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Bevacizumab With or Without Trebananib in Treating Patients With Recurrent Brain Tumors

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01609790
First received: May 30, 2012
Last updated: January 9, 2017
Last verified: January 2017

May 30, 2012
January 9, 2017
June 2012
October 2015   (Final data collection date for primary outcome measure)
  • Incidence of Dose-limiting Toxicity (Cohort 1) [ Time Frame: From start of treatment to 4 weeks. ]
    Dose-limiting toxicity (DLT), defined as a clinically significant adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications and meets any of the criteria below. Any DLT must be a toxicity possibly related to protocol treatment during first 4 weeks: grade 4 hematologic toxicity, grade 3/4 thrombocytopenia, or grade 3/4 non-hematologic toxicity; Gastrointestinal fistula, bowel perforation, intracranial hemorrhage, wound dehiscence, or reversible posterior leukoencephalopathy of any grade; Delay of treatment > 28 days. If 2+ of patients experience a DLT among 6 eligible patients, this drug combination will be considered unsafe and a lower dose of AMG will be explored; otherwise conclude that this drug combination is safe. The probability of claiming safe dose is no more than 16% when the true DLT rate is >45%, and the probability of claiming safe dose is at least 78% when the true DLT rate is <= 15%.
  • Six-month Progression-free Survival (Cohort 2) [ Time Frame: From randomization to six months. ]
    As determined by central review of MRI exams, assessed using RANO criteria for progression that is defined by any of the following: > 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared to the smallest tumor measurement obtained either at baseline (if no decrease) or best response, on stable or increasing doses of corticosteroids; Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation of therapy, not due to co-morbid events; Any new lesion; Clear clinical deterioration not attributable to other causes apart from the tumor or changes in corticosteroid dose; Failure to return for evaluation due to death or deteriorating condition; Clear progression of non-measurable disease.
  • Dose-limiting toxicity (DLT) (Cohort 1)
  • 6-month progression-free survival (Cohort 2)
Complete list of historical versions of study NCT01609790 on ClinicalTrials.gov Archive Site
  • Incidence of Grade 3+ Treatment-related Toxicity, Measured by CTCAE v. 4 (Cohort 2) [ Time Frame: From start of treatment up to 3 years. ]
    Adverse events (AEs) are graded by using CTCAE 4.0. Possibly/probably/definitely related to protocol treatment AEs are considered.
  • Overall Survival (Cohort 2) [ Time Frame: From randomization up to 3 years. ]
    Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. This analysis was planned to occur when all patients had been potentially followed for at least 6 months.
  • Progression-free Survival (Cohort 2) [ Time Frame: From randomization up to 3 years. ]
    Progression-free survival time is measured from randomization to the date of first progression or death or, otherwise, the last follow-up date on which the patient was reported alive. This analysis was planned to occur when all patients had been potentially followed for at least 6 months.
  • Radiographic Response Rate (Cohort 2) [ Time Frame: From randomization up to 3 years. ]
    Proportion of patients with best overall response of complete response (CR) or partial response (PR) recorded from the start of the treatment until disease progression/recurrence. Response determined by site-reported radiology review of MRI exams using Response Assessment in Neuro-Oncology Criteria (RANO) criteria. CR: Complete disappearance of all enhancing measurable disease (MD) + non-measurable disease (NMD) sustained >= 4 wks; No new lesions; Stable or improved non-enhancing (T2/FLAIR) lesions; Off corticosteroids (or on physiologic replacement doses only); Stable/improved clinically. PR: >= 50% decrease vs. baseline of sum of products of perpendicular diameters of all measurable enhancing lesions sustained >= 4 wks; No progression of NMD; No new lesions; Stable/improved non-enhancing (T2/FLAIR) lesions on <= dose of corticosteroids vs. baseline scan; Corticosteroid dose at evaluation scan <= baseline scan dose; Stable or improved clinically. NMD only cannot be a CR or PR.
  • Feasibility of Trebananib Weekly in Combination With Bevacizumab Every 2 Weeks, Measured by the Percentage of Patients Requiring Dose Reduction/Interruption or Discontinuation in the First 2 and Subsequent Courses (Cohort 1) [ Time Frame: From randomization up to 3 years. ]
  • Treatment-related toxicity, measured by CTCAE v. 4
  • Feasibility of AMG 386 weekly in combination with bevacizumab every 2 weeks, measured by the percentage of patients requiring dose reduction/interruption or discontinuation in the first 2 and subsequent cycle (Cohort 1)
  • Radiographic RR as measured by Revised Assessment in Neuro-Oncology (RANO) response criteria assessed up to 2 years (Cohort 2)
  • Overall survival (OS) from the time of study entry to death estimated by Kaplan-Meier method, assessed up to 2 years (Cohort 2)
  • Tumor genotype, expression profile, and circulating angiogenesis biomarkers (Cohort 2)
Tumor Genotype, Expression Profile, and Circulating Angiogenesis Biomarkers (Cohort 2) [ Time Frame: From randomization to date of death or last followup. Statistical analysis occurs when tumor genotype, expression profile and circulating angiogenesis biomarkers have been determined from the tissue specimens. ]
The association of tumor genotype, expression profile and circulating angiogenesis biomarkers with overall and progression-free survival will be explored through log rank tests. overall and progression-free survival will also be estimated for each subtype of glioblastoma and variants to serve an exploratory purpose.
Not Provided
 
