A Randomized, Double-blind, Placebo Controlled, Multicenter Phase II Study to Assess the Efficacy and Safety of Sorafenib Added to Standard Treatment With Topotecan in Patients With Platinum-resistant Recurrent Ovarian Cancer
Ovarian cancer continues to be a leading cause of cancer-related deaths in women and is the
leading cause of deaths attributed to gynecologic malignancies. Because ovarian cancer is
usually asymptomatic in its early stages, the disease often has spread outside of the pelvic
region at the time of diagnosis and requires debulking surgery followed by systemic
chemotherapy. First-line chemotherapy involves platinum-based treatments, including the
widely adopted regimens of cisplatin/paclitaxel, carboplatin/paclitaxel, and single-agent
carboplatin. Although these regimens yield relatively satisfactory tumor response rates, the
majority of patients experience disease recurrence and receive additional treatments. For
such patients, a number of antitumor agents with novel mechanisms of action (topotecan,
gemcitabine, pegylated liposomal doxorubicin, docetaxel, etoposide) have been applied, in
addition to retreatment with platinum, with the goal of re-establishing remission or disease
control, minimizing disease-related symptoms, improving quality of life, and extending
patient survival. Of these agents, topotecan (Hycamtin®; GlaxoSmithKline) is one of the
best-characterized agents in the recurrent setting.
Topotecan is an S-phase 1-dependent cytotoxic agent that targets the topoisomerase I enzyme
and exhibits broad activity in solid tumors and is approved for the treatment of recurrent
ovarian cancer in US and in most western countries.
Data from preclinical and clinical studies reported in the last 2 years demonstrate the
importance of several proangiogenic factors in the tumorigenesis and prognosis of ovarian
cancer, suggesting possible new targets for antiangiogenic therapy. Once-daily oral
treatment with Sorafenib produces broad spectrum antitumor efficacy in preclinical tumor
models including also xenograft models of ovarian carcinoma. Preliminary antitumor activity
has been reported in single ovarian cancer patients in several phase I and phase II studies.
Most promising strategy in the therapy of advanced and recurrent ovarian cancer seems to be
the combination of cytotoxic agents and targeted therapies. Furthermore an oral therapy to
achieve and maintain long term tumor control seems to be very attractive.
Therefore Sorafenib and Topotecan would make a rational therapeutic strategy for combination
in recurrent ovarian cancer.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
Primary objective: Determination of the progression-free survival (PFS) of patients treated with topotecan and sorafenib versus topotecan and placebo
The primary target value of this study is the comparison of the median progression-free survival time between the two study arms. Progression-free survival time (PFS) of a patient is defined as the time in months from start of the first therapy cycle until PD or death is observed
Jalid Sehouli Sehouli, Professor
Charité Campus Virchow-Klinikum, Berlin
Germany: Federal Institute for Drugs and Medical Devices