A phase II study of sorafenib in advanced uterine carcinoma/carcinosarcoma: A trial of the Chicago, PMH, and California Phase II Consortia

Abstract

Objectives

To determine the efficacy and safety of single agent sorafenib, an oral multi-targeted tyrosine kinase inhibitor, in patients with advanced uterine carcinoma and carcinosarcoma.

Methods

This multi-institutional non-randomized phase II trial enrolled two cohorts: patients with uterine carcinoma (cohort A) and uterine carcinosarcoma (cohort B). Eligibility criteria included measurable disease, 0–1 prior chemotherapy regimens, and ECOG performance status ≤ 2. Sorafenib at a dose of 400 mg was administered orally twice daily. A cycle was defined as 28 days. Objective tumor response was the primary endpoint and was assessed following every two cycles.

Results

Fifty-six patients (40 with carcinoma, 16 with carcinosarcoma) were enrolled between March 2005 and August 2007. Two (5%) patients with uterine carcinoma had a partial response (PR) and 17 (42.5%) achieved stable disease (SD). Five had SD lasting at least 4 months. The 6-month progression-free survival rate for patients with carcinoma was 29%, and the median overall survival was 11.4 months. No patients with carcinosarcoma had an objective response. Four (25%) had SD, and one had SD lasting 18 months. The 6-month progression-free survival rate was 13%, and the median overall survival was 5.0 months. Grade 3/4 drug related toxicities included: hypertension (13%), hand-foot syndrome (13%), hypophosphatemia (7%), anemia (5%), rash (5%), diarrhea (5%), thrombosis (5%), fatigue (5%) and bleeding (5%).

Conclusion

Sorafenib had minimal activity in patients with uterine carcinoma. Predictive factors for potential benefit are needed.

Introduction

Uterine cancer is the most common gynecologic malignancy in the United States with an estimated 40,100 new cases and 7470 deaths in 2008 [1]. The overall death rate is low as most endometrial cancer is diagnosed at an early stage when surgical resection is often curative. However, the median survival of women with recurrent or advanced endometrial carcinoma is only approximately one year, [2] and there is a substantial need for improved therapies in the treatment of advanced or recurrent disease. Although testing of conventional cytotoxics has been less exhaustive in endometrial cancer than in ovarian cancer, only taxanes have produced response rates over 20% in the setting of second-line systemic therapy, and these agents are now generally used in the first-line setting [3], [4].

Uterine carcinosarcomas (also known as malignant mixed Mullerian tumors) are less common but more aggressive than typical (endometrioid) uterine carcinomas. In the past, carcinosarcomas were treated as uterine sarcomas, but recent evidence suggests that these tumors are metaplastic carcinomas [5]. It is not clear whether they respond differently to systemic therapy than uterine carcinomas, and we elected to evaluate them in a parallel cohort.

There is preclinical evidence that the Ras/Raf/Mek/MAP pathway has a role in uterine cancer [6]. In addition, increased levels of VEGF and angiogenic markers are associated with poor outcomes in endometrioid endometrial carcinoma patients [7], and antiangiogenic agents appear to have activity in preclinical models of endometrial cancer [8]. Sorafenib is an oral agent that inhibits Raf-1 (wild-type) and mutant B-Raf, and multiple receptor tyrosine kinases, including vascular endothelial growth factor receptors. It is currently FDA-approved for use in renal cell carcinoma and hepatocellular carcinoma. This multicenter phase II study investigated the clinical activity and safety of sorafenib in patients with advanced uterine carcinoma and carcinosarcoma.