Bevacizumab With or Without Trebananib in Treating Patients With Recurrent Brain Tumors
Phase II Double-Blinded Placebo-Controlled Study of Bevacizumab With or Without AMG 386 in Patients With Recurrent Glioblastoma or Gliosarcoma
This randomized phase II trial with a safety run-in component studies the side effects and how well bevacizumab given with or without trebananib works in treating patients with brain tumors. Monoclonal antibodies, such as bevacizumab, may block tumor growth in different ways by targeting certain cells. Trebananib may stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether giving bevacizumab together with trebananib is more effective than bevacizumab alone in treating brain tumors.

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of AMG 386 (trebananib) 15 mg/kg weekly in combination with bevacizumab 10 mg/kg every 2 weeks (Cohort 1). (closed to accrual 10/2/12) II. To assess the efficacy of AMG 386 in combination with bevacizumab 10 mg/kg every 2 weeks compared to bevacizumab monotherapy in bevacizumab-naïve patients, as measured by 6-month progression-free survival (PFS6) (Cohort 2).

SECONDARY OBJECTIVES:

I. To further assess the toxicity profile (Cohorts 1 and 2). II. To assess feasibility of AMG 386 15 mg/kg weekly in combination with bevacizumab 10 mg/kg every 2 weeks (Cohort 1 [closed to accrual 10/2/12]), as measured by the percentage of patients requiring dose reduction/interruption or discontinuation in the first 2 and subsequent cycles.

III. To determine the radiographic response rate (RR), median progression-free survival (PFS), and overall survival (OS) in bevacizumab-naïve patients (Cohort 2).

IV. To assess the efficacy of AMG 386 15 mg/kg weekly in combination with bevacizumab 10 mg/kg every 2 weeks in patients who have progressed while on bevacizumab, as measured by overall survival (OS) (cross-over from placebo arm of Cohort 2).

V. To correlate outcome to treatment with tumor genotype, expression profile, and circulating angiogenesis biomarkers in tumor specimens (Cohort 2).

VI. To determine the RR, PFS6, and PFS in patients who have progressed while on bevacizumab therapy and receive AMG 386 in combination with bevacizumab (cross-over from placebo arm of Cohort 2).

VII. To determine the serum pharmacokinetics of AMG 386 in patients receiving bevacizumab (Cohort 1 and cross-over from placebo arm of Cohort 2).

OUTLINE: This is a safety study (cohort 1 [closed to accrual 10/2/12]) followed by a randomized study (cohort 2).

