Methoxyamine and Temozolomide in Treating Patients With Recurrent Glioblastoma

Phase II Study of TRC102 in Combination With Temozolomide for Recurrent Glioblastoma

This phase II trial studies how well methoxyamine works when added to standard temozolomide in treating patients with glioblastoma that has come back. Drugs used in chemotherapy, such as methoxyamine and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Study Overview

• Status: Terminated
• Conditions: Adult Brain Glioblastoma
• Intervention / Treatment: Drug: Temozolomide; Drug: Methoxyamine; Other: Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. To estimate the efficacy of TRC102 (methoxyamine) and temozolomide, as measured by response rate, in bevacizumab naïve glioblastoma. (Arm I) II. To estimate the efficacy of TRC102 and temozolomide, as measured by response rate, in bevacizumab refractory glioblastoma. (Arm II)

SECONDARY OBJECTIVES:

I. Evaluate the toxicities of oral TRC102 and temozolomide in this patient population.

II. Estimate the efficacy of TRC102 and temozolomide, as measured by progression-free survival, progression-free survival at 6 months and overall survival, in bevacizumab naïve glioblastoma.

III. Estimate the efficacy of TRC102 and temozolomide, as measured by progression-free survival in bevacizumab refractory glioblastoma.

TERTIARY OBJECTIVES:

I. Assess the tissue correlates of N-methylpurine-deoxyribonucleic acid (DNA) glycosylase (MPG), topoisomerase II-alpha (topo II a), and O-6-methylguanine-DNA methyltransferase (MGMT) status, with response, progression-free survival (PFS), and overall survival.

OUTLINE:

Patients receive methoxyamine orally (PO) once daily (QD) and temozolomide PO QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, every 2 months for 2 years, and then every 6 months thereafter.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham Cancer Center
  • California
    • Los Angeles, California, United States, 90095
      • UCLA / Jonsson Comprehensive Cancer Center
    • San Francisco, California, United States, 94143
      • UCSF Medical Center-Parnassus
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Cancer Center
    • Baltimore, Maryland, United States, 21231-1000
      • Adult Brain Tumor Consortium
  • Michigan
    • Brownstown, Michigan, United States, 48183
      • Henry Ford Cancer Institute¿Downriver
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • West Bloomfield, Michigan, United States, 48322
      • Henry Ford West Bloomfield Hospital
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute (UPCI)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must have histologically confirmed glioblastoma that is progressive or recurrent following radiation therapy and temozolomide
• Tumor MGMT methylation status must be available; results of routinely used methods for MGMT methylation testing (e.g. methylation-specific polymerase chain reaction [MSPCR ] or quantitative polymerase chain reaction [PCR]) are acceptable
• Arm 1 patients must have measurable (defined by at least 1 cm x 1 cm) contrast-enhancing disease by magnetic resonance imaging (MRI) imaging within 21 days of starting treatment
• 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
• 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)
• 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
• 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; availability of tissue is not a requirement for study participation

• 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 Food and Drug Administration [FDA]-approved) agents
  • 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., erlotinib, hydroxychloroquine, etc.)
• 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)
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9 g/dL
• Total bilirubin =< institutional upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 4 x institutional upper limit of normal
• Creatinine =< institutional upper limit of normal OR creatinine clearance >= 60 ml/min/1.73 m^2 for patients with creatinine levels above institutional normal
• Activated partial thromboplastin time (APTT) or partial thromboplastin time (PTT) =< 1.5 x institutional upper limit of normal
• Patients must be able to provide written informed consent
• 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
• 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
• Patients must be able to swallow capsules

Exclusion Criteria:

• Patients receiving any other investigational agents are ineligible
• Patient must not have known sensitivity to TRC102 or any formulation excipients
• 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
• Patients must not be on any anticoagulation
• Patient must not have prior gastrointestinal (GI) surgery or GI disease that might interfere with the absorption of TRC102
• Patients who have not recovered to < Common Terminology Criteria for Adverse Events (CTCAE) grade 2 toxicities related to prior therapy are ineligible
• Patients must not have active brain metastases from a systemic solid tumor
• 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
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with TRC102
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (methoxyamine, temozolomide); Patients receive methoxyamine PO QD and temozolomide PO QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Temozolomide; Given PO; Other Names: Temodar; SCH 52365; Temodal; Temcad; Methazolastone; RP-46161; Temomedac; CCRG-81045; M & B 39831; M and B 39831; Drug: Methoxyamine; Given PO; Other Names: TRC102; Other: Treatment; Correlative studies

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response as Assessed by Response Assessment in Neuro-Oncology (RANO) Criteria (Arm 1 and Arm 2)	To test the hypothesis that the combination treatment of temozolomide and methoxyamine will achieve 30% radiographic response rate (partial response + complete response) in patients with first recurrence of glioblastoma. Per Response Assessment in Neuro-Oncology (RANO) Criteria: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.	Up to at least 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity as Assessed by Number of Participants Who Experienced Adverse Events	Number of participants who experience adverse events graded 3 or higher as defined by National Cancer Institute CTCAE v4.0.	Up to 30 days following the last dose of study drug
Progression-free Survival	Will be analyzed using standard descriptive statistical methods. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions	Up to at least 2 years
Progression-free Survival at 6 Months	Will be analyzed using standard descriptive statistical methods.	6 months
Overall Survival	Will be analyzed using standard descriptive statistical methods.	Up to at least 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
MPG, Topo II-alpha, and MGMT Levels in Tissue Samples	MPG, topo II-alpha, and MGMT levels will be correlated with response, PFS, and overall survival. Will be analyzed using standard descriptive statistical methods.	Baseline

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Manmeet Ahluwalia, National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2015
• Primary Completion (Actual): February 16, 2017
• Study Completion (Actual): February 16, 2017

Study Registration Dates

• First Submitted: March 23, 2015
• First Submitted That Met QC Criteria: March 23, 2015
• First Posted (Estimate): March 24, 2015

Study Record Updates

• Last Update Posted (Actual): April 4, 2019
• Last Update Submitted That Met QC Criteria: March 14, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: NCI-2015-00356 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); UM1CA137443 (U.S. NIH Grant/Contract); 1402 (Adult Brain Tumor Consortium); ABTC-1402 (Other Identifier: CTEP); ABTC 1402 (Other Identifier: Adult Brain Tumor Consortium)