Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Related Information
Registry Information

Alternate Title

Sorafenib and Bevacizumab in Treating Patients With Refractory, Metastatic, or Unresectable Solid Tumors

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Treatment Closed 18 and over NCI NCI-05-C-0022 6750, NCI-6750, NCT00098592

Special Category: NCI Web site featured trial

Objectives

Primary

1. Determine the maximum tolerated dose of sorafenib and bevacizumab in patients with refractory, metastatic, or unresectable solid tumors.
2. Determine the safety and toxicity of this regimen in these patients.
3. Determine biochemical changes in the Ras-Raf-MAPK and VEGF signal transduction pathways in tumor and stromal cells from patients treated with this regimen.

Secondary

1. Determine the pharmacokinetic effects of this regimen in these patients.
2. Correlate genetic mutations in Ras and Raf in tumor tissue with clinical events in patients treated with this regimen.
3. Correlate changes in VEGF and other angiogenic cytokines in plasma with clinical outcomes of patients treated with this regimen.

Entry Criteria

Disease Characteristics:

• Histologically confirmed solid tumor malignancy
  • Metastatic, refractory, or unresectable disease
  • No known standard curative therapies exist or are no longer effective



• At least 1 lesion amenable to biopsy (part 2 only)



• No squamous cell carcinoma of the lung



• No history of any type of primary lung cancer with hemoptysis



• No brain metastases
  • Prior remote CNS metastases allowed at the discretion of the investigator provided patient has undergone curative therapy (e.g., radiotherapy, gamma knife therapy, or surgery) and has remained disease free for ≥ 2 years



• Hormone receptor status:
  • Not specified

Prior/Concurrent Therapy:

Biologic therapy

• At least 4 weeks since prior biologic therapy
• At least 8 weeks since prior monoclonal antibody therapy
• No prior bevacizumab

Chemotherapy

• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas, mitomycin, or carboplatin)

Endocrine therapy

• Patients with prostate cancer must continue to receive luteinizing hormone-releasing hormone agonist unless orchiectomy has been performed
• More than 4 weeks since prior hormonal therapy

Radiotherapy

• See Disease Characteristics
• At least 4 weeks since prior radiotherapy

Surgery

• See Endocrine therapy
• See Disease Characteristics
• More than 4 weeks since prior surgery

Other

• Recovered from all prior therapy
• At least 7 days since prior and no concurrent complementary therapy
• At least 7 days since prior antibiotic therapy for active infection
• No prior sorafenib
• No concurrent therapeutic anticoagulation therapy (e.g., warfarin, heparin, or heparinoids)
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent complimentary or alternative therapy unless approved by the investigator
• No concurrent over-the-counter agents unless approved by the investigator

Patient Characteristics:

Age

• 18 and over

Sex

• Male or female

Menopausal status

• Not specified

Performance status

• ECOG 0-1

Life expectancy

• More than 3 months

Hematopoietic

• WBC ≥ 3,000/mm³
• Absolute neutrophil count ≥ 1,200/mm³
• Platelet count ≥ 100,000/mm³
• No evidence of bleeding diathesis

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN
• PTT < 1.25 times ULN
• PT < 1.25 times ULN

  OR

• INR < 1.25 times ULN

Renal

• Creatinine ≤ 1.5 mg/dL

  OR

• Creatinine clearance ≥ 45 mL/min
• Urine protein:creatinine ratio < 0.5 OR urine protein < 1,000 mg on 24-hour urine collection

Cardiovascular

• No thrombotic or embolic event within the past 6 months, including any of the following:
  • Cerebrovascular accident
  • Transient ischemic attack
  • Unstable angina pectoris
  • Myocardial infarction
  • Deep vein thrombosis
• No New Heart Association class II-IV symptomatic congestive heart failure
• No cardiac arrhythmia
• No hypertension, defined as systolic blood pressure (BP) > 140 mm Hg or diastolic BP > 90 mm Hg despite optimal medical management

Pulmonary

• See Disease Characteristics
• No pulmonary embolism within the past 6 months
• No hemoptysis

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 2 months after study participation
• Amylase and lipase normal
• Able to swallow tablets
• No ongoing or active infection
• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
• No history of high-grade varices
• No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscesses within the past 28 days
• No serious nonhealing wound, including wounds healing by secondary intention
• No acute or nonhealing ulcers
• No bone fracture within the past 3 months
• No psychiatric illness or social situation that would preclude study compliance
• No other uncontrolled illness

Expected Enrollment

A total of 62 patients will be accrued for this study.

