Brivanib Metastatic Renal Cell Carcinoma

Phase 2

Terminated

Conditions: Renal Cell Carcinoma

Interventions: Drug: Brivanib alaninate
Genetic: Polymerase chain reaction
Other: Iodine I 124 chimeric monoclonal antibody G250
Procedure: Positron emission tomography/computed tomography
Genetic: Protein expression analysis
Other: Immunohistochemistry

Registration Number: NCT01253668

Lead Sponsor: Abramson Cancer Center at Penn Medicine

Brief Summary: This is a phase II study of an investigational agent, brivanib, in patients with refractory metastatic renal cell carcinoma. This study will evaluate the safety and effectiveness of brivanib in renal cell carcinoma, and explore the activity of this drug in this population to determine whether imaging and molecular features of the tumors can be used to predict response. Approximately 30 people with advanced kidney cancer will be enrolled on this study at the University of Pennsylvania.

Detailed Description: The primary objective of this clinical trial is to determine the efficacy of brivanib in the treatment of metastatic renal cell carcinoma in terms of progression-free survival (PFS) in patients who have progressed on treatment with sunitinib, sorafenib, bevacizumab, or pazopanib. The primary endpoint of the trial will be PFS at 16 weeks. The secondary objectives are to further examine the safety and tolerability profile of brivanib, to examine the efficacy of brivanib in this population in terms of best overall response, response rate, progression-free survival, and overall survival, to describe baseline and changes in I-cG250 PET/CT in relation to observed therapeutic effects, to describe novel baseline histologic features of these tumors in relation to observed therapeutic effects. Modalities will include Von Hippel-Lindau gene (VHL) and hypoxia-inducible factor 1 gene (HIF-1) expression assessment and a novel histo-cytometric assessment of the tumor microenvironment in terms of p-STAT3, p-ERK, Ki67, VEGFR2, FGFR1 expression, to describe changes in circulating collagen IV on brivanib in relation to therapeutic effects, to explore the relationship between single nucleotide polymorphisms in angiogenesis-related genes and the activity of brivanib in the treatment of these patients.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 10

Inclusion Criteria

Male and female adults with metastatic renal cell carcinoma
Patients will have tumors that bear a clear cell component that comprises greater than or equal to 50% of the tumor.
Disease must be measurable in accord with RECIST 1.1 guidelines.
Patients who have developed progressive disease or intolerance on treatment with sorafenib, sunitinib, bevacizumab, or pazopanib over a 60 day period who have not discontinued this therapy more than 100 days prior to study enrollment. Progressive disease per RECIST 1.1 guidelines will be preferred
Therapy with up to three prior systemic regimens will be allowed.
Patients may have been treated with any of the following: sorafenib, sunitinib, bevacizumab, pazopanib, temsirolimus, everolimus, interferon alpha, interleuken-2.
Treatment with up to one prior regimen that included cytotoxic chemotherapy will be allowed.
Patients may have been treated with more than 1 antiangiogenic therapy (e.g., patients may have been treated with both sorafenib and sunitinib or sunitinib and bevacizumab, or sequential combinations that include pazopanib).
Life expectancy of at least 3 months
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Tumor tissue must be available for correlative studies.
Patients must consent to allow the acquisition of formalin-fixed paraffin-embedded (FFPE) material (block or unstained slides) by study personnel for performance of correlative tissue studies.

Exclusion Criteria

Known brain metastases
Prior therapy with brivanib, or anti-FGFR (fibroblast growth factor receptor) therapy.
History of thrombotic or embolic events within the last six months such as a cerebrovascular accident (including transient ischemic attacks), pulmonary embolism.
Gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE version 4.0 Grade greater than 3 within 30 days prior to study entry.
Uncontrolled or significant cardiovascular disease.
QTc greater than 450 msec on two consecutive ECGs (Baseline ECG should be repeated if QTc is found to be greater than 450 msec.).
Active infection, less than 7 days after completing systemic antibiotic therapy.
History of non-healing wounds or ulcers or bone fractures within 3 months of fracture.
Major surgical procedure, open biopsy, or significant traumatic injury less than 3 weeks prior to study enrollment or those who receive minor surgical procedures (e.g. core biopsy or fine needle aspiration)within 1 week prior to study enrollment.
Cytotoxic chemotherapy within 3 weeks, bevacizumab within 2 months, or radiation therapy within 2 weeks, other targeted therapies (e.g., sorafenib, sunitinib, temsirolimus, everolimus)within 2 days.
Inability to swallow tablets or untreated malabsorption syndrome.
Pre-existing thyroid abnormality with thyroid function that cannot be controlled with medication.
History of HIV
Patients with centrally cavitating lung lesions.
Patients requiring therapeutic anticoagulation with warfarin at baseline. However, prophylactic therapy with a low molecular weight heparin at baseline is acceptable.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm 1	Protein expression analysis	Patients receive oral brivanib alaninate daily in the absence of disease progression or unacceptable toxicity.
Arm 1	Immunohistochemistry	Patients receive oral brivanib alaninate daily in the absence of disease progression or unacceptable toxicity.
Arm 1	Iodine I 124 chimeric monoclonal antibody G250	Patients receive oral brivanib alaninate daily in the absence of disease progression or unacceptable toxicity.
Arm 1	Polymerase chain reaction	Patients receive oral brivanib alaninate daily in the absence of disease progression or unacceptable toxicity.
Arm 1	Positron emission tomography/computed tomography	Patients receive oral brivanib alaninate daily in the absence of disease progression or unacceptable toxicity.
Arm 1	Brivanib alaninate	Patients receive oral brivanib alaninate daily in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	16 weeks	All patients will be followed through the entire 16-week period and will be given a binary outcome assignment: progressive disease or not.

Secondary Outcome Measures

Name	Time	Method
Molecular Markers	At baseline	Molecular markers expressed in patient tumor specimens as assessed by IHC and histocytometry (e.g., VHL, HIF, p-STAT3, p-ERK, and Ki67, VEGFR2, and FGFR1) (correlative studies)
Changes in Collagen IV Levels	At baseline and week 3	Changes in collagen IV levels for each patient (correlative studies)
Change in Total Antibody Binding as Assessed by 124I-cG250 PET/CT Imaging (Correlative Studies)	At baseline and 8 weeks	Will determine the baseline and change in total antibody binding in lesions from baseline to the time on treatment that patients are assessed. The analysis dataset will be quantitated radiotracer uptake data obtained via I-cG250 PET/CT for all evaluable patients who complete the trial.
Response Rate for All Patients	Every 8 weeks	Response Rate for all patients as assessed by RECIST 1.1 guidelines
Overall Survival	Every 8 weeks	Will record deaths on study, and, to the extent possible, after the study follow-up period is completed for each patient, will be captured. Reason for death will be identified and recorded where possible.
Germline Polymorphisms and Assessment of Relationship to Toxicity and Clinical Outcome	At baseline and week 3	Germline polymorphisms and assessment of relationship to toxicity and clinical outcome (correlative studies)
Blood Pressure Data	At baseline, day 1 weeks 3,6,8,12,16 and every 6-8 weeks thereafter	Blood pressure data
Best Overall Response Rated for Each Patients as Assessed by RECIST 1.1 Guidelines	Every 8 weeks	The best overall radiographic response to therapy as measured and assessed using RECIST 1.1 guidelines will be captured for each research subject.
Toxicity as Assessed by NCI CTCAE Version 4.0	Day 1, weeks 3,6,9,12,16, and every 6-8 weeks thereafter	Toxicity as assessed by NCI CTCAE version 4.0