Study of IDO Inhibitor and Temozolomide for Adult Patients With Primary Malignant Brain Tumors

Study Overview
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Brief Summary
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In this study, investigators will conduct a phase I/II trial in recurrent (temozolomide resistant) glioma patients. The overall goal of this study is to provide a foundation for future studies with indoximod tested in newly diagnosed glioblastoma patients with radiation and temozolomide, or in combination with vaccine therapies.

Detailed Description
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The aim of this study is to identify the safety profile and the recommended dose for phase 2 study of the combination of indoximod (portion 1, phase 1b study). Investigators will then evaluate the tolerability and the preliminary activity in patients with recurrent GBM in three different situations: Combination of indoximod and temozolomide (bevacizumab-naive patients) Combination of indoximod and temozolomide in patients currently receiving or having received and failed bevacizumab. Combination of indoximod and temozolomide with stereotactic radiation. Ancillary studies will be conducted to assess the correlation between intra-tumoral IDO expression or serum biomarkers (immune monitoring) and treatment efficacy. If the current study shows an acceptable safety profile and suggests preliminary evidence of activity, this will provide the justification for subsequent randomized phase 2 studies in refractory glioblastoma multiforme (GBM).

Official Title
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A Phase I/II Study of the Combination of Indoximod and Temozolomide for Adult Patients With Temozolomide-Refractory Primary Malignant Brain Tumors

Conditions
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Glioblastoma Multiforme, Glioma, Gliosarcoma, Malignant Brain Tumor

Intervention / Treatment
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* Drug: Indoximod
* Drug: Temozolomide
* Drug: Bevacizumab
* Radiation: Stereotactic Radiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven intracranial glioblastoma multiforme (WHO grade IV glioma) or gliosarcoma. In addition, the Phase 1b cohort will include patients with progressive WHO grade III glioma. Patients will be eligible if the original histology was lower grade glioma and a subsequent diagnosis of glioblastoma or gliosarcoma is made. Unequivocal radiographic evidence for tumor progression by MRI. It is understood that some patients may be resected prior to enrolling onto protocol Patients must have completed a course of radiation therapy and at least 2 adjuvant cycles of temozolomide for the phase 2 component. Patients enrolling onto Cohort 2b who have been taken off bevacizumab must have had at least a 28 day washout from any previous administration of bevacizumab. It is preferred that patients who fail bevacizumab prior to trial entry remain on bevacizumab in the trial. Prior temozolomide is not required for the phase 1 component; prior radiation is required for the phase 1 arm. Patients must be on a steroid dose less than or equal to 2 mg of dexamethasone daily (or equivalent), and this dose must not have increased for at least 14 days prior to obtaining the enrollment. ECOG performance status ≤1 or Karnofsky ≥70%. Age between 16 Must be 28 days from the administration of any investigational agent or prior cytotoxic therapy with the following exceptions: Must be 14 days from administration of non-cytotoxic agents (e.g., bevacizumab (except COHORT 2b), interferon, tamoxifen, thalidomide, cis-retinoic acid, tyrosine kinase inhibitor, etc.). Exclusion Criteria: Prior invasive malignancy that is not low-grade glioma, high-grade glioma, glioblastoma, or gliosarcoma (except non-melanomatous skin cancer or carcinoma in situ of the cervix) unless the patient has been disease free and off therapy for that disease for a minimum of 3 years. Patients on the phase 2 portion of the study may not have more than 2 prior regimens for recurrent disease for glioblastoma/gliosarcoma. Patients on the phase 1 portion of the study may not have had more than 3 prior regimens. Systemic corticosteroid therapy > 2 mg of dexamethasone daily (or equivalent) at study enrollment. Active or history of autoimmune disease

Ages Eligible for Study
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Minimum Age: 16 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b Cohort 1<br>Phase 1B patients will receive Indoximod given in escalating doses. Initial dosing will be 600 mg BID by mouth with escalation planned to 1200 mg BID by mouth. The medication should be taken twice daily for 28 days each cycle. Temozolomide will also be given by mouth at 150 mg/m^2 x 5 days at all dosing levels of indoximod. Each cycle is 28 days. Patients will continue until they experience disease progression or toxicity. | Drug: Indoximod<br> <br> * Other names: D-1MT;Drug: Temozolomide<br> <br> * Other names: Methazolastone;|
| Experimental: Cohort 2a<br>Bevacizumab naïve phase II patients who will receive indoximod with temozolomide. Indoximod will be dosed at 1200mg BID. Temozolomide will be dosed at 150 mg/m2 and may be escalated up to 200 mg/m2. | Drug: Indoximod<br> <br> * Other names: D-1MT;Drug: Temozolomide<br> <br> * Other names: Methazolastone;|
| Experimental: Cohort 2b<br>Phase II patients who will receive indoximod with temozolomide and bevacizumab who have previously been treated with bevacizumab. Indoximod will be dosed at 1200mg BID. Temozolomide will be dosed at 150 mg/m2 and may be escalated up to 200 mg/m2. Bevacizumab will be dosed at 10mg/kg. | Drug: Indoximod<br> <br> * Other names: D-1MT;Drug: Temozolomide<br> <br> * Other names: Methazolastone;Drug: Bevacizumab<br> <br> * Other names: Avastin;|
| Experimental: Cohort 2c<br>Phase II patients who will receive indoximod with temozolomide and stereotactic radiosurgery. Indoximod will be dosed at 1200mg BID. Temozolomide will be dosed at 150 mg/m2 and may be escalated up to 200 mg/m2. Single fraction SRS dose will be 16 or 20 Gy depending on target volume. The total 5-fraction SRT dose will be 27.5 Gy. | Drug: Indoximod<br> <br> * Other names: D-1MT;Drug: Temozolomide<br> <br> * Other names: Methazolastone;Radiation: Stereotactic Radiation<br> <br> * Other names: SRS or SRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Determine Phase 2 Dosing | Phase 1b component: Primary objective is to determine the recommended Phase 2 dose of indoximod and temozolomide in combination for treatment of progressive high-grade glioma (including glioblastoma multiforme) or gliosarcoma. | 3 months | 
| Phase 2: Efficacy | Six-month progression-free survival. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability | Phase 1b component: To determine the adverse event profile (event type, incidence severity, duration causality and treatment intervention) and identify regimen-limiting toxicities (RLT) of indoximod plus temozolomide in combination therapy. Specifically, investigators define regimen-limiting toxicity (RLT) as a toxicity that delays the planned administration of the next cycle of the backbone chemotherapy. The goal of the trial will be to find the maximum dose of indoximod that does not induce RLT in more than 1/6 of patients treated with temozolomide. | 1 year | 
| Overall Dose of Temozolomide Delivered Versus Historical Control | To test the hypothesis that the addition of indoximod will not reduce the overall dose of temozolomide delivered or delay the timing of administration, compared to historical controls using T-test. | 1 year | 
| Serum concentrations (Cmax/Steady State) of indoximod HLC | Phase 1b component: To determine the pharmacokinetic profile of indoximod in the setting of this treatment regimen. A thorough pharmacokinetic (PK) profile will be performed for each patient entered into the study through analysis of blood samples collected at protocol-defined time points. | 1 year | 
| Overall response rate | Assessed for Arms 2a, 2b and 2c | 18 months | 
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability | Assessed for Arms 2a, 2b and 2c | 18 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glioblastoma multiforme, glioma, gliosarcoma, malignant brain tumor