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

Phase 1

Completed

• Conditions: Glioma; Gliosarcoma; Glioblastoma Multiforme; Malignant Brain Tumor
• Interventions: Drug: Indoximod; Drug: Temozolomide; Drug: Bevacizumab; Radiation: Stereotactic Radiation

• Registration Number: NCT02052648
• Lead Sponsor: NewLink Genetics Corporation

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.

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 Timeline

• Study First Submitted: 2014-01-29
• Study First Submitted QC: 2014-01-30
• Study First Posted: 2014-02-03
• Study Start: 2014-03
• Primary Completion: 2018-04-18
• Disposition First Submitted: 2018-07-02
• Disposition First Submitted QC: 2018-07-02
• Disposition First Posted: 2018-07-05
• Study Completion: 2019-06-20
• Results First Submitted: 2023-10-16
• Status Verified: 2024-02
• Results First Submitted QC: 2024-02-28
• Last Update Submitted: 2024-02-28
• Results First Posted: 2024-03-27
• Last Update Posted: 2024-03-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 160

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.).

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 2b	Indoximod	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.
Cohort 2c	Indoximod	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.
Cohort 2b	Bevacizumab	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.
Cohort 2c	Stereotactic Radiation	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.
Phase 1b Cohort 1	Indoximod	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.
Phase 1b Cohort 1	Temozolomide	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.
Cohort 2a	Indoximod	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.
Cohort 2a	Temozolomide	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.
Cohort 2b	Temozolomide	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.
Cohort 2c	Temozolomide	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.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (17)

Augusta University; 🇺🇸 Augusta, Georgia, United States

University Cancer and Blood Center; 🇺🇸 Athens, Georgia, United States

UC Irvine Chao Family Comprehensive Cancer Center; 🇺🇸 Orange, California, United States

University of Chicago; 🇺🇸 Chicago, Illinois, United States

John Nasseff Neuroscience Institute; 🇺🇸 Minneapolis, Minnesota, United States

Cedars-Sinai Medical Center; 🇺🇸 Los Angeles, California, United States

Eden Medical Center; 🇺🇸 Castro Valley, California, United States

University of Kentucy; 🇺🇸 Lexington, Kentucky, United States

University of Iowa Hospitals and Clinics; 🇺🇸 Iowa City, Iowa, United States

University of New Mexico Comprehensive Cancer Center; 🇺🇸 Albuquerque, New Mexico, United States

Virginia Cancer Specialists; 🇺🇸 Fairfax, Virginia, United States

Texas Oncology; 🇺🇸 Austin, Texas, United States

Huntsman Cancer Center; 🇺🇸 Salt Lake City, Utah, United States

Children's Healthcare of Atlanta; 🇺🇸 Atlanta, Georgia, United States

Penn State Hershey Medical Center; 🇺🇸 Hershey, Pennsylvania, United States

Moffitt Cancer Center; 🇺🇸 Tampa, Florida, United States

Wake Forest Baptist Health Comprehensive Cancer Center; 🇺🇸 Winston-Salem, North Carolina, United States