After completion of study treatment, patients are followed up at 30 days, every 2 months for 1 year, every 6 months for 1 year, and then annually thereafter.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Adult Anaplastic Oligodendroglioma
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Adult Oligodendroglioma
  • Recurrent Adult Brain Neoplasm
  • Drug: Bevacizumab
    10 mg/kg on days 1 and 15 of each 28-day cycle. It should be administered as a continuous intravenous infusion using a rate-regulating device. Number of cycles: until progression or unacceptable adverse events or intercurrent illness that prevents further administration of treatment or patient decides to withdraw from the study or pregnancy
    Other Names:
    • Anti-VEGF
    • Anti-VEGF Humanized Monoclonal Antibody
    • Anti-VEGF rhuMAb
    • Avastin
    • Bevacizumab Biosimilar BEVZ92
    • Bevacizumab Biosimilar BI 695502
    • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
    • Recombinant Humanized Anti-VEGF Monoclonal Antibody
    • rhuMab-VEGF
  • Other: Placebo
    Given IV
    Other Names:
    • placebo therapy
    • PLCB
    • sham therapy
  • Drug: AMG 386
    15 mg/kg on days 1, 8, 15, and 22 of each 28-day cycle. Infuse over 60 minutes via an infusion pump. Number of cycles: until progression or unacceptable adverse events or intercurrent illness that prevents further administration of treatment or patient decides to withdraw from the study or pregnancy
    Other Names:
    • Trebananib
    • Angiopoietin 1/2-Neutralizing Peptibody AMG 386
  • Experimental: Cohort 1: Safety Run-In
    Bevacizumab every 2 weeks + AMG 386 weekly until disease progression.
    Interventions:
    • Drug: Bevacizumab
    • Drug: AMG 386
  • Active Comparator: Cohort 2: Bevacizumab+Placebo
    Bevacizumab every 2 weeks + placebo weekly until disease progression. Patients who progress will be allowed to cross over and receive treatment with bevacizumab + AMG 386
    Interventions:
    • Drug: Bevacizumab
    • Other: Placebo
  • Experimental: Cohort 2: Bevacizumab+AMG 386
    Bevacizumab every 2 weeks + AMG 386 weekly until disease progression.
    Interventions:
    • Drug: Bevacizumab
    • Drug: AMG 386
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
137
Not Provided
October 2015   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Histologically proven diagnosis of glioblastoma or variants (gliosarcoma, glioblastoma with oligodendroglial features, giant cell glioblastoma); patients will be eligible if the original histology was a lower grade glioma and a subsequent histological diagnosis of glioblastoma or variants is made
  • The tumor must be supratentorial; patients with infratentorial disease, spinal cord disease, and/or leptomeningeal disease are excluded
  • Patients must have shown unequivocal evidence for tumor progression on the previous treatment regimen (prior to enrollment on this study) by magnetic resonance imaging (MRI) scan of the brain with and without contrast within 14 days prior to registration; the dose of steroids must be stable or decreasing for at least 5 days prior to the scan; patients with tumor progression who then undergo surgical resection prior to enrollment on study may be eligible as long as pathology confirms progressive or recurrent glioblastoma multiforme (GBM) (or variants); for patients who undergo surgical resection, registration on study may not occur any sooner than 28 days from surgery; an MRI scan of the brain with and without contrast is still required within 14 days prior to registration on study but is not required to demonstrate measurable disease or tumor progression after surgery
  • Patients unable to undergo MRI because of non-compatible devices can be enrolled, provided computed tomography (CT) scans are obtained and are of sufficient quality; patients without non-compatible devices may not have CT scans performed to meet this requirement
  • History/physical examination within 14 days prior to registration
  • Karnofsky performance scale >= 70
  • Patients who have received prior treatment with interstitial brachytherapy, stereotactic radiosurgery, or implanted chemotherapy sources, such as wafers of polifeprosan 20 with carmustine, must have confirmation of progressive disease within 14 days prior to registration based upon nuclear imaging, magnetic resonance (MR) spectroscopy, perfusion imaging, or histopathology
  • Leukocytes > 3,000/mm^3
  • Absolute neutrophil count (ANC) >= 1,500 cells/mm^3
  • Hemoglobin >= 10.0 g/dL (note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 10.0 g/dL is acceptable)
  • Platelets >= 100,000 cells/mm^3
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT))/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) < 2.5 X institutional upper limit of normal
  • Bilirubin =< 2.0 mg/dL
  • Creatinine within normal upper institutional limits or creatinine clearance > 60 mL/min/1.73 m^2 (per 24 hour urine collection or calculated according to the Cockcroft-Gault formula) for subjects with creatinine levels above the institutional normal

    • Patients with creatinine levels below normal institutional limits are eligible
  • Prothrombin time (PT)/international normalized ratio (INR) =< 1.5
  • Urinary protein =< 30 mg/dL in urinalysis or =< 1+ on dipstick
  • Generally well-controlled blood pressure with systolic blood pressure =< 140 mm Hg AND diastolic blood pressure =< 90 mm Hg within 5 days prior to registration; the use of anti-hypertensive medications to control hypertension is permitted
  • Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin (HCG) pregnancy test within 14 days prior to registration
  • Women of childbearing potential and male patients who are sexually active must practice adequate contraception during therapy and for 180 days (6 months) afterwards
  • Patient must provide study specific informed consent prior to study entry

