Medical Summary
The primary objective of this study is to determine the efficacy of the combination of VX-710 and paclitaxel in the treatment of patients with paclitaxel refractory ovarian cancer (including primary peritoneal or fallopian tube tumours of equivalent histology). Most patients with ovarian cancer are diagnosed with late stage disease and the overall five year survival ranges from 10-20%. Although many of these patients will have a remission following surgical debulking and adjuvant treatment, most patients will subsequently relapse. For patients who relapse during adjuvant treatment or shortly thereafter, at the time of relapse, the disease is characterized by a broad cross resistance to various treatments. Several retrospective studies have evaluated multi-drug resistance in ovarian cancer, however, differences in techniques used to identify the presence of PGP (P-glycoprotein), LRP (lung resistance protein) and MRP (multi-drug resistance-associated protein) make these studies difficult to compare. Results showing a correlation between MDR-1 (p-glycoprotein expression) and lower response rate to chemotherapy and a correlation between LRP positive tumours and shorter disease free interval and overall survival support the potential role of an agent such as VX-710 in restoring sensitivity to multi-drug resistant cells.
VX-710 is a dicitrate salt that restores drug sensitivity to multi-drug resistant cells by binding directly to P-glycoprotein to block efflux of cytotoxic drugs. VX-710 is also effective in restoring sensitivity of cell lines expressing MRP to the cytotoxic effects of doxorubicin, vincristine and etoposide. To date there have been less than 50 patients treated with the combination of VX-710 (24 hour infusion) with paclitaxel. The most common toxicities observed (> 10%) include the following: asthenia, tachycardia, anorexia, nausea, vomiting and vasodilatation. Also, there have been three patients with grade 4 neutropenia, one episode of neutropenia with sepsis, one episode of elevated liver enzymes and one episode of chemical phlebitis when the VX-710 was administered peripherally. Pharmacokinetic data show that there is a significant reduction in paclitaxel clearance when administered with a 24 hour infusion of VX-710 at 120 mg/m2/hour in combination with paclitaxel doses of 60 and 80 mg/m². The co-administration of 60 mg/m2 or 80 mg/m² of paclitaxel with VX-710 (120 mg/m2/hour) resulted in an AUC similar to that reported when paclitaxel is administered alone at doses of 135/m² or 175 mg/m² respectively.. Patients in this study will have demonstrated a clinical resistance to paclitaxel treatment through documentation of progressive disease while receiving paclitaxel or within 4 months of completing first or second line paclitaxel treatment. Patients will be treated with VX-710 120 mg/m²/hour by continuous infusion for 24 hours. Paclitaxel will be administered via a 3 hours infusion at 4 hours after initiation of the VX-710 infusion. VX-710 will be administered through a central venous catheter. All patients will have pharmacokinetic sampling performed during their first cycle of treatment to further establish the plasma pharmacokinetics of paclitaxel when administered in combination with VX-710.

References:

1. Holzmayer TA, Hilsenbeck S, et al. Clinical correlates of MDR-1 (P-glycoprotein) gene expression in ovarian and small cell lung carcinomas. J. Natl. Cancer Institute 1992, 85:1460-1486.
2. Izquierdo MA, Van Der Zee, Ate GJ et al. Drug resistance associated marker LRP for prediction of response to chemotherapy and prognoses in advanced ovarian carcinoma. J. Natl Cancer Institute 1995, 87 (16):1230-1237.
3. Huizing MT, Kenny ACF, Rosing H, et al. Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum pretreated ovarian cancer patients. J. Clin Oncol. 1993, 11:2127-2135.

Lay Summary
For some tumors, after multiple courses of chemotherapy the tumor is no longer responsive to treatment. This is due to a biochemical change in the individual tumor cells called resistance. This study is designed to test the ability of a new compound to block this resistance phenomena. One of the eligibility criteria requires that the patientŐs most recent treatment include Taxol. PatientŐs will be required to have blood tests and a CT scan prior to starting treatment. Since this treatment requires the administration of both Taxol and VX-710 and several blood samples which need to be drawn within the first 24 hours, patients will be required to have placement of a port-a-cath (a minor surgical procedure where permanent access is made to a central vein in the upper chest area). Patients must remain in hospital overnight for the first treatment. Subsequent treatments are on an out-patient basis ie., no overnight stay is required. The treatment is given every three weeks. Patients are required to return to clinic every week for a blood test and to assess any side effects that may be experienced. CT scans will be repeated every 6 weeks to determine whether or not the tumor demonstrates a response.

1. Patients must have histologically confirmed epithelial ovarian cancer that is metastatic or locally advanced. Patients with primary peritoneal or fallopian tube tumors of equivalent histology are also eligible. Patients must have disease that is unsuitable for definitive surgical resection.
2. Patients must be paclitaxel-refractory as defined by progressive disease after a minimum of 2 cycles of paclitaxel treatment or patients whose ovarian cancer recurs within 4 months after stopping paclitaxel treatment for complete response (CR) or partial response (PR).
3. Patients must not have received more than 2 complete courses of chemotherapy treatment. If 2 courses of paclitaxel treatment have been completed or if patients received a non-paclitaxel containing regimen as a first-line treatment, patients would be eligible only if recurrence occurs within 4 months of completion of the second line treatment with paclitaxel.
4. Patients must have bi-dimensional measurable disease. Minimum size of indicator lesion must be as follows:
   Chest X-Ray >= 1 x 1 cm
   CT Scan >= 2 x 2 cm
   Skin lesion or lymph node >= 1 x 1 cm
5. Documented progressive disease/recurrence at the time of protocol entry.
6. ECOG performance status must be 0, 1 or 2.
7. Age > 18 years.
8. Informed consent must be obtained.
9. Laboratory values obtained within 14 days prior to registration:
   Absolute granulocytes >= 2.0 x 10⁹/L
   Platelets >=100 x 10⁹/L
   Serum creatinine >= 1.5 x UNL
   Bilirubin >= 1.5 x UNL
   AST >=2.0 x UNL (<= 3 x UNL if documented liver metastases)

1. Patients of childbearing potential not using medically approved contraceptive methods or pregnant women. A negative pregnancy test (urine or serum) must be documented at baseline for women of childbearing potential. Patients may not breast-feed while on study.
2. Patients with an unstable or serious concurrent medical condition are excluded. These include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 6 months) myocardial infarction, major seizure disorder, grade 3 neuropathies, spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.
3. Patients will be excluded if they are taking any of the following drugs at the time of enrollment:
   - Drugs that interfere with Cytochrome P450