Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

This randomized phase II trial is studying different combinations of bevacizumab, temsirolimus, and sorafenib tosylate to see how well they work compared with bevacizumab alone in treating patients with metastatic kidney cancer. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab and sorafenib tosylate may stop the growth of tumor cells by blocking blood flow to the tumor. Temsirolimus and sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving different combinations of bevacizumab, sorafenib tosylate, and temsirolimus may be more effective than bevacizumab alone in treating metastatic kidney cancer.

Further Study Information

PRIMARY OBJECTIVES:

I. To assess progression-free survival on each arm of combination targeted therapy (CTT) compared to that of bevacizumab alone.

SECONDARY OBJECTIVES:

I. To assess the significance of changes in tumor size over early time points as a predictor of PFS.

II. To quantify the number and percent of patients who have stable disease at 6 months of therapy (failure to progress) in each treatment arm of CTT in patients with metastatic RCC.

III. To evaluate the safety of each treatment arm of combination targeted therapy (CTT) in patients with metastatic RCC.

IV. To assess overall survival in each arm of the study. V. To assess the objective response rate in each treatment arm of CTT in patients with metastatic RCC.

VI. To assess pathology, angiogenesis histology and to assess activation status of MAP kinase and VEGFR2 pathways and relate to clinical outcome.

TERTIARY OBJECTIVES:

I. To analyze the pharmacokinetic and pharmacogenetic properties of sorafenib including angiogenesis, monooxygenases polymorphisms and MDR.

II. To relate changes in tumor perfusion and vascular permeability on serial dynamic contrast-enhanced MRI to clinical outcome and radiologic regression detected by other standard methods.

III. To assess the potential of DCE MRI imaging as a biomarker for response to therapy and/or as a prognostic indicator of disease progression.

IV. To assess site readiness and ability in acquiring DCE-MRI data. V. To determine the relationship between tumor and blood biomarkers and clinical outcomes of patients treated with the combination of targeted agents.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to prior cytokine or vaccine therapy (no vs yes) and Motzer risk category (low vs intermediate vs high). Patients are randomized to 1 of 4 treatment arms.

ARM A: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15.

ARM B: Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 and bevacizumab as in arm A.

ARM C: Patients receive bevacizumab as in arm A and sorafenib tosylate orally (PO) twice daily on days 1-28.

ARM D: Patients receive temsirolimus as in arm B and sorafenib tosylate as in arm C.

In all arms treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for 5 years.

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed clear cell renal cell carcinoma

• Primary or metastatic lesion

• Less than 25% of any other histology (papillary, chromophobe, or oncocytic)

• Sufficient pathology material available for diagnostic review

• Core-needle biopsy allowed

• No fine-needle aspirations as only source for diagnosis

• Measurable metastatic disease

• Lesions that can be accurately measured in ≥ 1 dimension(longest diameter to be recorded) as > 20 mm (2.0 cm) with conventional techniques or as ≥ 10 mm (1.0 cm) with spiral CT scan

• Not curable by standard radiotherapy or surgery

• Prior nephrectomy required, with the following exceptions:

• Primary tumor ≤ 5 cm

• Extensive liver metastases (> 30% of liver parenchymal) or multiple (> 5) bone metastases

• Unresectable primary tumor due to invasion into adjacent organs or encasing the aorta or vena cava

• No history or clinical evidence of CNS disease, including primary brain tumor or brain metastases

• ECOG performance status 0-1

• Life expectancy > 3 months

• WBC ≥ 3,000/mm³

• Absolute granulocyte count ≥ 1,200/mm³

• Platelet count ≥ 100,000/mm³

• Hemoglobin ≥ 9.0 g/dL (transfusions allowed)

• Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance ≥ 55 mL/min

• Bilirubin ≤ 1.5 times ULN

• AST/ALT ≤ 2.5 times ULN (5.0 times ULN in the presence of liver metastases)

• INR ≤ 1.5 and aPTT normal

• Fasting cholesterol < 350 mg/dL

• Fasting triglycerides < 400 mg/dL

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for 6 months after completion of study treatment

• No seizures not controlled with standard medical therapy

• No stroke within the past 12 months

• No other malignancies within the past 5 years except basal cell skin cancer, squamous cell skin cancer, carcinoma in situ of the cervix, or ductal or lobular carcinoma in situ of the breast

• No history of allergic reactions attributed to Chinese hamster ovary cell products, other recombinant human antibodies, or compounds of similar chemical or biologic composition to sorafenib tosylate, temsirolimus, or bevacizumab

• No history of bleeding diathesis or coagulopathy

• No condition that impairs ability to swallow pills

• No significant traumatic injury within the past 28 days

• No clinically significant cardiovascular disease, including any of the following:

• Uncontrolled hypertension

• Blood pressure must be ≤ 150/100 mm Hg on a stable antihypertensive regimen

• Myocardial infarction or unstable angina within the past 6 months

• New York Heart Association class II-IV congestive heart failure

• Serious cardiac arrhythmia requiring medication

• Unstable angina pectoris

• Peripheral vascular disease ≥ grade 2

• No serious, nonhealing wound, ulcer, or bone fracture

• No significant proteinuria

• If urine protein: creatinine ratio > 0.5, 24-hour urine protein must be < 1,000 mg

• No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parental antibiotics on day 0 or psychiatric illness or social situations that would preclude compliance with study requirements

• No concurrent prophylactic hematopoietic colony-stimulating factors

• No prior cytotoxic chemotherapy

• No prior antiangiogenic therapy including, but not limited to, sunitinib malate, ZD6474, or VEGF Trap

• No prior bevacizumab, mTOR inhibitors (including, but not limited to, temsirolimus), or sorafenib tosylate

• Prior thalidomide or interferon alfa allowed as adjuvant therapy or for metastatic disease

• More than 4 weeks since prior immunotherapy and recovered

• No more than 1 prior vaccine or cytokine-based immunotherapy regimen for metastatic disease

• More than 2 weeks since prior radiotherapy and recovered

• More than 4 weeks since prior major surgery or open biopsy

• No concurrent major surgery

• No concurrent or recent full-dose anticoagulants or thrombolytic agents (unless required to maintain patency of pre-existing or permanent indwelling IV catheters)

• No concurrent cytochrome P450 enzyme-inducing drugs including any of the following:

• Phenytoin

• Carbamazepine

• Phenobarbital

• Rifampin

• No concurrent combination antiretroviral therapy for HIV-positive patients

• No other concurrent anticancer therapies or investigational agents

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Keith Flaherty

Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00378703
Information obtained from ClinicalTrials.gov on March 26, 2013

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