Exclusion Criteria:

  • Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
  • Prior systemic cytotoxic chemotherapy within (ie, =<) 28 days (42 days for nitrosoureas or mitomycin C) prior to registration, or patients who have not returned to baseline or =< Common Terminology Criteria for Adverse Events (CTCAE) version 4 (v. 4) grade 2 from adverse events (excluding alopecia) due to agents administered more than 28 days prior to registration
  • Patients who received non-cytotoxic drug therapy must be off treatment for at least 14 days prior to registration; prior treatment with anti-vascular endothelial growth factor (VEGF) targeted agents; AMG 386 therapy; or other molecules that inhibit angiopoietins or TEK tyrosine kinase, endothelial (Tie2) receptor including, but not limited to, XL-820, XL-184 (cabozantinib-s-malate), and CVX-060/PF-4856884 is not allowed regardless of time frame
  • Patients who have not yet completed at least 21 days (30 days for prior monoclonal antibody therapy) since ending other investigational device or drug trials, or who are currently receiving other investigational treatments
  • Treatment within 30 days prior to enrollment with strong immune modulators, including but not limited to systemic cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, methotrexate, azathioprine, rapamycin, thalidomide, lenalidomide, and targeted immune modulators such as abatacept (CTLA-4-Ig), adalimumab, alefacept, anakinra, belatacept (LEA29Y), efalizumab, etanercept, infliximab, or rituximab
  • Prior radiotherapy within 90 days (3 months) prior to registration unless there is either: a) histopathologic confirmation of recurrent tumor; or b) new enhancement on MRI outside of the radiation treatment field
  • Major surgical procedure (including craniotomy and open brain biopsy) or significant traumatic injury within 28 days prior to registration or those patients who receive a non-central nervous system (CNS) minor surgical procedures (e.g. core biopsy or fine needle aspiration) within 3 days prior to registration; there is no waiting period for central line placement; there is a 7-day window for recovery prior to registration for patients who underwent stereotactic biopsy of the brain
  • Prior therapy with anti-VEGF targeted agents (e.g. bevacizumab, cediranib, vandetanib, aflibercept, sunitinib, sorafenib, etc.); prior therapy with thalidomide and lenalidomide is allowed as long as treatment has not occurred within 30 days prior to enrollment
  • More than 2 relapses
  • Therapeutic anticoagulation with warfarin < 7 days prior to registration; (therapeutic or prophylactic therapy with aspirin, a low-molecular weight heparin, or a Factor Xa inhibitor is acceptable)
  • Intratumoral hemorrhage or peritumoral hemorrhage, demonstrated by MRI or CT scan, CTCAE, v. 4 grade 2 or greater or evidence of significant hemorrhage (regardless of CTCAE, v. 4 grade) defined as > 1 cm diameter of blood (including postoperative hemorrhage)
  • Gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE, v. 4 grade 3 or greater within 30 days prior to study entry
  • Severe, active co-morbidity, defined as follows:

    • Unstable angina and/or congestive heart failure requiring hospitalization within 180 days (6 months) prior to registration
    • Transmural myocardial infarction within 180 days (6 months) prior to registration
    • History of stroke, cerebral vascular accident (CVA), or transient ischemic attack within 180 days (6 months) prior to registration
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
    • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
    • Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol
    • Known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhages in the past
    • History of non-healing wounds or ulcers, or bone fractures within 90 days (3 months) prior to registration
    • History of venous or arterial thromboembolism within 12 months prior to registration
  • Prior allergic reaction to the study drugs involved in this study
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States,   Canada
 
 
NCT01609790
NCI-2012-01969
NCI-2012-01969 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000734205
RTOG 1122 ( Other Identifier: NRG Oncology )
RTOG-1122 ( Other Identifier: CTEP )
U10CA180868 ( US NIH Grant/Contract Award Number )
U10CA021661 ( US NIH Grant/Contract Award Number )
Yes
Not Provided
Not Provided
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Eudocia Lee NRG Oncology
National Cancer Institute (NCI)
January 2017

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