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

Sponsor

NewLink Genetics Corporation (Industry)

Overall Status

Completed

CT.gov ID

NCT02052648

Collaborator

(none)

160

Enrollment

Locations

Arms

63.6

Duration (Months)

9.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma Multiforme Glioma Gliosarcoma Malignant Brain Tumor	Drug: Indoximod Drug: Temozolomide Drug: Bevacizumab Radiation: Stereotactic Radiation	Phase 1/Phase 2

Detailed Description

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).

Study Design

Study Type:

Interventional

Actual Enrollment :

160 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Mar 1, 2014

Actual Primary Completion Date :

Apr 18, 2018

Actual Study Completion Date :

Jun 20, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1b Cohort 1 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 Other Names: 1-methyl-D-tryptophan D-1MT Drug: Temozolomide Other Names: Temodar Methazolastone
Experimental: Cohort 2a 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 Other Names: 1-methyl-D-tryptophan D-1MT Drug: Temozolomide Other Names: Temodar Methazolastone
Experimental: Cohort 2b 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 Other Names: 1-methyl-D-tryptophan D-1MT Drug: Temozolomide Other Names: Temodar Methazolastone Drug: Bevacizumab Other Names: Avastin
Experimental: Cohort 2c 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 Other Names: 1-methyl-D-tryptophan D-1MT Drug: Temozolomide Other Names: Temodar Methazolastone Radiation: Stereotactic Radiation Other Names: SRS or SRT

Outcome Measures

Primary Outcome Measures

Phase 1: Determine Phase 2 Dosing [3 months]
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.
Phase 2: Efficacy [18 months]
Six-month progression-free survival.

Secondary Outcome Measures

Number of Participants with Adverse Events as a Measure of Safety and Tolerability [1 year]
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.
Overall Dose of Temozolomide Delivered Versus Historical Control [1 year]
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.
Serum concentrations (Cmax/Steady State) of indoximod HLC [1 year]
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.
Overall response rate [18 months]
Assessed for Arms 2a, 2b and 2c
Number of Participants with Adverse Events as a Measure of Safety and Tolerability [18 Months]
Assessed for Arms 2a, 2b and 2c

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Eden Medical Center	Castro Valley	California	United States	94546
2	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
3	UC Irvine Chao Family Comprehensive Cancer Center	Orange	California	United States	92868
4	Moffitt Cancer Center	Tampa	Florida	United States	33612
5	University Cancer and Blood Center	Athens	Georgia	United States	30607
6	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30342
7	Augusta University	Augusta	Georgia	United States	30912
8	University of Chicago	Chicago	Illinois	United States	60637
9	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
10	University of Kentucy	Lexington	Kentucky	United States	40536
11	John Nasseff Neuroscience Institute	Minneapolis	Minnesota	United States	55407
12	University of New Mexico Comprehensive Cancer Center	Albuquerque	New Mexico	United States	87131
13	Wake Forest Baptist Health Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157
14	Penn State Hershey Medical Center	Hershey	Pennsylvania	United States	17033
15	Texas Oncology	Austin	Texas	United States	78705
16	Huntsman Cancer Center	Salt Lake City	Utah	United States	84112
17	Virginia Cancer Specialists	Fairfax	Virginia	United States	22031