Efficacy and Safety Study of Sorafenib With Topotecan in Patients With Platinum-resistant Recurrent Ovarian Cancer (TRIAS 2009)
It is assumed, that the patients of the standard arm show a median progression-free survival time of 4.4 months those of the experimental arm of at least 6.9 months. Assuming a recruitment period of 18 months and follow-up for at least 12 months a total sample size of 174 patients is required (two-sided, α=0.05, 80% power). To account for 5% drop-outs 184 patients will be randomized.
A Data Monitoring and Safety Board (DMSB) will be established. This board will evaluate the safety profile of the drug combination after 6 patients and after 12 patients have received 1 cycle of treatment.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Official Title:||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|
- Primary objective: Determination of the progression-free survival (PFS) of patients treated with topotecan and sorafenib versus topotecan and placebo [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]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
- Overall survival [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]Overall survival (OS) of a patient being defined as the time in months from start of the first therapy cycle to death or the end of study
- Response rate [ Time Frame: 18 months ] [ Designated as safety issue: No ]Response rates, i.e. percentage of patients showing overall response (CR+PR), progression or stable disease
- Duration of response [ Time Frame: 18 months ] [ Designated as safety issue: No ]Duration of response is the time in months from first assessment of CR or PR until the first date of PD or death
- Time to progression (TTP) [ Time Frame: 18 months ] [ Designated as safety issue: No ]Time to progression (TTP) of a patient being defined as the time in months from start of the first therapy cycle until PD is observed
- Safety and tolerability [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
Incidence and type of AE in terms of:
- All AE,
- Related AE,
- Related SAE,
- NCI-CTC grade 3 and 4 AE,
- Related NCI-CTC grade 3 and 4 AE,
- AE leading to treatment discontinuation,
- Incidence of, and reason for, deaths
- Assessment of quality of life over time as defined by EORTC-QLQ C 30 and Ovar 28 questionnaire [ Time Frame: 18 months ] [ Designated as safety issue: No ]Assessment of Quality of life over time as defined by EORTC-QLQ C 30 and Ovar 28 questionnaire and, in case of participation in the sub-study, FOSI questionnaire, respectively
|Study Start Date:||January 2010|
|Study Completion Date:||February 2015|
|Primary Completion Date:||February 2015 (Final data collection date for primary outcome measure)|
Topotecan 1,25 mg/m²/d administered as an i.v. infusion over 30 minutes once daily on days 1-5, every 21 days and Sorafenib 400 mg orally twice daily (total daily dose 800 mg) administered
Other Name: Nexavar®
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01047891
|Charité Campus Virchow-Klinikum|
|Berlin, Germany, 13355|
|Principal Investigator:||Jalid Sehouli Sehouli, Professor||Charité Campus Virchow-Klinikum, Berlin|