Bevacizumab With or Without Anti-Endoglin Monoclonal Antibody TRC105 in Treating Patients With Recurrent Glioblastoma Multiforme

Study Overview
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Brief Summary
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This partially randomized phase I/II trial studies the side effects and the best dose of anti-endoglin monoclonal antibody TRC105 when given together with bevacizumab and to see how well they work in treating patients with glioblastoma multiforme that has come back. Monoclonal antibodies, such as anti-endoglin monoclonal antibody TRC105 and bevacizumab, may find tumor cells and help kill them. Giving anti-endoglin monoclonal antibody TRC105 together with bevacizumab may be an effective treatment for glioblastoma multiforme.

Detailed Description
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PRIMARY OBJECTIVES: I. To establish a maximum tolerated dose (MTD) of TRC105 (anti-endoglin monoclonal antibody TRC105) combined with bevacizumab in this patient population. (Phase I) II. To assess the safety and adverse events of TRC105 in combination with bevacizumab in this patient population. (Phase II) III. To determine the efficacy of TRC105 in combination with bevacizumab in recurrent glioblastoma as measured by progression-free survival and compare it with the efficacy of bevacizumab alone in this patient population. (Phase II) SECONDARY OBJECTIVES: I. To assess the proportion of patients, who are progression free at 6 months, treated with TRC105 in combination with bevacizumab as compared to bevacizumab alone. (Phase II) II. To assess the overall survival of patients treated with TRC105 in combination with bevacizumab compared to bevacizumab alone. (Phase II) III. To compare the impact of the treatment on the patients quality of life (QOL) using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire (QLQ)-C15-Palliative Care (PAL) and QLQ-brain neoplasm (BN)20 Patient Questionnaires. (Phase II) IV. To estimate patient recommendations for study participation to others using the Was It Worth It (WIWI) Questionnaire. (Phase II) TERTIARY OBJECTIVES: I. To evaluate the pharmacokinetics of TRC105. (Phase I) II. To evaluate the immunogenicity of TRC105. (Phase I) III. To determine the relationship between tumor biomarkers, circulating biomarkers of vascular response and vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) single-nucleotide polymorphisms (SNPs) in predicting efficacy and/or toxicity of treatment. (Phase II) IV. To assess the utility of magnetic resonance imaging (MRI) imaging including apparent diffusion coefficient (ADC) as a predictor of response and survival. (Phase II) V. To assess the utility of dynamic contrast enhanced (DCE) MRI as a predictor of response to bevacizumab with or without TRC105. (Phase II) OUTLINE: This is a phase I dose-escalation study of anti-endoglin monoclonal antibody TRC105, followed by a randomized phase II study. Phase I (closed to accrual 1/14/14): Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Phase II: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive bevacizumab IV over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 3 years.

Official Title
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Phase I/Comparative Randomized Phase II Trial of TRC105 Plus Bevacizumab Versus Bevacizumab in Bevacizumab-Naive Patients With Recurrent Glioblastoma Multiforme

Conditions
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Adult Giant Cell Glioblastoma, Adult Gliosarcoma, Adult Mixed Glioma, Recurrent Adult Brain Neoplasm, Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Glioblastoma

