Methoxyamine and Temozolomide in Treating Patients With Recurrent Glioblastoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT02395692
• Collaborator: (none)
• Enrollment: 20
• Locations: 12
• Arm: 1
• Actual Duration (Months): 14
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0.1

Study Details

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:

1. 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:

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

2. 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.

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

TERTIARY OBJECTIVES:

1. 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
• 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: Dec 18, 2015
• Actual Primary Completion Date: Feb 16, 2017
• Actual Study Completion Date: Feb 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 Names: 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) [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 [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 [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 [6 months]

   Will be analyzed using standard descriptive statistical methods.

4. Overall Survival [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 [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

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
2	UCLA / Jonsson Comprehensive Cancer Center	Los Angeles	California	United States	90095
3	UCSF Medical Center-Parnassus	San Francisco	California	United States	94143
4	Adult Brain Tumor Consortium	Baltimore	Maryland	United States	21231-1000
5	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
6	Henry Ford Cancer Institute¿Downriver	Brownstown	Michigan	United States	48183
7	Henry Ford Hospital	Detroit	Michigan	United States	48202
8	Henry Ford West Bloomfield Hospital	West Bloomfield	Michigan	United States	48322
9	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
10	Case Western Reserve University	Cleveland	Ohio	United States	44106
11	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
12	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)

• Study Protocol and Statistical Analysis Plan - Sep 28, 2015

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02395692
• Other Study ID Numbers: NCI-2015-00356; NCI-2015-00356; 1402; ABTC-1402; ABTC 1402; ABTC-1402; UM1CA137443
• First Posted: Mar 24, 2015
• Last Update Posted: Apr 4, 2019
• Last Verified: Mar 1, 2019

• Additional relevant MeSH terms: Glioblastoma; Temozolomide

Study Results

Participant Flow

Pre-assignment Detail	1 subject withdrew before start of study

Arm/Group Title	Arm1 Methoxyamine &Temozolomide (Bevacizumab-naïve)	Arm2 Methoxyamine & Temozolomide (Bevacizumab-refractory)
Arm/Group Description	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. Bevacizumab-naive Laboratory Biomarker Analysis: Correlative studies Methoxyamine: Given PO Temozolomide: Given PO	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. Bevacizumab-refractory Laboratory Biomarker Analysis: Correlative studies Methoxyamine: Given PO Temozolomide: Given PO
Period Title: Overall Study
STARTED	19	0
COMPLETED	19	0
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Treatment (Methoxyamine, Temozolomide)
Arm/Group Description	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. Laboratory Biomarker Analysis: Correlative studies Methoxyamine: Given PO Temozolomide: Given PO
Overall Participants	19
Age, Customized (years) [Median (Full Range) ]
Median (Full Range) [years]	60
Sex: Female, Male (Count of Participants)
Female	10 52.6%
Male	9 47.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 10.5%
Not Hispanic or Latino	17 89.5%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	18 94.7%
More than one race	0 0%
Unknown or Not Reported	1 5.3%
Region of Enrollment (participants) [Number]
United States	19 100%
Karnofsky Performance Score (KPS) (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	80

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

This was a 2 stage design study. if there were less than 2 responders in first 19 subjects, study would terminate and Arm2 would not accrue any subjects.

Arm/Group Title	Arm1 Methoxyamine&Temozolomide (Bevacizumab-naïve)	Arm2 Methoxyamine&Temozolomide (Bevacizumab-refractory)
Arm/Group Description	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. (Bevacizumab-naïve) Laboratory Biomarker Analysis: Correlative studies Methoxyamine: Given PO Temozolomide: Given PO	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. Bevacizumab-refractory Laboratory Biomarker Analysis: Correlative studies Methoxyamine: Given PO Temozolomide: Given PO
Measure Participants	19	0
Count of Participants [Participants]	0 0%

2. Secondary Outcome

Title	Toxicity as Assessed by Number of Participants Who Experienced Adverse Events
Description	Number of participants who experience adverse events graded 3 or higher as defined by National Cancer Institute CTCAE v4.0.
Time Frame	Up to 30 days following the last dose of study drug

Outcome Measure Data

Analysis Population Description

Patients diagnosed with glioblastoma

Arm/Group Title	Treatment (Methoxyamine, Temozolomide)
Arm/Group Description	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. Treatment (methoxyamine, temozolomide): Correlative studies Methoxyamine: Given PO Temozolomide: Given PO
Measure Participants	19
Count of Participants [Participants]	19 100%

3. Secondary Outcome

Title	Progression-free Survival
Description	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
Time Frame	Up to at least 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Methoxyamine, Temozolomide)
Arm/Group Description	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. Laboratory Biomarker Analysis: Correlative studies Methoxyamine: Given PO Temozolomide: Given PO
Measure Participants	19
Median (Full Range) [months]	2

4. Secondary Outcome

Title	Progression-free Survival at 6 Months
Description	Will be analyzed using standard descriptive statistical methods.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Methoxyamine, Temozolomide)
Arm/Group Description	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. Laboratory Biomarker Analysis: Correlative studies Methoxyamine: Given PO Temozolomide: Given PO
Measure Participants	19
Count of Participants [Participants]	2 10.5%

5. Secondary Outcome

Title	Overall Survival
Description	Will be analyzed using standard descriptive statistical methods.
Time Frame	Up to at least 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Methoxyamine, Temozolomide)
Arm/Group Description	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. Laboratory Biomarker Analysis: Correlative studies Methoxyamine: Given PO Temozolomide: Given PO
Measure Participants	19
Median (95% Confidence Interval) [months]	11

6. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

Data was not collected to assess this outcome measure.

