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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01648348
First received: July 20, 2012
Last updated: October 23, 2014
Last verified: July 2014

July 20, 2012
October 23, 2014
November 2012
December 2014   (final data collection date for primary outcome measure)
  • MTD of TRC105 combined with bevacizumab based on the incidence of dose-limiting toxicity graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0 (Phase I) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    The number and severity of all adverse events (overall, by dose level, by treatment received) will be tabulated and summarized. The grade 3+ adverse events will also be described and summarized in a similar fashion.
  • Progression-free survival (PFS) (Phase II) [ Time Frame: The time from study randomization to documentation of disease progression, assessed up to 2 years ] [ Designated as safety issue: No ]
    The time-to-progression distribution will be estimated using the Kaplan-Meier method.
  • MTD of TRC105 combined with bevacizumab based on the incidence of dose-limiting toxicity (DLT) assessed up to 2 courses (Phase I) [ Designated as safety issue: Yes ]
  • Adverse event profile as assessed by as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0 will be tabulated and summarized (Phase I) [ Designated as safety issue: Yes ]
  • Progression-free survival (PFS) defined as the time from study randomization to documented diseases progression (Phase II) [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01648348 on ClinicalTrials.gov Archive Site
  • Overall survival (Phase I and II) [ Time Frame: The time from start of study therapy to death due to any cause, assessed up to 2 years ] [ Designated as safety issue: No ]
    The distribution of overall survival for both groups of the study will be estimated using the Kaplan-Meier method, and be compared using logrank tests.
  • PFS (Phase II) [ Time Frame: The time from study randomization to documentation of disease progression, assessed at 6 months ] [ Designated as safety issue: No ]
    The 6-month progression-free survival percentage will be estimated and confidence intervals calculated based on the Kaplan-Meier curves for the two arms. Cox-models will be used that incorporate the stratification factors to test for differences in treatment arms after adjusting for age (>/=< 70) and resection at recurrence (yes/no).
  • Incidence of adverse events as assessed by NCI CTCAE v. 4.0 (Phase II) [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
    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. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing. The overall adverse event rates for grade 3 or higher adverse events will be compared using Chi-Square or Fisher's Exact tests between the 2 treatment groups.
  • QOL as assessed by the EORTC QLQ-C15-PAL and QLQ-BN20 Patient Questionnaires and the WIWI questionnaire (Phase II) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Population-level and subject-level longitudinal plots will be plotted to display the trend of patient-reported QOL. Interaction plots will be used to display the effects of treatment group and time on QOL.
  • Objective response (Phase I) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease.
  • Time until any treatment-related toxicity (Phase I) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Simple summary statistics will be supplemented with Kaplan-Meier survival estimates and relevant confidence intervals.
  • Time until treatment-related grade 3+ toxicity (Phase I) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Simple summary statistics will be supplemented with Kaplan-Meier survival estimates and relevant confidence intervals.
  • Time to progression (Phase I) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Simple summary statistics will be supplemented with Kaplan-Meier survival estimates and relevant confidence intervals.
  • Time to treatment failure (Phase I) [ Time Frame: Time from registration to documentation of progression, unacceptable toxicity, or refusal to continue participation by the patient, assessed up to 2 years ] [ Designated as safety issue: No ]
    Simple summary statistics will be supplemented with Kaplan-Meier survival estimates and relevant confidence intervals.
  • Overall survival defined as time from start of study therapy to death due to any cause and estimated by the Kaplan-Meier method (Phase II) [ Designated as safety issue: No ]
  • PFS at 6 months (Phase II) [ Designated as safety issue: No ]
  • Adverse events (AEs) as assessed by NCI CTCAE v. 4.0 ; overall AE rates of grade 3 or higher will be compared using Chi-Square or Fisher's Exact tests (Phase II) [ Designated as safety issue: Yes ]
  • QOL as assessed by the EORTC QLQ-C15-PAL and QLQ-BN20 Patient Questionnaires and the WIWI questionnaire (Phase II) [ Designated as safety issue: No ]
  • Relationship between tumor biomarkers and circulating biomarkers; binary endpoints and categorical endpoints will be compared using Chi-Squared or Fisher's Exact tests between treatment arms (Phase II) [ Designated as safety issue: No ]
  • MRI ADC utility as predictor of response and survival using Kaplan-Meier survival curves, logrank, and Cox regression tests (Phase II) [ Designated as safety issue: No ]
  • DCE-MRI utility as predictor of response using Kaplan-Meier survival curves, logrank, and Cox regression tests (Phase II) [ Designated as safety issue: No ]
  • Changes in tumor and circulating biomarkers [ Time Frame: Baseline to up to 2 years ] [ Designated as safety issue: No ]
    Binary endpoints and categorical endpoints will be compared using Chi-Squared or Fisher's Exact tests between treatment groups. Continuous endpoints will be analyzed using change-from-baseline measures and compared using t-tests between treatment groups and time-points. Cox proportional hazards regression will be used to determine if there are differences in PFS and OS between the treatment groups after correcting for each biomarker in conjunction with standard clinical variables.
  • Change in MRI ADC utility [ Time Frame: Baseline to up to 2 years ] [ Designated as safety issue: No ]
    MRI ADC histogram metrics such as overall ADC, mean ADC of lower curve, percentage of ADC in lower curve, and skewness at baseline and change from baseline to the first follow-up MRI will be analyzed for association with progression free and overall survival. Kaplan-Meier survival curves, logrank and Cox regression tests will be used to estimate and compare the equality of the overall survival and progression-time distributions of patient subsets defined by the ADC histogram metrics.
  • Change in DCE-MRI utility [ Time Frame: Baseline to up to 2 years ] [ Designated as safety issue: No ]
    Associations between the change of DCE-MRI and PFS6 will be assessed using two-sample t-test.
Not Provided
 