Intervention / Treatment
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* Biological: Anti-Endoglin Chimeric Monoclonal Antibody TRC105
* Biological: Bevacizumab
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological confirmation of grade 3 or 4 glioma, including astrocytoma, oligodendroglioma, and mixed gliomas, as determined by pre-registration central pathology review (Phase I) Histological confirmation of glioblastoma multiforme (grade 4 astrocytoma) as determined by pre-registration central pathology review; note: gliosarcomas and other grade 4 astrocytoma variants (e.g., giant cell) are eligible; glioblastoma (GBM) with oligodendroglial features are NOT PERMITTED in this study if they are 1p19q co-deleted; sites submitting GBM with oligodendroglial features will be asked to provide results of 1p/19q co-deletion status (Phase II) Evidence of tumor progression by MRI or computed tomography (CT) scan following radiation therapy or following the most recent anti-tumor therapy; note: patients who have had surgical treatment at recurrence are eligible if they had a resection with measurable or non-measurable residual disease on postoperative imaging or if there is imaging evidence of disease progression as compared to the first postoperative scan Measurable or evaluable disease by gadolinium MRI or contrast CT scan; note: patients who have had a gross total resection (GTR) are eligible on the basis of evaluable disease Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 Absolute neutrophil count (ANC) >= 1,500/mm^3 Platelet count >= 100,000/mm^3 White blood cells (WBC) >= 3,000/mL Hemoglobin >= 10.0 g/dL; note: this level may be reached by transfusion Total bilirubin =< institutional upper limit of normal (ULN) Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2 x ULN Creatinine =< ULN Life expectancy >= 12 weeks Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only Urine protein creatinine (UPC) ratio < 1; note: urine protein must be screened by urine analysis for UPC ratio; for UPC ratio >= 1.0, 24-hour urine protein must be obtained and the level should be < 1,000 mg for registration Fixed or decreasing dose of corticosteroids (or no corticosteroids) >= 7 days prior to registration Calculated glomerular filtration rate (GFR) must be >= 60 ml/min; GFR will be calculated as needed per institutional guidelines Any number of prior chemotherapy regimens for recurrent disease (Phase I); =< 1 chemotherapy or other non-antiangiogenic regimen for recurrent disease (Phase II) Last dose of bevacizumab >= 2 weeks prior to registration (Phase I); note: for the phase II study only, prior exposure to bevacizumab is not allowed Surgery >= 4 weeks prior to registration Completion of radiation therapy >= 12 weeks prior to registration and prior chemotherapy >= 4 weeks prior to registration (>= 6 weeks from nitrosourea-containing regimens) Small molecular cell cycle inhibitors >= 2 weeks from registration Ability to provide informed written consent Ability to complete questionnaire(s) by themselves or with assistance Willing to return to enrolling institution for follow-up Willing to discontinue use of medications that inhibit platelet function >= 10 days prior to registration; aspirin at doses greater than 325 mg/day must be discontinued >= 10 days prior to registration and avoided through the study; note: nonsteroidal anti-inflammatory drug (NSAID) medications are recommended in place of aspirin; if NSAIDs or aspirin are used, histamine (H)-2 blockers and proton pump inhibitor (PPI) medications are recommended Willing to provide mandatory blood and tissue samples for correlative research purposes (Phase I and II) Exclusion Criteria: Any of the following: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception throughout the duration of the study and for at least 6 months after treatment has ended Prior hypersensitivity to bevacizumab or toxicity requiring discontinuation of bevacizumab (Phase I) Any prior exposure to any VEGF or VEGF inhibitor including, but not limited to, bevacizumab, cediranib, vandetanib, sunitinib, pazopanib, aflibercept, or sorafenib (Phase II) Prior hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies (Phase I and II) Prior hypersensitivity to triptan derivatives (Phase I and II) Other active malignancy =< 3 years prior to registration; exceptions: non-melanotic skin cancer or carcinoma-in-situ of the cervix; note: if there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy) for their cancer Uncontrolled infection Immunocompromised patients or patients known to be human immunodeficiency virus (HIV) positive and currently receiving combination antiretroviral therapy; patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and adverse events of the prescribed regimens Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements History of hypertensive crisis or hypertensive encephalopathy Clinically significant cardiovascular disease defined as follows: Inadequately controlled hypertension (i.e., systolic blood pressure [SBP] > 160 mm Hg and/or diastolic blood pressure [DBP] > 90 mm Hg despite antihypertensive therapy) History of cerebrovascular accident (CVA) within 6 months Myocardial infarction or unstable angina within 6 months New York Heart Association classification II, III, or IV cardiovascular disease Serious and inadequately controlled cardiac arrhythmia Significant vascular disease (i.e., aortic aneurysm, history of aortic dissection) Clinically significant peripheral vascular disease Evidence or history of bleeding diathesis (greater than normal risk of bleeding, i.e., hereditary hemorrhagic telangiectasia type I or HHT-1) or coagulopathy in the absence of therapeutic anti-coagulation or any hemorrhage/bleeding event > grade 3 within 4 weeks prior to registration; note: patients with full-dose anticoagulants are eligible provided the patient has been on a stable dose for at least 2 weeks of low molecular weight heparin; therapeutic Coumadin and aspirin doses > 325 mg daily are not allowed Receiving any other investigational agent that would be considered as a treatment for the primary neoplasm Prior treatment with TRC105 Serious or non-healing wound, active ulcer, or untreated bone fracture History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess =< 6 months prior to registration History of invasive procedures defined as follows: Major surgical procedure, open biopsy, or significant traumatic injury =< 28 days prior to registration Anticipation of need for major surgical procedures during the study Core biopsy =< 7 days prior to registration History of significant vascular disease (i.e., aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis) within 6 months prior to registration

