Comparison of Paclitaxel/Carboplatin and Lonafarnib to Paclitaxel/Carboplatin for First-line Treatment of Ovarian Cancer

Today the standard therapy for patients with advanced ovarian carcinoma is paclitaxel and carboplatin. Lonafarnib is a farnesyl transferase inhibitor (FTI) that is active against a broad spectrum of tumor cell lines in vitro and tumor xenografts in nude mice. Lonafarnib has single-agent antitumor activity as well as enhanced activity in combination with taxanes in a number of tumor cell lines and in vivo models.

Inclusion criteria

• Previously untreated patients with a histologically confirmed diagnosis of cancer of the ovary, the fallopian tube or extra-ovarian papillary serous tumors FIGO stage IIB-IV, regardless of measurable or non-measurable disease
• Age >= 18 years
• ECOG performance status <= 2
• Life-expectancy of at least 6 months
• Adequate bone marrow, renal and hepatic function:

WBC >= 3.0 x 10^9/l; Neutrophils (ANC) >= 1.5 x 10^9/l; Platelets >= 100 x 10^9/l; Hemoglobin > 6 mmol/l (> 10.0 g/dl); Bilirubin <= 1 x upper limit of normal range; Alkaline phosphatase <= 2.5 x upper limit of normal range; estimated GFR >= 50 ml/min according to Jelliffe or Cockroft-Gault formula

• Patients who have given their signed and written informed consent to participate in the trial after fully understanding the implication and constraints of the protocol
• Patients must be geographically accessible for treatment and follow-up
• Time between definitive surgery and randomization into the study <= 6 weeks

Exclusion criteria

• Ovarian tumors of low malignant potential (borderline tumors)
• Non-epithelial ovarian or mixed epithelial/nonepithelial tumors (e.g. Mixed Mullerian tumors)
• Patients who have received previous chemotherapy or radiotherapy
• Prior treatment with FT inhibitors
• Patients with a prior diagnosis of any malignancy not cured by surgery alone less than 5 years before study entry (except in situ carcinoma of the cervix or adequately treated basal cell carcinoma of the skin)
• Complete bowel obstruction or the presence of symptomatic brain metastases
• Concurrent severe medical problems unrelated to malignancy which would significantly limit full compliance with the study or expose the patient to extreme risk or decreased life expectancy
• Patients with a history of seizure disorder or central nervous system disorders; pre-existing motor or sensory neurologic pathology or symptoms > NCI grade 1
• History of congestive heart failure (NYHA Classification > 2, even if medically controlled.
• History of clinical and electrocardiographically documented myocardial infarction within the last 6 months.
• History of atrial or ventricular arrhythmias (>= LOWN II)
• Patients with significant Fridericia QTc (QTcF) prolongation at Baseline (ie. QTcF >= 470 msec)
• Patients with severe active infection
• Patients with a history of severe hypersensitivity reactions to products containing Cremophor EL (cyclosporin or vitamin K) and/or patients with known hypersensitivity to compounds chemically related to Carboplatin and Paclitaxel
• Women with childbearing potential and who are sexually active and unwilling to use a medically acceptable method of contraception (oral contraceptive, diaphragm with spermicide, intrauterine device, condom with spermicide)
• Women who are pregnant or breast feeding
• Administration of other anticancer therapy or simultaneous chemotherapeutic and/or hormonal drugs, or radiotherapy during the study treatment period (except: hormonal replacement therapy and/or steroid antiemetics)
• Patients who are participating in any other clinical study
• Dementia or significantly altered mental status that would prohibit the understanding and giving of informed consent