Bevacizumab With or Without Anti-Endoglin Monoclonal Antibody TRC105 in Treating Patients With Recurrent Glioblastoma Multiforme
Phase I/Comparative Randomized Phase II Trial of TRC105 Plus Bevacizumab Versus Bevacizumab in Bevacizumab-Naïve Patients With Recurrent Glioblastoma Multiforme

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.

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.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Adult Anaplastic Astrocytoma
  • Adult Anaplastic Oligodendroglioma
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Adult Mixed Glioma
  • Recurrent Adult Brain Tumor
  • Biological: anti-endoglin monoclonal antibody TRC105
    Given IV
    Other Name: TRC105
  • Biological: bevacizumab
    Given IV
    Other Names:
    • anti-VEGF humanized monoclonal antibody
    • anti-VEGF monoclonal antibody
    • Avastin
    • rhuMAb VEGF
  • Other: laboratory biomarker analysis
    Correlative studies
  • Other: pharmacological study
    Correlative studies
    Other Name: pharmacological studies
  • Other: quality-of-life assessment
    Ancillary studies
    Other Name: quality of life assessment
  • Experimental: Arm I (bevacizumab and TRC105)
    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.
    Interventions:
    • Biological: anti-endoglin monoclonal antibody TRC105
    • Biological: bevacizumab
    • Other: laboratory biomarker analysis
    • Other: pharmacological study
    • Other: quality-of-life assessment
  • Active Comparator: Arm II (bevacizumab)
    Patients receive bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Biological: bevacizumab
    • Other: laboratory biomarker analysis
    • Other: pharmacological study
    • Other: quality-of-life assessment
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
128
Not Provided
December 2014   (final data collection date for primary outcome measure)

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 (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 antiinflammatory 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: nonmelanotic 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 or Coumadin and has an international normalized ratio (INR) range of 2 to 3; 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
Both
18 Years and older
No
United States
 
NCT01648348
NCI-2012-01989, NCI-2012-01989, CDR0000737109, NCCTG-N1174, N1174, N1174, U10CA025224, U10CA180821
Yes
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Evanthia Galanis Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
July 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP