Bevacizumab and Sorafenib in Treating Patients With Unresectable Stage III or Stage IV Malignant Melanoma

A Phase II, Pharmacokinetic (PK), Pharmacodynamic (PD) and Biological Correlative Study of the Efficacy and Safety of Dual Antiangiogenic Inhibition Using Bevacizumab and Sorafenib in Patients With Advanced Malignant Melanoma

This phase II trial is studying how well giving bevacizumab together with sorafenib works in treating patients with unresectable stage III or stage IV malignant melanoma. 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. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab and sorafenib may also stop the growth of melanoma by blocking blood flow to the tumor. Giving bevacizumab together with sorafenib may kill more tumor cells.

Study Overview

• Status: Completed
• Conditions: Stage IV Skin Melanoma; Recurrent Melanoma; Stage III Skin Melanoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Biological: Bevacizumab; Drug: Sorafenib Tosylate

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the clinical biologic activity of sorafenib tosylate and bevacizumab, defined as the sum of complete response, partial response, and prolonged stable disease for ≥ 16 weeks, in patients with unresectable stage III or stage IV malignant melanoma previously treated with at least 2 regimens of immunotherapy, cytokines, biologic therapy, or vaccine therapy or in previously untreated patients who are not appropriate candidates to receive aldesleukin-based treatment.

SECONDARY OBJECTIVES:

I. Evaluate the safety and tolerability of sorafenib tosylate and bevacizumab in these patients.

II. Evaluate the biologic activity of this regimen, in terms of time to progression, progression-free survival at 6 months, and overall survival, in these patients.

III. Describe significant pharmacokinetic interactions between bevacizumab and sorafenib tosylate.

IV. Characterize the pharmacodynamic relationships between the plasma concentration of sorafenib tosylate and bevacizumab and the effects of treatment on normal organ function and tumor tissue in these patients.

V. Identify predictive biomarkers of response to this regimen in these patients.

VI. Correlate changes in biological measurements with patient outcomes.

OUTLINE: This is an open-label, multicenter study.

Patients receive oral sorafenib tosylate on days 1-5, 8-12, 15-19, and 22-26 and bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days in the absence of unacceptable toxicity or disease progression. Blood samples and tumor biopsies are obtained periodically for pharmacokinetic and pharmacodynamic studies. Samples are examined by liquid chromatography, mass spectrometry, immunohistochemistry, gene expression analysis, DNA mutation analysis, and genomic analysis for biological markers.

After completion of study treatment, patients are followed for 4 weeks.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • Cancer Therapy and Research Center at The UT Health Science Center at San Antonio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Criteria:

• No substance abuse

• Histologically or cytologically confirmed melanoma:

  • Unresectable (stage III) or metastatic (stage IV) disease

• Measurable disease, defined as >= 1 lesion that can be accurately and serially measured in >= 1 dimension as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan:

  • Cutaneous lesions measuring >= 1 cm will be considered measurable disease
• No primary ocular melanoma

• No active CNS metastatic brain or meningeal tumors:

  • Prior CNS disease allowed provided it was definitely treated >= 3 months ago AND there is no CNS disease by MRI or CT scan within the past 4 weeks
  • No residual disease
• Life expectancy > 12 weeks
• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• WBC >= 3,000/mm3
• Absolute neutrophil count >= 1,500/mm3
• Platelet count >= 100,000/mm3
• Bilirubin =< 1.5 times upper limit of normal (ULN)
• AST and ALT =< 2.5 times ULN
• Creatinine =< 1.5 times ULN OR creatinine clearance >= 60 mL/min
• Serum amylase < 1.5 times ULN OR lipase < 1.5 times ULN
• Urine protein:creatinine ratio < 1.0 OR urine protein < 1,000 mg by 24-hour urine collection
• No significant traumatic injury in the past 28 days
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for >= 6 months after completion of study treatment
• No history of allergic reactions attributed to compounds of similar chemical or biological composition to sorafenib tosylate and bevacizumab or other agents used in the study
• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
• None of the following medical conditions:

New York Heart Association class III-IV congestive heart failure; Cardiac arrhythmias, including atrial fibrillation if not adequately controlled; Active coronary artery disease or ischemia (e.g., unstable angina, cerebrovascular accident, transient ischemic attack, or myocardial infarction within the past 6 months); Uncontrolled hypertension

• None of the following medical conditions: Clinically significant peripheral vascular disease; Evidence of bleeding diathesis or coagulopathy
• No seizure disorder requiring medication (e.g., antiepileptics)
• No prior or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis, or T1) or any cancer treated with intent to cure, rather than for palliation, < 3 years prior to study entry
• No more than 2 prior immunotherapy, cytokine therapy, biologic therapy, or vaccine therapy regimens (e.g., aldesleukin) for advanced or metastatic disease:
• (continued from above) Prior single-agent immunotherapy or combinations of immunotherapy as first treatment for advanced or metastatic disease allowed; Prior immunotherapy, cytokine therapy, biologic therapy, or vaccine therapy regimens in the adjuvant setting allowed
• No immunotherapy, cytokine therapy, biologic therapy, or vaccine therapy (e.g., aldesleukin) for advanced or metastatic disease within the past 4 weeks
• No prior organ allograft or stem cell transplantation
• No prior Ras-pathway inhibitors (including trastuzumab [Herceptin], farnesyl transferase inhibitors, or MEK inhibitors)
• No prior treatment with a drug that targets vascular endothelial growth factor (e.g., bevacizumab)
• No prior thalidomide or sorafenib tosylate
• No chemotherapy or radiotherapy within the past 4 weeks (6 weeks for nitrosoureas or mitomycin C) and recovered:

Radiographic evidence of progression required for prior irradiated lesions

• No major surgical procedure or open biopsy within the past 28 days
• No Hypericum perforatum (St. John's wort) or rifampin within the past 3 weeks
• Concurrent full-dose anticoagulants (e.g., warfarin) with PT INR > 1.5 allowed provided the following criteria are met:

Patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin

• AND (continued from above) Patient has no active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
• No other concurrent investigational agents
• No other concurrent anticancer agents or therapies
• No concurrent carbamazepine, phenytoin, or phenobarbital (drugs that induce CYP450 3A activity)
• No concurrent St. John's wort or rifampin
• No concurrent radiotherapy
• No concurrent major surgery
• No history of or suspected HIV infection or clinically significant hepatitis B or C
• No serious or nonhealing wound, ulcer, or bone fracture
• No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days
• No active clinically serious infections
• No dysphagia (difficulty swallowing)
• No medical, psychological, or social condition that may preclude study participation or evaluation of the study results

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm I; Patients receive oral sorafenib tosylate on days 1-5, 8-12, 15-19, and 22-26 and bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days in the absence of unacceptable toxicity or disease progression.

Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Biological: Bevacizumab; Given IV; Other Names: Avastin; Anti-VEGF; Anti-VEGF Humanized Monoclonal Antibody; Anti-VEGF rhuMAb; 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; Drug: Sorafenib Tosylate; Given orally; Other Names: BAY 54-9085; Nexavar; BAY 43-9006 Tosylate; sorafenib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response	Clinical biologic activity of treatment, defined as the sum of complete response, partial response, and prolonged stable disease for ≥ 16 weeks, upon treatment with the combination of sorafenib and bevacizumab, in patients with advanced metastatic melanoma previously treated with immunotherapy or in previously untreated patients who are not appropriate candidates to receive IL-2-based treatment. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started of the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability	Safety and tolerability of treatment, in terms of toxicity profile and incidence and rating of toxicity, according to NCI CTCAE v3.0 criteria.	6 months
Survival	Determined by time to progression, progression-free suvival, and overall survival.	6 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Muralidhar Beeram, Cancer Therapy and Research Center at The UT Health Science Center at San Antonio

Publications and helpful links

General Publications

• Mahalingam D, Malik L, Beeram M, Rodon J, Sankhala K, Mita A, Benjamin D, Ketchum N, Michalek J, Tolcher A, Wright J, Sarantopoulos J. Phase II study evaluating the efficacy, safety, and pharmacodynamic correlative study of dual antiangiogenic inhibition using bevacizumab in combination with sorafenib in patients with advanced malignant melanoma. Cancer Chemother Pharmacol. 2014 Jul;74(1):77-84. doi: 10.1007/s00280-014-2479-8. Epub 2014 May 10.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2006
• Primary Completion (Actual): September 1, 2009
• Study Completion (Actual): January 1, 2010

Study Registration Dates

• First Submitted: October 12, 2006
• First Submitted That Met QC Criteria: October 12, 2006
• First Posted (Estimate): October 13, 2006

Study Record Updates

• Last Update Posted (Actual): November 22, 2017
• Last Update Submitted That Met QC Criteria: October 19, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Skin Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Antibodies; Sorafenib; Immunoglobulins; Bevacizumab; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Immunoglobulin G; Endothelial Growth Factors
• Other Study ID Numbers: NCI-2009-00134 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA054174 (U.S. NIH Grant/Contract); U01CA069853 (U.S. NIH Grant/Contract); CDR0000502282; 05-25 (Other Identifier: Cancer Therapy and Research Center at The UT Health Science Center at San Antonio); 7200 (Other Identifier: CTEP)