ACTIVITY OF JM9 IN ADVANCED OVARIAN-CANCER - A PHASE-I-II TRIAL

Abstract

Thirty-nine patients with advanced solid tumors, including 28 with ovarian cancer, were entered in a phase I-II trial of a new platinum analog, JM9. Twenty-three patients had received prior chemotherapy which did not include cisplatin. Based on preliminary information from an ongoing study, starting dose was 180 mg/m2. The total dose of JM9 was administered in 1 l of saline infused over 1 h, with no additional hydration or electrolyte supplementation. Courses were repeated at 3-wk intervals or after full recovery from thrombocytopenia. A total of 139 courses (range, 1-6 per patient) were administered at 4 dose levels as follows: 180 mg/m2 (13 courses); 240 mg/m2 (64 courses); 300 mg/m2 (45 courses); and 350 mg/m2 (17 courses). The dose-limiting toxic effect was thrombocytopenia, which was dose-related and cumulative. Median platelet count nadirs were 50, 47, 25, and 28 .times. 109/l for previously treated patients at dose levels of 180, 240, 300, and 350 mg/m2, respectively. For patients who had not received prior chemotherapy, the corresponding values were 403, 61, 44, and 36 .times. 109/l. The nadir was predictable at Day 14 with recovery by Day 21 in earlier courses, but with delay of recovery to Days 28-42 in later courses and at higher dose levels. Twenty-five courses of chemotherapy in 15 patients were associated with a platelet count nadir of < 20 .times. 109/l, but, despite this, serious hemorrhage was rare. Leukopenia was dose-related and mild; the median wbc [white blood cell] count (.times. 109/l) was 2.2 (range, 1.0-7.3) at the highest dose level of 350 mg/m2. The leukocyte count nadir was later than that for the platelet count (Days 21-28) and recovery was often not complete by the time of retreatment. All patients showed a progressive rise in mean corpuscular volume in successive courses, often accompanied by a fall in hemoglobin. Transfusions were required in 14 patients, 12 of whom had received prior chemotherapy. Nausea and vomiting, starting within 1 h of drug administration, occurred in all patients, but appeared to be less severe and prolonged compared to that occurring with cisplatin. Diarrhea occurred in most patients at the 2 higher dose levels. There was no evidence of significant renal impairment, electrolyte, disturbance, hearing loss, or peripheral neuropathy. Two patients had mild allergic reactions shortly after drug infusion and 2 others developed vasculitic rashes which were self-limiting. Responses were only seen in patients with ovarian cancer: 6 complete and 2 partial responses were achieved in 10 patients who had not received prior chemotherapy. One complete and 3 partial responses were achieved in 16 patients who had previously been treated with alkylating agents. Second-look laparotomies were performed in 6 complete responders, 3 of whom were pathologically disease-free.