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

The purpose of this study is to compare the effects of Paclitaxel/Carboplatin and Lonafarnib to those of Paclitaxel/Carboplatin in primary treatment of patients with epithelial 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.

Eligibility Criteria:
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