Phase I trial of escalating dose doxorubicin administered concurrently with alpha 2-interferon.

The clinical use of alpha 2-interferon and doxorubicin is based on in vitro and preclinical in vivo observations of synergistic antitumor efficacy. To test this combination a Phase I clinical and pharmacokinetic study of the concurrent use of alpha 2-interferon and doxorubicin was initiated in patients with malignant solid tumors. Each 5-wk treatment cycle consisted of 3 wk of drug administration and 2 wk of rest. The alpha 2-interferon was administered s.c. at a constant dose of 10 million IU/m2 on Mondays, Wednesdays, and Fridays in all patients while the doxorubicin was administered weekly beginning with a dose of 5 mg/m2 and escalated to the maximum tolerated dose of 25 mg/m2. At least three evaluable patients were entered at each dose level, and no dose escalations were allowed within patients. The dose-limiting toxicities were granulocytopenia and thrombocytopenia. Hepatic enzyme elevations and systemic symptoms due to interferon occurred at all dose levels. None was severe or dose limiting, and all were reversible. These toxicity data suggest that the hepatotoxic effects of interferon do not enhance doxorubicin toxicity when given by this dose and schedule. Doxorubicin plasma levels were measured at each dose level. The recommended dose of doxorubicin is 25 mg/m2 per wk when administered with 10 million IU/m2 of interferon in this schedule. This schedule allows for the administration of a greater total dose of doxorubicin than has been achieved when given every 3 wk with the same dose and schedule of alpha 2-interferon in a parallel study.

Phase II study of carboplatin in recurrent ovarian cancer: severe hematologic toxicity in previously treated patients.

Carboplatin (CBDCA) is a second-generation cisplatin analog that has shown activity in early clinical trials. Its spectrum of toxicity is quantitatively and qualitatively different from that of the parent compound. Between November 1984 and September 1986 we conducted a phase II trial of CBDCA in 46 women with epithelial ovarian cancer. All patients had undergone at least one prior chemotherapy regimen; 41 (89%) had previously received cisplatin (mean cumulative dose, 540 mg/m2). The CBDCA dose was based on renal function and was injected i.v. once every 4 weeks. Patients were stratified on the basis of baseline creatinine clearance: those with a baseline creatinine clearance of greater than or equal to 60 ml/min received 400 mg/m2 CBDCA; those with a creatinine clearance between 30 and 60 ml/min received an initial dose calculated according to a previously published formula that corrected for renal insufficiency and projected nadir platelet counts of 75,000/mm3. Of 41 evaluable patients, 6 (15%) had an objective response [2 complete responses (CRs); 4 partial responses (PRs)]; 5 of the 6 responders had previously responded to cisplatin treatment. No responses were observed in 12 patients who had not responded to prior cisplatin therapy. Significant hematologic toxicity was seen. Of 18 patients with a creatinine clearance of greater than or equal to 60 ml/min (dose, 400 mg/m2), 6 had nadir platelet counts of less than 25,000/mm3, 4 with symptomatic bleeding. Of the 21 evaluable patients for whom the dose-modification formula was applied, 10 had nadir platelet counts of less than 75,000/mm3; 5 had counts of less than 50,000/mm3. CBDCA has activity even in patients who have previously undergone extensive cisplatin therapy; however, its toxicity is variable and thrombocytopenia is dose-limiting. We did not confirm the ability of the above-mentioned formula to calculate the CBDCA dose and accurately predict the nadir platelet count for all patients. Other factors, such as prior radiotherapy, may also be important in the dosing of CBDCA in pretreated patients.