Methoxyamine and Temozolomide in Treating Patients With Recurrent Glioblastoma

• ClinicalTrials.gov Identifier: NCT02395692
• Recruitment Status: Terminated
• First Posted: March 24, 2015
• Results First Posted: April 4, 2019
• Last Update Posted: April 4, 2019
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Adult Brain Glioblastoma	Other: Treatment; Drug: Methoxyamine; Drug: Temozolomide	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of TRC102 in Combination With Temozolomide for Recurrent Glioblastoma
• Actual Study Start Date: December 18, 2015
• Actual Primary Completion Date: February 16, 2017
• Actual Study Completion Date: February 16, 2017

Arms and Interventions

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.	Other: Treatment; Correlative studies; Drug: Methoxyamine; Given PO; Other Name: TRC102; Drug: Temozolomide; Given PO; Other Names: CCRG-81045; M & B 39831; M and B 39831; Methazolastone; RP-46161; SCH 52365; Temcad; Temodal; Temodar; Temomedac

Outcome Measures

Primary Outcome Measures :

1. Objective Response as Assessed by Response Assessment in Neuro-Oncology (RANO) Criteria (Arm 1 and Arm 2) [ Time Frame: Up to at least 2 years ]

   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.

Secondary Outcome Measures :

1. Toxicity as Assessed by Number of Participants Who Experienced Adverse Events [ Time Frame: Up to 30 days following the last dose of study drug ]
   Number of participants who experience adverse events graded 3 or higher as defined by National Cancer Institute CTCAE v4.0.
2. Progression-free Survival [ Time Frame: Up to at least 2 years ]
   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
3. Progression-free Survival at 6 Months [ Time Frame: 6 months ]
   Will be analyzed using standard descriptive statistical methods.
4. Overall Survival [ Time Frame: Up to at least 2 years ]
   Will be analyzed using standard descriptive statistical methods.

Other Outcome Measures:

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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, United States, 35233

United States, California

UCLA / Jonsson Comprehensive Cancer Center

Los Angeles, California, United States, 90095

UCSF Medical Center-Parnassus

San Francisco, California, United States, 94143

United States, Maryland

Adult Brain Tumor Consortium

Baltimore, Maryland, United States, 21231-1000

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, United States, 21287

United States, Michigan

Henry Ford Cancer Institute¿Downriver

Brownstown, Michigan, United States, 48183

Henry Ford Hospital

Detroit, Michigan, United States, 48202

Henry Ford West Bloomfield Hospital

West Bloomfield, Michigan, United States, 48322

United States, North Carolina

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States, 27157

United States, Ohio

Case Western Reserve University

Cleveland, Ohio, United States, 44106

Cleveland Clinic Foundation

Cleveland, Ohio, United States, 44195

United States, Pennsylvania

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, United States, 15232

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Manmeet Ahluwalia; National Cancer Institute (NCI)

  Study Documents (Full-Text)

Documents provided by National Cancer Institute (NCI):

Study Protocol and Statistical Analysis Plan  [PDF] September 28, 2015

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02395692
• Other Study ID Numbers: NCI-2015-00356; NCI-2015-00356 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 1402 ( Other Identifier: Adult Brain Tumor Consortium ); ABTC-1402 ( Other Identifier: Adult Brain Tumor Consortium ); ABTC 1402 ( Other Identifier: Adult Brain Tumor Consortium ); ABTC-1402 ( Other Identifier: CTEP ); UM1CA137443 ( U.S. NIH Grant/Contract )
• First Posted: March 24, 2015
• Results First Posted: April 4, 2019
• Last Update Posted: April 4, 2019
• Last Verified: March 2019

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Temozolomide; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents