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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2016 by NewLink Genetics Corporation
Sponsor:
Information provided by (Responsible Party):
NewLink Genetics Corporation
ClinicalTrials.gov Identifier:
NCT02052648
First received: January 29, 2014
Last updated: March 25, 2016
Last verified: March 2016
  Purpose
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 Intervention Phase
Glioblastoma Multiforme
Glioma
Gliosarcoma
Malignant Brain Tumor
Drug: Indoximod
Drug: Temozolomide
Drug: Bevacizumab
Radiation: Stereotactic Radiation
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by NewLink Genetics Corporation:

Primary Outcome Measures:
  • Phase 1: Determine Phase 2 Dosing [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]

    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 [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    Six-month progression-free survival.


Secondary Outcome Measures:
  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

    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 [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    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.

  • Pharmacokinetics [ Time Frame: 1 year ] [ Designated as safety issue: No ]

    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 [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    Assessed for Arms 2a, 2b and 2c

  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 18 Months ] [ Designated as safety issue: Yes ]
    Assessed for Arms 2a, 2b and 2c


Estimated Enrollment: 144
Study Start Date: March 2014
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: SRS or SRT

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 with 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).

  Eligibility

Ages Eligible for Study:   16 Years and older   (Child, Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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. There must be imaging confirmation (with and without gadolinium contrast) of tumor progression or regrowth.
  • 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. It is suggested (but not required) that patients be at least 3 months post radiation to reduce the chances of pseudoprogression.
  • 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
  • Normal organ functions, which includes adequate:

Bone marrow function as defined by the following laboratory values:

  • Absolute Neutrophil Count (ANC) ≥ 1.0 x 10^9/L
  • Platelets ≥ 100 x 10^9/L
  • Hemoglobin ≥ 9.0 g/dL

    • Renal function (creatinine level within normal institutional limit, or creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal).
    • Liver function (AST/ALT ≤2.5 X institutional upper limit of normal, Total bilirubin ≤ 1.5 times ULN, INR within 1.5 times ULN (or if receiving anticoagulant therapy an INR of ≤ 3.0 is allowed with concomitant increase in PT or an aPTT ≤ 2.5 × control).
    • Must be 28 days from the administration of any investigational agent or prior cytotoxic therapy with the following exceptions:

      o 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.).

    • Patients with prior therapy that included interstitial brachytherapy, Gliadel wafer, or stereotactic radiosurgery must have confirmation of progressive disease, rather than radiation necrosis, by PET scanning, Thallium scanning, MRI spectroscopy, or surgical documentation.
    • The effects of indoximod on the developing human fetus are unknown. For this reason and because indoximod may affect maternal immune tolerance of the fetus, sexually active women of child-bearing potential must agree to use two forms of contraception (hormonal and barrier method of birth control or abstinence) prior to study entry and for the duration of study participation. Use of contraception or abstinence should continue for a minimum of 1 month after completion of the study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should discontinue the study drug and inform her treating physician immediately. Also men should be discouraged from fathering children while on treatment.

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.
  • Active systemic infection requiring treatment, including any HIV infection or toxoplasmosis.
  • Systemic corticosteroid therapy > 2 mg of dexamethasone daily (or equivalent) at study enrollment.
  • Baseline QTc interval of >470 at study entry or patients with congenital long QT syndrome.
  • Systemic corticosteroid therapy > 2 mg of dexamethasone daily (or equivalent) at study enrollment
  • Patients with significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol must have a legally authorized representative (LAR) willing to participate and support the patient throughout the trial. Affected patients without a LAR are excluded from participation.
  • Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.
  • Active or history of autoimmune disease
  • Pregnant women are excluded from this study, where pregnancy is confirmed by a positive serum hCG laboratory test (> 5 mIU/mL); breastfeeding should be discontinued.
  • Patients with known autoimmune thyroid disease or positive anti-TPO antibodies (anti-Thyroid Peroxidase) at time of screening.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02052648

