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 1, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
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
Biological: bevacizumab
Other: laboratory biomarker analysis
Other: pharmacological study
Other: quality-of-life assessment
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/Comparative Randomized Phase II Trial of TRC105 Plus Bevacizumab Versus Bevacizumab in Bevacizumab-Naïve Patients With Recurrent Glioblastoma Multiforme

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Other Outcome Measures:
  • 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.


Estimated Enrollment: 128
Study Start Date: November 2012
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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
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.
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

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01648348

  Show 209 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Evanthia Galanis Alliance for Clinical Trials in Oncology
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01648348     History of Changes
Other Study ID Numbers: NCI-2012-01989, NCI-2012-01989, CDR0000737109, NCCTG-N1174, N1174, N1174, U10CA025224, U10CA180821
Study First Received: July 20, 2012
Last Updated: October 1, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Oligodendroglioma
Glioblastoma
Astrocytoma
Gliosarcoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Bevacizumab
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses
Immunologic Factors

ClinicalTrials.gov processed this record on October 02, 2014