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 October 2014 by NewLink Genetics Corporation
Sponsor:
Information provided by (Responsible Party):
NewLink Genetics Corporation
ClinicalTrials.gov Identifier:
NCT02052648
First received: January 29, 2014
Last updated: October 14, 2014
Last verified: October 2014
  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
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group 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 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.



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.



Estimated Enrollment: 18
Study Start Date: March 2014
Estimated Primary Completion Date: March 2015 (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

Indoximod will be administered in escalating doses. Initial dosing will be 600 mg BID by mouth with escalation planned to 1200 mg BID by mouth

Indoximod in the form of 200 mg capsules will be given (3, 5, and 6 capsules depending on the escalated dose). Indoximod should be taken with water by mouth one hour before breakfast and one hour prior to dinner. The medication should be taken twice daily for 28 days each cycle. Patients will continue until they experience disease progression or toxicity.

If temozolomide is discontinued due to toxicity, patients may continue to receive indoximod alone.

Phase 2 Treatment Plan (Cohort 2):

This group of patients will receive fixed doses of indoximod determined in the phase 1 part, based on tolerability.

Other Names:
  • 1-methyl-D-tryptophan
  • D-1MT
Drug: Temozolomide

Phase 1 portion:

Temozolomide to 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.

Other Names:
  • Temodar
  • Methazolastone

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 to 70 Years
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.
  • Patients must have completed a course of radiation therapy and at least 2 adjuvant cycles of temozolomide for the phase 2 component.
  • 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 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 and 70
  • 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.
  • Life expectancy greater than 6 months.

Exclusion Criteria:

  • Prior invasive malignancy that is not the 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.
  • 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, Georgia
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, 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, 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: Karin Choquette    571-389-0873    karin.choquette@usoncology.com   
Principal Investigator: Alexander Spira, MD         
Sponsors and Collaborators
NewLink Genetics Corporation
Investigators
Study Director: Nicholas Vahanian, MD NewLink Genetics Corporation
  More Information

No publications provided

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: October 14, 2014
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
Gliosarcoma
Neoplasms
Astrocytoma
Brain Diseases
Central Nervous System Neoplasms
Glioma
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Nervous System Neoplasms
Neuroectodermal Tumors
Dacarbazine
Temozolomide
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 30, 2014