Details

Details

Title Phase II Study of TRC102 in Combination with Temozolomide for Recurrent Glioblastoma

IRB ABTC1402

CC 15-1529

Hospital Main Campus

Stage Recurrent/Relapsed

Phase Phase 2

Disease Brain, Glioblastoma

Drug Temozolomide, TRC102

Description

Description

Primary Objectives
  • Arm 1
    • To estimate the efficacy of TRC102 and temozolomide, as measured by response rate, in bevacizumab naive glioblastoma
  • Arm 2 (opens only if Arm 1 meets efficacy criteria)
    • To estimate the efficacy of TRC102 and temozolomide, as measured by response rate, in bevacizumab refractory Glioblastoma
Secondary Objectives
  • Evaluate the toxicities of oral TRC102 and temozolomide in this patient population
  • Estimate the efficacy of TRC102 and temozolomide, as measured by progression-free survival, progression-free survival at 6 months and overall survival, in bevacizumab naive Glioblastoma
  • Estimate the efficacy of TRC102 and temozolomide, as measured by progression-free survival in bevacizumab refractory Glioblastoma
Exploratory Objective
  • Assess the tissue correlates of methylpurine DNA-glycosylase (MPG) and topoisomerase IIα (Topo IIα), and O6-methylguanine DNA methyltransferase (MGMT) status, with response, PFS, and overall survival
Inclusion Criteria

Inclusion Criteria

  1. Patients must have histologically confirmed glioblastoma that is progressive or recurrent following radiation therapy and temozolomide.
  2. Tumor MGMT methylation status must be available. Results of routinely used methods for MGMT methylation testing (e.g. MSPCR or quantitative PCR) are acceptable.
  3. Arm 1 patients must have measurable (defined by at least 1 cm x 1 cm) contrast-enhancing disease by MRI imaging within 21 days of starting treatment.
  4. Patients must be able to undergo MRI of the brain with gadolinium. Patients must be maintained on a stable or decreasing dose of corticosteroid regimen (no increase for 5 days) prior to this baseline MRI.
  5. Arm 1 patients must be in first recurrence of glioblastoma following radiation therapy and temozolomide.Arm 2 patients may have an unlimited number of prior therapy regimens but may not have received prior antiangiogenesis therapy except for bevacizumab (patients may not have received aflibercept, ramucirumab, cediranib, cabozantinib, or XL184).
  6. Arm 1 patients must have not received bevacizumab previously.Arm 2 patients must have progressed/recurred on bevacizumab as the most recent regimen. Patients on Arm 2 should continue on bevacizumab as clinically necessary to control brain edema.
  7. Patients must have a tumor tissue form indicating availability of archived tissue from initial resection at diagnosis of glioblastoma completed and signed by a pathologist. See Section 9.5.1. Availability of tissue is not a requirement for study participation.
  8. Patients must have recovered from severe toxicity of prior therapy. The following intervals from previous treatments are required to be eligible:
    • 12 weeks from the completion of radiation
    • 6 weeks from a nitrosourea chemotherapy
    • 3 weeks from a non-nitrosourea chemotherapy
    • 4 weeks from any investigational (not FDA-approved) agents
    • 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., erlotinib, hydroxychloroquine, etc.)
  9. Patients must be 18 years of age or older.
  10. Patients must have a Karnofsky Performance Status ≥ 60% (i.e. the patient must be able to care for himself/herself with occasional help from others).
  11. Patients must have the following organ and marrow function:
    • Absolute neutrophil count >1,500/mcL
    • Platelets >100,000/mcL
    • Hemoglobin > 9 g/dL
    • Total bilirubin ≤ institutional upper limit of normal
    • AST (SGOT)/ALT (SGPT) ≤ 4 x institutional upper limit of normal
    • Creatinine ≤ institutional upper limit of normal OR
    • Creatinine clearance >60 ml/min/1.73m2 for patients with creatinine levels above institutional normal
    • APTT or PTT ≤ 1.5 x institutional upper limit of normal
  12. Patients must be able to provide written informed consent.
  13. Women of childbearing potential must have a negative serum pregnancy test prior to study start. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and through 30 days after the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and through 30 days after the last dose of study drug.
  14. Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder. Patients with prior malignancies must be disease-free for ≥ five years.
  15. Patients must be able to swallow capsules.
Exclusion Criteria

Exclusion Criteria

  1. Patients receiving any other investigational agents are ineligible.
  2. Patient must not have known sensitivity to TRC102 or any formulation excipients.
  3. Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for treatment on this protocol. Patients may be on non-enzyme inducing anti-epileptic drugs or not be taking any anti-epileptic drugs. Patients previously treated with EIAED may be enrolled if they have been off the EIAED for 10 days or more prior to the first dose of TRC102.
  4. Patients must not be on any anticoagulation.
  5. Patient must not have prior gastrointestinal (GI) surgery or GI disease that might interfere with the absorption of TRC102.
  6. Patients who have not recovered to <CTCAE grade 2 toxicities related to prior therapy are ineligible.
  7. Patients must not have active brain metastases from a systemic solid tumor.
  8. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, clinically significant cardiac disease, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible.
  9. Pregnant women are excluded from this study because TRC102 has potential for teratogenic or abortifacients effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with TRC102, breastfeeding should be discontinued if the mother is treated with TRC102.
  10. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with TRC102. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.