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (bevacizumab and TRC105)<br>Patients receive bevacizumab IV over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. | Biological: Anti-Endoglin Chimeric Monoclonal Antibody TRC105<br>* Given IV<br>* Other names: TRC105;Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Active Comparator: Arm II (bevacizumab)<br>Patients receive bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. | Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) (Phase I) as Measured by the Number of Participants With Dose Limiting Toxicities | MTD for this study will be defined as the highest safely tolerated dose level where at most 1 out of 6 patients experience dose-limiting toxicity (DLT) with the next higher dose having at least 2 patients out of a maximum of 6 patients experience DLT. A total of 6 patients treated at the MTD will be sufficient to identify common toxicities at the MTD. The number of DLT's will be reported here. | 28 days | 
| Progression-free Survival (PFS) (Phase II) | Progression Free Survival time is defined as the time from study randomization to documentation of disease progression. Patients who die without documentation of progression will be considered to have had tumor progression at the time of death. Patients who fail to return for evaluation after beginning therapy will be censored for progression on the last day of therapy or date last known to be alive, whichever is later. Patients who are still alive and have not progressed will be censored for progression at the time of the last tumor assessment. The time-to-progression distribution will be estimated using the Kaplan-Meier method. | The time from study randomization to documentation of disease progression, assessed up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Toxicity Rate for Grade 3 or Higher Adverse Events Considered at Least Possibly Related to Treatment (Phase II) | The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment will be compared using a Fisher's Exact test between the 2 treatment groups. | Up to 2 years | 
| Overall Survival (Phase II) | Survival time is defined to be the length of time from start of study therapy to death due to any cause. All patients meeting the eligibility criteria that have signed a consent form and begun treatment will be considered evaluable for estimation of the survival distribution. The distribution of overall survival for both groups of the study will be estimated using the Kaplan-Meier method, and be compared using log-rank tests. | The time from start of study therapy to death due to any cause, assessed up to 2 years | 
| Progression Free Survival at 6 Months (PFS6) (Phase II) as Measured by the Percentage of Participants With Progression Free Survival at 6 Months | PFS6 is defined as the time from start of study therapy to the date of first observation of disease progression or death due to any cause (whichever comes first). The medians and confidence intervals given are the Kaplan-Meier estimates. | The time from study randomization to documentation of disease progression, assessed at 6 months | 
| Quality of Life (QOL) as Assessed by the EORTC QLQ-C15-PAL Questionnaire [Item 15: Global Health Status/Quality of Life] (Phase II) | Quality of Life (QOL) as assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C15-PAL questionnaire, as measured by the change from baseline to the end of cycle 2 (4 weeks) in the EORTC QLQ-C15-PAL item 15, Global health status/quality of life, score. The assessment was scored using EORTC's scoring algorithms. The score range is from 0-100 (0 corresponding to worst outcome; 100 corresponding to best outcome). Range of the change in scores from baseline to cycle 2 (4 weeks) is (-100,100). The mean change in score and 95% confidence interval of the change from baseline to the end of cycle 2 (4 weeks) are reported below. | Baseline and 4 weeks | 
| QOL Assessed by EORTC-QLQ-BN20 Patient Questionnaire [Items 1-20] (Phase II) | QOL assessed by EORTC-QLQ-BN20 Patient Questionnaire (Brain cancer module), as measured by the change from baseline to the end of cycle 2 (4 weeks) in the EORTC QLQ-BN20 Items 1-20 are used to score the following 11 symptom scales: Future uncertainty (Items 1-3,5), Visual disorder (Items 6-8), Motor dysfunction (Items 10,15, 19), Communication deficit (Items 11-13), Headaches (Item 4), Seizures (Item 9), Drowsiness (Item 14), Itchy Skin (Item 17), Hair Loss (Item 16), Weakness of legs (Item 18), and Bladder control (Item 20). The assessment was scored using EORTC's scoring algorithms. The score range for each of the 11 symptom scales is from 0-100 (0 corresponding to not severe;100 corresponding to most severe). Range of changes in scores from baseline to cycle 2 (4 weeks) is (-100,100). The mean change in score and 95% confidence interval of each symptom scale are reported below. | Baseline and 4 weeks | 
| QOL Assessed by WIWI Questionnaire (Phase II) | Quality of life (QOL) assessed by Was it worth it? (WIWI) questionnaire, as measured by the percentage of patients answering yes to the question Was it worthwhile for you to participate in this research study? | Up to 4 weeks |