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

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

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.

Study Overview

• Status: Completed
• Conditions: Glioma; Glioblastoma Multiforme; Gliosarcoma; Malignant Brain Tumor
• Intervention / Treatment: Drug: Temozolomide; Drug: Bevacizumab; Drug: Indoximod; Radiation: Stereotactic Radiation

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 Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Castro Valley, California, United States, 94546
      • Eden Medical Center
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Orange, California, United States, 92868
      • UC Irvine Chao Family Comprehensive Cancer Center
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Georgia
    • Athens, Georgia, United States, 30607
      • University Cancer and Blood Center
    • Atlanta, Georgia, United States, 30342
      • Children's Healthcare of Atlanta
    • Augusta, Georgia, United States, 30912
      • Augusta University
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University Of Kentucy
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • John Nasseff Neuroscience Institute
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico Comprehensive Cancer Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health Comprehensive Cancer Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
  • Texas
    • Austin, Texas, United States, 78705
      • Texas Oncology
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / 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: Temozolomide; Other Names: Temodar; Methazolastone; Drug: Indoximod; Other Names: 1-methyl-D-tryptophan; D-1MT
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: Temozolomide; Other Names: Temodar; Methazolastone; Drug: Indoximod; Other Names: 1-methyl-D-tryptophan; D-1MT
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: Temozolomide; Other Names: Temodar; Methazolastone; Drug: Bevacizumab; Other Names: Avastin; Drug: Indoximod; Other Names: 1-methyl-D-tryptophan; D-1MT
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: Temozolomide; Other Names: Temodar; Methazolastone; Drug: Indoximod; Other Names: 1-methyl-D-tryptophan; D-1MT; Radiation: Stereotactic Radiation; Other Names: SRS or SRT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Regimen-Limiting Toxicities (RLTs) in Phase 1 Subjects	Number of RLTs observed in each dose level.	3 months
Phase 2: Number of Phase 1 Participants With Efficacy Outcomes	Six-month progression-free survival.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate for Phase 2 Participants	Subjects with a complete response or partial response by RANO assessment. Overall Response Rate was only assessed in phase 2 subjects on this trial.	18 months
Number of Participants With Adverse Events as a Measure of Safety and Tolerability	Number of subjects with at least 1 treatment emergent adverse event.	18 Months

Collaborators and Investigators

• Sponsor: NewLink Genetics Corporation

Publications and helpful links

Helpful Links

• Sponsor website

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): April 18, 2018
• Study Completion (Actual): June 20, 2019

Study Registration Dates

• First Submitted: January 29, 2014
• First Submitted That Met QC Criteria: January 30, 2014
• First Posted (Estimated): February 3, 2014

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: February 28, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: glioma; glioblastoma multiforme; gliosarcoma; malignant brain tumor
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Glioblastoma; Brain Neoplasms; Gliosarcoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Psychotropic Drugs; Antidepressive Agents; Antidepressive Agents, Second-Generation; Temozolomide; Bevacizumab; Tryptophan
• Other Study ID Numbers: NLG2102