Clinical trial NCT01253668: Brivanib Metastatic Renal Cell Carcinoma
Official title: Brivanib (BMS-582664, Brivanib Alaninate) in Treatment of Refractory Metastatic Renal Cell Carcinoma - A Phase II Pharmacodynamic and Baseline Biomarker Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Renal Cell Carcinoma
Lead sponsor: Abramson Cancer Center at Penn Medicine
Sponsor class: OTHER
First posted: 2010-12-03
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 16 weeks
Secondary outcomes:
measure: Best Overall Response Rated for Each Patients as Assessed by RECIST 1.1 Guidelines
timeFrame: Every 8 weeks
measure: Overall Survival
timeFrame: Every 8 weeks
measure: Change in Total Antibody Binding as Assessed by 124I-cG250 PET/CT Imaging (Correlative Studies)
timeFrame: At baseline and 8 weeks
measure: Response Rate for All Patients
timeFrame: Every 8 weeks
measure: Molecular Markers
timeFrame: At baseline
measure: Changes in Collagen IV Levels
timeFrame: At baseline and week 3
measure: Germline Polymorphisms and Assessment of Relationship to Toxicity and Clinical Outcome
timeFrame: At baseline and week 3
measure: Blood Pressure Data
timeFrame: At baseline, day 1 weeks 3,6,8,12,16 and every 6-8 weeks thereafter
measure: Toxicity as Assessed by NCI CTCAE Version 4.0
timeFrame: Day 1, weeks 3,6,9,12,16, and every 6-8 weeks thereafter
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Abramson Cancer Center of the University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: Abramson Cancer Center at Penn Medicine
name: Stephen Keefe, MD
role: PRINCIPAL_INVESTIGATOR
References: