Sorafenib in Treating Patients With Metastatic, Locally Advanced, or Recurrent Sarcoma

A Multicenter Phase II Study of Sorafenib (BAY43-9006) in Non-GIST Sarcomas

This phase II trial is studying how well sorafenib works in treating patients with metastatic, locally advanced, or recurrent sarcoma. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Study Overview

• Status: Completed
• Conditions: Uterine Carcinosarcoma; Ovarian Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Uterine Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Uterine Sarcoma; Adult Angiosarcoma; Adult Epithelioid Sarcoma; Adult Leiomyosarcoma; Adult Synovial Sarcoma; Adult Malignant Fibrous Histiocytoma; Adult Neurofibrosarcoma; Uterine Leiomyosarcoma
• Intervention / Treatment: Drug: sorafenib tosylate

Detailed Description

PRIMARY OBJECTIVES:

I. The primary endpoint is the response rate (CR+PR) for each stratum of sarcoma patients treated with sorafenib as defined by RECIST.

SECONDARY OBJECTIVES:

I. Progression-free survival (defined as CR + PR + SD, assessed at 3 months or 6 months).

II. Overall survival. III. Pharmacokinetics of sorafenib in this patient population (all sites will participate).

IV. Frequency of B-raf mutations in the patients' sarcomas treated as part of this study and correlation with response or resistance to sorafenib (all sites will participate).

V. Ras-raf kinase pathway activation in pre-treatment existing tumor specimens (paraffin section immunohistochemistry; all sites will participate).

VI. At MSKCC only: Pre and post treatment specimen changes in downstream events of ras signaling, specifically inhibition of ERK phosphorylation. Only patients with angiosarcoma and MPNST will undergo biopsy (up to 10 patients).

VII. At MSKCC only: Circulating Endothelial Cells (CECs), VE-cadherin levels, and soluble protein levels (VEGF, bFGF, endostatin) as a measures of angiogenesis before and after starting sorafenib therapy.

OUTLINE: This is an open-label, non-randomized, multicenter study. Patients are stratified according to sarcoma histology (angiosarcoma vs malignant peripheral nerve sheath tumor vs leiomyosarcoma [closed to accrual as of 11/29/06] vs high-grade undifferentiated pleomorphic sarcoma [i.e., malignant fibrous histiocytoma (including myxofibrosarcoma)(closed to accrual as of 11/29/06)] vs synovial sarcoma (closed to accrual as of 11/29/06) vs all other types of sarcoma).

Patients receive oral sorafenib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study, patients are followed at 4 weeks.

• Study Type: Interventional
• Enrollment (Actual): 147
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically or cytologically confirmed sarcoma, including any of the following neoplastic subtypes:

  • Giant hemangioma
  • Angiosarcoma (including epithelioid hemangioendothelioma)
  • Malignant peripheral nerve sheath tumor
  • Leiomyosarcoma (closed to accrual as of 11/29/06)
  • High-grade undifferentiated pleomorphic sarcoma (i.e., malignant fibrous histiocytoma [including myxofibrosarcoma]) (closed to accrual as of 11/29/06)
  • Synovial sarcoma (closed to accrual as of 11/29/06)
  • Carcinosarcoma (closed to accrual as of 11/29/06)
• Metastatic, locally advanced, or locally recurrent disease

• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan

  • Lesions in a previously irradiated area may be considered measurable provided there is evidence of subsequent disease progression that cannot be attributed to necrosis or bleeding
• No gastrointestinal stromal tumor
• No known brain metastases
• Performance status - ECOG 0-2
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• No evidence of bleeding diathesis
• Bilirubin ≤ 1.5 mg/dL
• INR ≤ 1.5
• AST and ALT ≤ 2.5 times upper limit of normal
• Creatinine ≤ 1.5 mg/dL
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• No uncontrolled hypertension
• No history of allergic reaction to compounds of similar chemical or biologic composition to sorafenib
• No known HIV positivity
• No active or ongoing infection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No psychiatric illness or social situation that would preclude study compliance
• No swallowing dysfunction that would preclude the swallowing of tablets
• Other malignancies allowed provided sarcoma is the primary disease requiring treatment
• No other uncontrolled illness

• No more than 1 prior chemotherapy regimen for recurrent or metastatic disease (≤ 3 regimens for angiosarcoma or malignant peripheral nerve sheath tumor)

  • Adjuvant chemotherapy completed > 1 year prior to study entry is not considered a line of prior treatment
• More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• At least 3 weeks since prior radiotherapy

• Recovered from prior antitumor therapy

  • Alopecia allowed
• No prior sorafenib
• No prior small molecule inhibitors of MAPK signaling intermediates

• No concurrent therapeutic anticoagulation

  • Prophylactic anticoagulation (i.e., low-dose warfarin) of venous or arterial devices allowed provided requirements for PT, INR, or PTT requirements are met
• No other concurrent investigational agents
• No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital)
• No concurrent rifampin or Hypericum perforatum (St. John's wort)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm I; Patients receive oral sorafenib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: sorafenib tosylate; Given orally; Other Names: BAY 43-9006; BAY 43-9006 Tosylate Salt; BAY 54-9085; Nexavar; SFN

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST	A 5% response rate is considered not promising, a 20% response rate is considered promising. For each stratum, the response rate will be estimated and a confidence interval will be constructed.	Up to 4 weeks

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Robert Maki, Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (ACTUAL): March 1, 2011
• Study Completion (ACTUAL): March 1, 2011

Study Registration Dates

• First Submitted: October 25, 2005
• First Submitted That Met QC Criteria: October 25, 2005
• First Posted (ESTIMATE): October 27, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): May 23, 2014
• Last Update Submitted That Met QC Criteria: May 7, 2014
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Neuromuscular Diseases; Neoplasms, Nerve Tissue; Peripheral Nervous System Diseases; Nervous System Neoplasms; Neoplasms, Complex and Mixed; Neoplasms, Connective Tissue; Neoplasms, Vascular Tissue; Neoplasms, Muscle Tissue; Nerve Sheath Neoplasms; Peripheral Nervous System Neoplasms; Neoplasms, Fibrous Tissue; Fibrosarcoma; Neurofibroma; Sarcoma; Recurrence; Carcinosarcoma; Leiomyosarcoma; Hemangiosarcoma; Neurofibrosarcoma; Sarcoma, Synovial; Histiocytoma, Malignant Fibrous; Histiocytoma; Histiocytoma, Benign Fibrous; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Sorafenib
• Other Study ID Numbers: NCI-2012-01469 (REGISTRY: CTRP (Clinical Trial Reporting Program)); N01CM62201 (U.S. NIH Grant/Contract); P30CA008748 (U.S. NIH Grant/Contract); N01CM62206 (U.S. NIH Grant/Contract); NCI-7060; CDR0000449962; MSKCC-05081; 05-081 (OTHER: Memorial Sloan-Kettering Cancer Center); 7060 (OTHER: CTEP)