Outcomes

Safety and toxicity by physical exam, history, patient diary, blood pressure (BP) monitoring, and clinical blood and urine tests at baseline and every 2 weeks (BP daily)
Resp. to tx at max. tol. dose of sorafenib+bevacizumab by biochem. chges in Ras-Raf-MAPK & VEGF signal transduction pathways by tumor lys. microarray of biopsied tumor & stromal cells at baseline, 2 wks after monotx, and after 2 wks of combo tx

Pharmacoproteomic effect of combotx on mol. sig. events compared to monotx focused on angiogenesis, survival, & apoptotic pathways by tumor lys. array of biopsied tumor and stroma at baseline, after 2 wks of monotx, and after 2 wks of combotx
Pharmacokinetic effects as measured in serum samples immediately pre-dose, and at 0.25, 0.50, 1, 2, 4, 6, 8, 12, and 24 hours after ingestion of study treatment day 1 of courses 1 and 2 for cohort 2
Pharmacogenomics evaluation of sorafenib by genotyping of CYP3S4/5 according to the Medical Oncology Clinical Research Unit (MOCRU) Clinical Pharmacokinetics core standard operating procedure (SOP) at baseline
Correlation of identified genetic tumor mutations in Ras and Raf with clinical events as measured by tumor lysates array analysis at baseline, after 2 weeks of monotherapy, and after 2 weeks of combination therapy
Correlation of changes in VEGF and other angiogenic cytokines in plasma with clinical outcomes at baseline, every 2 weeks for 2 months, and then monthly
Tumor vascularity as evaluated by Dynamic Contrast Enhanced Magnetic Resonance Imaging at baseline and weeks 2, 4, and 6
Tumor vascularity as evaluated by positron-emission tomography at baseline and weeks 2 and 6

Outline

This is an open-label, dose-escalation study followed by a randomized study.

• Part 1: Patients receive oral sorafenib once daily on days 1-28 OR once daily on days 1-5, 8-12, 15-19, and 22-26 and bevacizumab IV over 30-90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

  Cohorts of 3-6 patients receive escalating doses of sorafenib and bevacizumab until the maximum tolerated dose (MTD) of the combination is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD.




• Part 2: Patients are randomized to 1 of 2 treatment arms for course 1.
  • Arm I: Patients receive oral sorafenib at the MTD once daily on days 1-21.
  
  
  
  • Arm II: Patients receive bevacizumab IV at the MTD over 30-90 minutes on days 1 and 15.
  
  
  

  Beginning in course 2, all patients receive oral sorafenib twice daily on days 1-21 and bevacizumab IV on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Azad NS, Posadas EM, Kwitkowski VE, et al.: Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol 26 (22): 3709-14, 2008.[PUBMED Abstract]

Posadas EM, Kwitkowski V, Liel MS, et al.: Combinatorial signal transduction inhibition against vascular endothelial growth factor receptor (VEGFR): early results from a phase I study of BAY 43-9006 (sorafenib) with bevacizumab in patients with advanced solid tumors. [Abstract] American Association for Cancer Research: 96th Annual Meeting, April 16-20, 2005, Anaheim/Orange County, CA. 46: A-LB-213, 2005.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Elise Kohn, MD, Principal investigator		Ph: 301-402-2726

Related Information

Featured trial article

Registry Information
Official Title		A Phase I Trial of BAY 43-9006 (Sorafenib) and Bevacizumab in Refractory Solid Tumors With Biologic and Proteomic Analysis
Trial Start Date		2004-12-20
Trial Completion Date		2007-07-08 (estimated)
Registered in ClinicalTrials.gov		NCT00098592
Date Submitted to PDQ		2004-10-22
Information Last Verified		2008-04-06