Medical Summary
This protocol is an open label multicenter phase II study of VX-710 in combination with paclitaxel in women with advanced carcinoma of the breast that is refractory to paclitaxel.
Breast cancer is a disease that usually responds to chemotherapy, however, the cure rate is suboptimal and is often due to tumor cell resistance to the drugs. Multidrug resistance (MDR) is a principle reason for treatment failure. Paclitaxel is an effective treatment for women with metastatic breast cancer, however, resistance to paclitaxel therapy or relapse following treatment is the usual outcome for patients with advanced disease. Higher levels of MDR protein have previously been reported in biopsy samples from paclitaxel refractory patients compared to low or undetectable levels in patients who responded to paclitaxel treatment. VX-710 is a new compound that restores drug sensitivity to multidrug resistant tumor cells. VX-710 functions by blocking efflux of cytotoxic drugs and is not cytotoxic alone at levels necessary to effect reversal of resistance.
A phase I/II study of VX-710 with paclitaxel currently underway in patients with advancing cancer has established the dose range for this study. Adverse events experienced to date include headache, vomiting, nausea, constipation, diarrhea, fever, anemia, leucopenia, anorexia, jaundice, low blood pressure and rapid heart beat.
The study is designed to test the ability and safety of VX-710, given in combination with paclitaxel, to overcome clinical drug resistance in women with advanced breast carcinoma. The study population consists of patients who have previously been treated with paclitaxel followed by progressive disease within 3 months of enrollment. VX-710 will be administered by intravenous infusion over a 24-hour period beginning 4 hours prior to the initiation of treatment with paclitaxel. Paclitaxel will be administered intravenously over a 3-hour period. This regimen will be repeated every 21 days until evidence of disease progression, intolerable adverse events, or withdrawal of patients consent .

References:

1. Chan HSL, DeBoer G, Thorner PS, et al. Multidrug resistance, Clinical Opportunities in Diagnosis and circumvention. New Drug Ther. 8:383-410, 1994..
2. Nabholtz J-M, Gelmon K, Bontelbal M et al. Multicenter, randomized comparitive study of two doses of paclitaxel in patients with metastatic breast cancer. J. Cancer Oncol. 14:1858-1867, 1996).
3. Uziely B, Delaflor-Weiss E, Lenz HJ, et al. Paclitaxel (Taxol) in refractory breast cancer: response correlates with low levels of MDR1 gene expression. Proc. Am. Soc. Clin. Oncol. 13:75, 1994.

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 carcinoma of the breast that is metastatic or locally advanced. Patients must have disease that is unsuitable for definitive surgical resection.
2. Patients must have received prior therapy for breast cancer, as follows:
   a. Patients must be paclitaxel-refractory as defined by progressive disease within 3 months of enrollment, following prior paclitaxel therapy,
   b. Patients must have received at least one but no more than two prior chemotherapy regimens for advanced disease,
   c. Patients must not have received prior bone marrow transplantation or radiation therapy to greater than 33% of bone marrow containing bone,
   d. The most recent prior therapy for advanced disease must have included at least two doses of paclitaxel at a starting dose of 175 mg/m² or greater, and
   e. Any number of prior hormonal or immunotherapies are permitted.
3. Patientsmust have bi-dimensionally measurable disease, defined as at least one lesion >(or =) 1 x 1 cm .
4. Patients must have sufficiently recovered from reversible toxicities of prior therapies.
5. Patients must have an ECOG performance of status of <= 2.
6. Patients must be >= 18 years of age.
7. Patients must have adequate bone marrow function as defined by a peripheral absolute granulocyte count of >= 1,500/mm³ and platelet count of >= 100,000/mm³.
8. Patients must have adequate liver and renal function as defined by serum creatinine and bilirubin levels within the institution's normal limits and SGOT or SPGT <= 1.5 times the institution's upper normal limits, regardless of whether there is liver involvement secondary to tumor.
9. Patients must sign an informed consent form indicating that they are aware of the investigational nature of this study in keeping with the policies of the institution.