Medical Summary
Alkylating agents such as melphalan lead to interstrand DNA crosslinks and ultimately to cell death. The developing of acquired resistance limits the effectiveness of chemotherapy in treatment of cancer patients. In particular, intracellular elevation of glutathione (GSH) have been shown to be associated with resistance to chemotherapy and radiotherapy.

BSO (DL-Buthionine, R-Sulfoximine) selectively binds to the active site of gamma-glutamylcysteine synthetases, the rate limiting step in GSH synthesis. GSH depletion by BSO markedly sensitizes melanoma cell lines to melphalan. In a phase I study of the combination of BSO + Melphalan one complete response was observed. These and other data provide the rationale for investigation the combination of BSO plus melphalan in melanoma patients.

The primary objectives of this study are:
1) To measure the activity (response rate, time to progression and response duration) of intravenous melphalan (L-PAM) with buthionine sulfoximine (BSO) in patients with ovarian cancer refectory to a taxol/combination in Phase II trial.
2) To describe the relationship between glutathione depletion by BSO in peripheral mononuclear cells (PMN) and the activity and toxicity of the combined treatment as a possible predictor of toxicity and/or response in this population.
3) To verify the degree of GSH depletion by BSO in ovarian tumour cells in a cohort of patients with refractory ovarian cancer.
4) To relate depletion of tumour GSH to changes in PMN GSH, and to baseline -GCS expression.
5) To further characterize L-PAM pharmacokinetics following BSO treatment.

Lay Summary
This study is designed to test the potential of the drug BSO to decrease a major cellular defence against the chemotherapy drug melphalan, in patients with ovarian cancer whose tumor has recurred after initial treatment with other therapy. In laboratory tests, BSO does enhance the tumor cell killing by melphalan. It requires the continuous presence of BSO. This Bso has been partially developed in research laboratories in the Translational Research Centre, and the clinical trial is coordinated by the U.S. National Cancer Institute.In the clinical trial, patients will receive a continuous intravenous infusion of BSO for 48 hours, at which point blood samples, and in some cases tumor biopsies will be performed. The melphalan is then given, and the BSO infusion continues for another 24 hours. This is repeated every 3-4 weeks, while we follow the tumor measurements and markers to see if they have reduced in response to the therapy. For patients who have received more than one previous regimen of chemotherapy, they are eligible but may be required to permit biopsies with a small needle of the tumor before treatment, at 48 hours of BSO infusion, and at the end of the infusion ON THE FIRST CYCLE OF THERAPY ONLY. After that there are no required biopsies. Patients are followed as well to detect and treat toxic side effects.This study has been active for over a year, and some responses have been observed. Further details of the experience to date should be requested.

1. Patients must have histological proof of an epithelial ovarian cancer.
2. Phase A - Cohort 1:
   a. Patients are eligible if they have failed or progressed within 6 months of a platinum (cisplatin or carboplatin) and Taxol containing regimen; other agents included in this regimen do not make the patient ineligible.
   b. Patients may have received one other regimen after progressing within 6 months of failing a platinum and Taxol containing regimen.
   c. Patients initially responsive to a platinum containing regimen who are treated with a platinum containing regimen as their second line therapy will be eligible if they fail to respond or relapse within 6 months of this second regimen.
   d. Patients will be ineligible if they have received more than 2 prior chemotherapy regimens.
   e. Tamoxifen is not considered a chemotherapy regimen.
   
   Phase B - Cohort 2: Patients may have failed greater than 1 regimen and may have received radiation therapy. Patients must have biopsiable disease and must consent to biopsy sampling as a condition of enrollment. Ascites and pleural effusions are not adequate for biopsiable disease.
3. Patients in Cohort 1 require evaluable disease nut need not have bidimensionally measurable disease.* Patients in Cohort 2 will require bidimensionally measurable disease. Patients with hepatomegaly or other evaluable disease will not be eligible.
   *An isolated rise in CA-125 is not sufficient for evaluable disease.
4. Patients must not have been previously treated with intravenous L-PAM.
5. Patients must have recovered from all toxicities or prior treatment. Patients must not have had prior chemotherapy or radiotherapy within 4 weeks of entry to this study.
6. Patients must be > 18 years of age. Patients must have a minimum life expectancy of 12 weeks and an ECOG performance status of 2 or better.
7. Patients must have adequate bone marrow function (WBC 4,000/mm3 or AGC >(or =) 2,000 mm3, platelets >(or =) 100,000 mm3), adequate liver function (bilirubin <(or =) 1.5 mg/dl, and SGOT <(or =) 4 x upper normal value), and adequate renal function (serum creatinine <(or =) 1.5 mg/dl; if serum creatinine is >(or =) 1.5 mg/dl, then creatinine clearance must be >(or =) 60 cc/min).
8. Active, uncontrolled infection renders a patient ineligible.
9. Patients of reproductive potential must have a negative pregnancy test pre-study, and must practice adequate contraception while on study and for two months after going off study. Patients who are lactating or gestational are ineligible for study.
10. Patients entering this study must be informed of the investigational nature of the treatment they will receive, the results which may be expected, and the toxicity which might reasonably be anticipated. All patients must indicate their willingness to participate in this protocol by signing the appropriate Consent Forms to the clinical and pharmacologic aspects of the study.