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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 November 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: November 2, 2016
Last verified: November 2016
January 29, 2014
November 2, 2016
March 2014
December 2016   (Final data collection date for primary outcome measure)
  • Phase 1: Determine Phase 2 Dosing [ Time Frame: 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 [ Time Frame: 18 months ]
    Six-month progression-free survival.
Phase 2 Dosing [ Time Frame: 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.

Complete list of historical versions of study NCT02052648 on ClinicalTrials.gov Archive Site
  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 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 [ Time Frame: 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.
  • Pharmacokinetics [ Time Frame: 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 [ Time Frame: 18 months ]
    Assessed for Arms 2a, 2b and 2c
  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 18 Months ]
    Assessed for Arms 2a, 2b and 2c
  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 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 temozolimide.

  • Overall Dose of Temozolomide Delivered Versus Historical Control [ Time Frame: 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.
  • Pharmacokinetics [ Time Frame: 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.

Not Provided
Not Provided
 
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.

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).

Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Glioblastoma Multiforme
  • Glioma
  • Gliosarcoma
  • Malignant Brain Tumor
  • Drug: Indoximod
    Other Names:
    • 1-methyl-D-tryptophan
    • D-1MT
  • Drug: Temozolomide
    Other Names:
    • Temodar
    • Methazolastone
  • Drug: Bevacizumab
    Other Name: Avastin
  • Radiation: Stereotactic Radiation
    Other Name: SRS or SRT
  • 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.

    Interventions:
    • Drug: Indoximod
    • Drug: Temozolomide
  • 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.
    Interventions:
    • Drug: Indoximod
    • Drug: Temozolomide
  • 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.

    Interventions:
    • Drug: Indoximod
    • Drug: Temozolomide
    • Drug: Bevacizumab
  • 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.
    Interventions:
    • Drug: Indoximod
    • Drug: Temozolomide
    • Radiation: Stereotactic Radiation
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
144
Not Provided
December 2016   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
16 Years and older   (Child, Adult, Senior)
No
United States
 
 
NCT02052648
NLG2102
Yes
Not Provided
Not Provided
Not Provided
NewLink Genetics Corporation
NewLink Genetics Corporation
Not Provided
Study Director: Nicholas Vahanian, MD NewLink Genetics Corporation
NewLink Genetics Corporation
November 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP