To assess frequency, severity, and recoverability of AEs for the treatment regimen
Frequency of cycle delays for toxicity
To assess whether the immunotherapy contributes to delays in starting subsequent cycles of the chemotherapy drugs
Frequency of dose-reductions of the chemotherapy regimen
To assess whether the immunotherapy contributes to reductions in the doses of the chemotherapy drugs
Complete Response Rate (CRR)
Defined as the proportion of patients with a best objective response of CR using iRANO criteria
Partial Response Rate (PRR)
Defined as the proportion of patients with a best objective response of PR using iRANO criteria
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
iRANO-PFS
Time of Progression-Free Survival (PFS), defined as time from study entry to progression using iRANO criteria
Overall Survival (OS)
Time from study entry to death

Full Information

First Posted
October 22, 2021
Last Updated
October 4, 2023
Sponsor
Theodore S. Johnson
Collaborators
Augusta University
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1. Study Identification

Unique Protocol Identification Number
NCT05106296
Brief Title
Chemo-immunotherapy Using Ibrutinib Plus Indoximod for Patients With Pediatric Brain Cancer
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 8, 2022 (Actual)
Primary Completion Date
August 2026 (Anticipated)
Study Completion Date
September 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Theodore S. Johnson
Collaborators
Augusta University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
37 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment Regimen
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Ibrutinib
Intervention Description
Ibrutinib will be taken by mouth once daily, on days 1-21 of each treatment cycle.
Intervention Type
Drug
Intervention Name(s)
Indoximod
Intervention Description
Indoximod will be taken by mouth twice daily, throughout each treatment cycle.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
Cyclophosphamide will be taken by mouth once daily, on days 1-21 of each treatment cycle.
Intervention Type
Drug
Intervention Name(s)
Etoposide
Intervention Description
Etoposide will be taken by mouth once daily, on days 1-21 of each treatment cycle.
Primary Outcome Measure Information:
Title
Incidence of regimen-limiting toxicity (RLT)
Description
To determine the pediatric recommended phase 2 dose (RP2D) of ibrutinib, when combined with indoximod-based chemo-immunotherapy (4-drug combination therapy)
Time Frame
First 90 days of treatment
Title
Objective Response Rate (ORR)
Description
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
Time Frame
Up to 5 years
Secondary Outcome Measure Information:
Title
Adverse events (AEs)
Description
To assess frequency, severity, and recoverability of AEs for the treatment regimen
Time Frame
Up to 19 months
Title
Frequency of cycle delays for toxicity
Description
To assess whether the immunotherapy contributes to delays in starting subsequent cycles of the chemotherapy drugs
Time Frame
Up to 18 months
Title
Frequency of dose-reductions of the chemotherapy regimen
Description
To assess whether the immunotherapy contributes to reductions in the doses of the chemotherapy drugs
Time Frame
Up to 18 months
Title
Complete Response Rate (CRR)
Description
Defined as the proportion of patients with a best objective response of CR using iRANO criteria
Time Frame
Up to 5 years
Title
Partial Response Rate (PRR)
Description
Defined as the proportion of patients with a best objective response of PR using iRANO criteria
Time Frame
Up to 5 years
Title
Modified Objective Response Rate (mORR)
Description
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
Time Frame
Up to 5 years
Title
iRANO-PFS
Description
Time of Progression-Free Survival (PFS), defined as time from study entry to progression using iRANO criteria
Time Frame
Up to 5 years
Title
Overall Survival (OS)
Description
Time from study entry to death
Time Frame
Up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Theodore S. Johnson, MD, PhD
Phone
706-721-4962
Email
thjohnson@augusta.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Taylor King, RN
Phone
706-721-2949
Email
TAYKING@AUGUSTA.EDU
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Theodore S. Johnson, MD, PhD
Organizational Affiliation
Augusta University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Augusta University, Georgia Cancer Center
City
Augusta
State/Province
Georgia
ZIP/Postal Code
30912
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Theodore S Johnson, MD, PhD
Phone
706-721-4962
Email
thjohnson@augusta.edu
First Name & Middle Initial & Last Name & Degree
Taylor King, RN
Phone
706-721-2949
Email
TAYKING@AUGUSTA.EDU
First Name & Middle Initial & Last Name & Degree
Theodore S Johnson, MD, PhD

12. IPD Sharing Statement

Citations:
PubMed Identifier
37715730
Citation
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.
Results Reference
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PubMed Identifier
34614413
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.
Results Reference
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Chemo-immunotherapy Using Ibrutinib Plus Indoximod for Patients With Pediatric Brain Cancer

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