Locations
United States, California
Eden Medical Center Recruiting
Castro Valley, California, United States, 94546
Contact: Catherine Ndungu-Case    510-727-8267      
Principal Investigator: Tyler Kang, MD         
Cedars-Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
Contact: Cherry Sanchez, RN    310-423-6839      
Principal Investigator: Surasak Phuphanich, MD         
United States, Florida
Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
Contact: Stephan Bart    813-745-1689    Stephan.Bart@Moffitt.org   
Principal Investigator: Solmaz Sahebjam, MD         
United States, Georgia
University Cancer and Blood Center Recruiting
Athens, Georgia, United States, 30607
Contact: Jamie Hodgson, CCRC    706-353-2990 ext 279      
Principal Investigator: Petros Nikolinakos, MD         
Children's Healthcare of Atlanta Recruiting
Atlanta, Georgia, United States, 30342
Contact: Patty Church, RN    404-785-0232      
Principal Investigator: Tobey MacDonald, MD         
Georgia Regents University Recruiting
Augusta, Georgia, United States, 30912
Contact: Christine Sanchez, RN    706-721-0660    csanchez@gru.edu   
Principal Investigator: Samir Khleif, MD         
United States, Illinois
University of Chicago Recruiting
Chicago, Illinois, United States, 60637
Contact: Jennifer Nam    773-702-7716    jnam@medicine.bsd.uchicago.edu   
Principal Investigator: Lukas Rimas, MD         
United States, Iowa
University of Iowa Hospitals and Clinics Recruiting
Iowa City, Iowa, United States, 52242
Contact: Melanie Frees, RN, BSN, CCRC    319-356-1228    melanie-frees@uiowa.edu   
Principal Investigator: Mohammed Milhem, MD         
United States, Kentucky
University of Kentucy Recruiting
Lexington, Kentucky, United States, 40536
Contact: April Howard    859-257-2208      
Principal Investigator: John Villano, MD         
United States, Minnesota
John Nasseff Neuroscience Institute Recruiting
Minneapolis, Minnesota, United States, 55407
Contact: Amy Schrecengost, BS, CCRC    612-863-6562    Amy.Schrecengost@Allina.com   
Principal Investigator: John Trusheim, MD         
United States, North Carolina
Wake Forest Baptist Health Comprehensive Cancer Center Recruiting
Winston-Salem, North Carolina, United States, 27157
Contact: Joyce Festernmaker    336-713-3155      
Principal Investigator: Glenn Lesser, MD         
United States, Pennsylvania
Penn State Hershey Medical Center Recruiting
Hershey, Pennsylvania, United States, 17033
Contact: Cynthia Campbell-Baird, RN    717-531-5777    cbaird@hmc.psu.edu   
Principal Investigator: Michael Glantz, MD         
United States, Texas
Texas Oncology Recruiting
Austin, Texas, United States, 78705
Contact: Kristen Brueggemann, RN    512-421-4108      
Principal Investigator: Charles Conrad, MD         
United States, Utah
Huntsman Cancer Center Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Karthik Sonty    801-587-5562    karthik.sonty@hci.utah.edu   
Principal Investigator: Howard Colman, MD         
United States, Virginia
Virginia Cancer Specialists Recruiting
Fairfax, Virginia, United States, 22031
Contact: Noel Swafford    703-208-3192    noel.swafford@USOncology.com   
Principal Investigator: Alexander Spira, MD         
Sponsors and Collaborators
NewLink Genetics Corporation
Investigators
Study Director: Nicholas Vahanian, MD NewLink Genetics Corporation
  More Information

Additional Information:
Responsible Party: NewLink Genetics Corporation
ClinicalTrials.gov Identifier: NCT02052648     History of Changes
Other Study ID Numbers: NLG2102 
Study First Received: January 29, 2014
Last Updated: March 25, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by NewLink Genetics Corporation:
glioblastoma multiforme
glioma
gliosarcoma
malignant brain tumor

Additional relevant MeSH terms:
Brain Neoplasms
Central Nervous System Diseases
Nervous System Diseases
Glioblastoma
Glioma
Gliosarcoma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Bevacizumab
Temozolomide
Dacarbazine
Tryptophan
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents

ClinicalTrials.gov processed this record on August 25, 2016