Phase I clinical investigation of fludarabine phosphate by a loading-dose and continuous-infusion schedule.

Fludarabine phosphate was studied in a phase I trial of a loading-dose/continuous-infusion schedule. The schedule was chosen to rapidly achieve and maintain concentrations that have been shown in vitro to achieve maximal inhibition of cell growth. The initial level was a loading dose of 20 mg/m2 followed by a 48-hour continuous iv (CIV) infusion of 30 mg/m2 every 24 hours. For the single-dose escalation, the loading dose was held constant while the CIV dose was increased to 45 mg/m2/24 hours for 48 hours. The dose-limiting toxicity was myelosuppression, especially leukopenia. No other significant toxicity was encountered. The maximum tolerated dose was 20 mg/m2 by iv push followed by a 48-hour CIV infusion of 30 mg/m2/24 hours for 48 hours. The recommended starting dose for phase II trials is 20 mg/m2 by iv push followed by a 48-hour CIV infusion of 30 mg/m2/24 hours. This dose level achieved the target plasma levels in the 2 patients studied.

Trimetrexate: a phase 2 study in previously treated patients with metastatic breast cancer.

Trimetrexate, a nonclassical antifolate, was administered to 28 patients with progressive, metastatic breast cancer. The starting dose was 8 mg/m2 administered intravenously (IV) as a short infusion daily for 5 days, repeated every 3 weeks with dose adjustments depending on patient tolerance. The median age of the 28 females in this study was 58.5 years. Their median performance status on the Zubrod scale was 1. Nine of the patients were estrogen-receptor positive. The sites of metastasis included the pulmonary system (50%), bone (40%), and liver (35%). Twenty patients were evaluable for response. Three patients (15%; [95% confidence interval 0.0, 30.6]) achieved a partial response with a median time to partial response of 9.1 weeks and a median duration of partial response of 13.1 weeks. Two of the responders were estrogen-receptor positive. Median survival for all 28 patients was 41 + weeks with 15 patients alive at the last follow-up. Hematologic grade 3-4 toxicity occurred as follows: leukopenia (21%), thrombocytopenia (18%), and granulocytopenia (18%). There was no significant nonhematologic toxicity seen.

Phase II trial of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate in non-Hodgkin's lymphoma: prospective comparison of response with deoxycytidine kinase activity.

A phase II study of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate was done in non-Hodgkin's lymphoma with a loading dose/continuous intravenous infusion schedule, consisting of a 20 mg/m2 loading dose followed by a continuous i.v. infusion of 30 mg/m2/24 h for 48 h. The loading dose was held constant while the continuous i.v. dose was escalated or decreased as appropriate for toxicity. Twenty-six patients were entered on the study; 25 are evaluable for response. The patients' median age was 61 years (range 25 to 73); their mean performance status was 1.1. They had received a mean of 2.6 prior chemotherapeutic regimens, and six also had prior radiation therapy. There was one complete response lasting 9+ months, and there were seven partial responses lasting 20, 13, 11, 11, 10, 5, and 2 months (response rate 32%). Toxicity was acceptable and consisted mainly of myelosuppression. 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate is dephosphorylated in vivo and then is thought to be activated intracellularly to 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-triphosphate. The rate-limiting enzyme is deoxycytidine kinase. Deoxycytidine kinase activity was determined on pretreatment tumor samples for correlation with response. There was no difference between the values for responders and nonresponders. There was a trend for higher values in more malignant histological subtypes.

High-dose mitoxantrone in metastatic breast cancer: a phase I-II trial.

Eighteen women with metastatic breast cancer entered a phase I-II study of high-dose mitoxantrone (MXT). They were heavily pretreated (mean, 2.3 prior regimens) with drugs including both doxorubicin (14 patients) and MXT at usual doses (three). Doses studied were 16, 20, 25, and 30 mg/m2, repeated every 3-4 weeks. Marked leukopenia was seen at all dose levels (four episodes of infection were successfully treated). Fatigue and malaise were the most common nonhematologic toxic effects. At 25 mg/m2, six of 13 courses resulted in severe fatigue and malaise. MXT is tolerated at doses up to 25 mg/m2 every 3-4 weeks. Cardiac function must be closely monitored. No responses were seen in these heavily pretreated patients.

Low-dose deoxycoformycin in lymphoid malignancy.

Deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase (ADA), was explored for its antineoplastic potential in 28 patients with advanced lymphoid malignancy. Both normal and malignant B lymphocytes have low levels of ADA activity, and low doses of dCF profoundly inhibit this enzyme in the peripheral blood of patients with chronic lymphocytic leukemia (CLL). The low doses of dCF administered in this trial (4 mg/m2) were not associated with prohibitive toxicity. Five of 28 patients had an objective response. Four additional patients had clinical improvement. No significant difference in the pretreatment ADA activity existed between responding patients and treatment failures. The demonstration of responses to dCF following failure on standard alkylating agents suggests that dCF may not be cross-resistant with current agents used to treat CLL. Additional studies should be pursued using low-dose dCF in patients with advanced malignancy.