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
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
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.
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.
Inclusion Criteria:
Patients with histologically confirmed epithelial ovarian cancer, primary peritoneal carcinomatosis or fallopian tube cancer
Patients must have platinum resistant (relapse-free interval < 6 months of a platinum-containing primary or secondary therapy) or platinum refractory (progression during primary or secondary platinum treatment) disease defined by measurable disease according to RECIST or elevated CA-125 level according the GCIG-criteria.
Definition of relapse: Demonstration of measurable or non-measurable tumour according to RECIST criteria by an imaging procedure (where applicable before relapse surgery) or increase in the tumour marker CA-125 to twice the upper laboratory value of normal for the hospital or histological confirmation of tumour relapse by biopsy or surgery.
No more than 2 prior treatment regimens for recurrent epithelial ovarian cancer.
Elevated CA-125-value before study entry in order to assess the response according the GCIG-criteria (see below). Patients without elevated CA-125 may be enrolled if they show a measurable or not-measurable disease (according RECIST) evaluated by imaging techniques (measurable disease - at least one unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan) or histologically or cytologically confirmed relapse
ECOG Performance Status of 0 or 1
≥ 18 years age
The patient must be recovered from a prior operation. The operation must be performed at least 4 weeks prior to start of study drug,
Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening
Life expectancy of at least 12 weeks
Signed and dated written informed consent before the start of specific protocol procedures.
Exclusion Criteria:
History of cardiac disease: congestive heart failure >NYHA class 2; active coronary artery disease (CAD) or myocardial infarction within the past 6 months (MI more than 6 months prior to study entry is allowed); cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) or uncontrolled arterial hypertension with systolic blood pressure >160 mmHg or diastolic blood pressure > 90 mm Hg despite optimal treatment
Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer curatively treated > 5 years prior to study entry
Prior radiological or clinical evidence of CNS metastases including previously treated, resected, or asymptomatic brain lesions or leptomeningeal involvement by head CT scan or MRI
Known or suspected hypersensitivity reaction to topotecan or any ingredient of topotecan or sorafenib or any ingredient of sorafenib
Active clinically serious infections (> grade 2 NCI-CTC version 3.0)
History of HIV infection or chronic hepatitis B or C
History of organ allograft
Patients with history of colon perforation
Patients with history of colitis or neutropenia colitis
Patients with evidence or history of bleeding diathesis
Serious non healing wound, fracture or ulcer
Patients undergoing renal dialysis
Patients unable to swallow oral medications
Significant disease which, in the investigator's opinion, would exclude the patient from the study
Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
Patients with seizure disorder requiring medication (such as steroids or anti-epileptics)
Medical or psychological conditions that would not permit the subject to complete the study or sign informed consent
Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study
Legal incapacity or limited legal capacity
Participation in another clinical study with experimental therapy within the 30 days before start of treatment
Subjects housed in an institution on official or legal orders.
Excluded therapies and medications, previous and concomitant:
Patients with prior therapy containing topotecan
Patients with prior therapy containing Avastin or other VEGFR TK1
Any other anticancer chemotherapy or immunotherapy or investigational drug therapy outside of this trial during the study or within 4 weeks prior to study entry.
Radiotherapy during study or within 4 weeks prior to start of study drug and prior radiotherapy of > 25% of the bone marrow (exception: palliative radiotherapy of non-target lesions or pain therapy or local bone irradiation)
Autologous bone marrow transplant or stem cell rescue within 4 months of study