Arm/Group Title	Treatment (Methoxyamine, Temozolomide)
Arm/Group Description	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. Laboratory Biomarker Analysis: Correlative studies Methoxyamine: Given PO Temozolomide: Given PO
Measure Participants	0

Adverse Events

Time Frame	Day 1 and 30 days after the last dose of the study drug
Arm/Group Title	Treatment (Methoxyamine, Temozolomide)
Arm/Group Description	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. Laboratory Biomarker Analysis: Correlative studies Methoxyamine: Given PO Temozolomide: Given PO
All Cause Mortality
	Treatment (Methoxyamine, Temozolomide)
	Affected / at Risk (%)	# Events
Total	9/19 (47.4%)
Serious Adverse Events
	Treatment (Methoxyamine, Temozolomide)
	Affected / at Risk (%)	# Events
Total	0/19 (0%)
Other (Not Including Serious) Adverse Events
	Treatment (Methoxyamine, Temozolomide)
	Affected / at Risk (%)	# Events
Total	18/19 (94.7%)
Blood and lymphatic system disorders
Anemia	17/19 (89.5%)	42
Endocrine disorders
Cushingoid	1/19 (5.3%)	1
Gastrointestinal disorders
Constipation	9/19 (47.4%)	10
diarrhea	2/19 (10.5%)	2
Nausea	7/19 (36.8%)	8
Abdominal pain	1/19 (5.3%)	1
Anal hemorrhage	1/19 (5.3%)	1
INCREASED BOWEL MOVEMENTS	1/19 (5.3%)	1
COLON POLYP	1/19 (5.3%)	1
Vomiting	1/19 (5.3%)	1
General disorders
fatigue	7/19 (36.8%)	11
Fever	2/19 (10.5%)	2
Gait disturbance	1/19 (5.3%)	1
Infections and infestations
Urinary tract infection	1/19 (5.3%)	1
Investigations
Alanine Aminotransferase increased	7/19 (36.8%)	7
Aspartate aminotransferase increased	5/19 (26.3%)	5
Blood bilirubin increased	9/19 (47.4%)	9
Lymphocyte count decreased	2/19 (10.5%)	4
Neutrophil count decreased	2/19 (10.5%)	2
Platelet count decreased	4/19 (21.1%)	9
White blood cell decreased	10/19 (52.6%)	21
Cholesterol high	1/19 (5.3%)	1
Investigations - Other, TRIGLYCERIDES HIGH	1/19 (5.3%)	1
Alkaline phosphatase increased	1/19 (5.3%)	1
Weight Gain	1/19 (5.3%)	1
Metabolism and nutrition disorders
anorexia	4/19 (21.1%)	4
Hypocalcemia	1/19 (5.3%)	1
Hyponatremia	1/19 (5.3%)	1
Musculoskeletal and connective tissue disorders
Myalgia	2/19 (10.5%)	2
Arthralgia	1/19 (5.3%)	1
Generalized muscle weakness	1/19 (5.3%)	1
Muscle weakness left-sided	1/19 (5.3%)	1
Musculoskeletal and connective tissue disorder - Other	1/19 (5.3%)	1
Myositis	1/19 (5.3%)	1
Nervous system disorders
Dizziness	3/19 (15.8%)	3
Dysphasia	2/19 (10.5%)	2
Headache	4/19 (21.1%)	5
Ataxia	1/19 (5.3%)	1
Cognitive disturbance	1/19 (5.3%)	1
Nervous system disorders - Other, EXTREMELY HOT SENSATION	1/19 (5.3%)	1
Nervous system disorders - Other, Vasogenic Edema	1/19 (5.3%)	1
Stroke	1/19 (5.3%)	1
Renal and urinary disorders
Urine discoloration	1/19 (5.3%)	2
Skin and subcutaneous tissue disorders
Pruritus	2/19 (10.5%)	2
Rash maculo-papular	1/19 (5.3%)	1
Skin and subcutaneous tissue disorders - Other, SORE IN GROIN AREA	1/19 (5.3%)	1

Limitations/Caveats

n for this study 31 subjects w/ a 2 stage design. 19 subjects were treated in stage one with TRC102 and TMZ in recurrent GBM. If no more than 2 responses were observed among the initial 19 patients the study would be terminated and declared negative

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.