[Early phase II clinical trial of amrubicin hydrochloride in patients with malignant lymphoma].

An early phase II multi-center collaborative study of amrubicin hydrochloride, a novel synthetic anthracycline derivative anticancer agent, was conducted for malignant lymphoma at 12 institutions nationwide. A total of 41 patients were enrolled in this study between January 1988 and October 1990. Of these, 36 patients, six patients with Hodgkin's disease (HD) and 30 patients with non-Hodgkin's lymphoma (NHL), were eligible for the study. The starting dose of amrubicin hydrochloride was 100 mg/m2 (body surface area) and it was administered once every three weeks, in principle. The efficacy was assessed for 34 patients, excluding two patients: one who has not been followed up adequately and the other violated the dosing schedule (once per week). The overall response rates (CR + PR) were 50.0% (3/6) for HD and 42.9% (12/28) for NHL. Furthermore, a relatively high response rate was noted in 8 (36.4%) of 22 NHL patients who had been treated with other anthracycline derivatives prior to the trial. The safety of amrubicin hydrochloride was assessed for 36 eligible patients. Leukopenia (grade 3 or higher) and thrombocytopenia were noted in 21 patients (58.3%) and 10 patients (27.8%), respectively. Anorexia, nausea/vomiting, fever, alopecia, decrease in hemoglobin and elevations of GOT and GPT levels were observed with a relatively high frequency. Other than myelosuppression, the following adverse reactions (grade 3 or higher) occurred during the course of the trial: diarrhea (two patients), alopecia (two patients), stomatitis (one patient), anorexia (one patient), nausea/vomiting (one patient) and fever (one patient). In conclusion, these results indicate that amrubicin hydrochloride is effective in the treatment of patients with malignant lymphoma.

Phase I study of NKT-01.

A phase I study of NKT-01 (deoxyspergualin), which is a derivative of an antitumor antibiotic, spergualin, was performed by a cooperative study group. NKT-01 was given intravenously by 3-h infusion. The effect of single administration was studied prior to evaluation of daily administration for 5 consecutive days. In all, 5 and 33 patients with various malignancies, including leukemia, were entered into the trials of single and daily administration, respectively. In the single-administration study, all patients were evaluable and no clear adverse effect was observed at doses ranging from 20 to 320 mg/m2. In the daily-administration study, 28 evaluable patients (16 men and 12 women; median age, 55.5 years) were treated with a daily dose of 20-500 mg/m2. Toxicities such as myelosuppression, mild nausea/vomiting, anorexia, alopecia, tongue and perioral numbness, and hypotension were observed dose-dependently during or after the treatment. Grade 2 leukopenia, thrombocytopenia, and anemia were experienced at a dose of 500 mg/m2. These usually recovered to normal values by approximately 3 weeks after treatment. A pharmacokinetic analysis of single administration revealed rapid plasma clearance, with mean half-lives for the alpha and beta phases being 28 min and 6.9 h, respectively. Approximately 12% of the infused dose was excreted into the urine in unmetabolized form. The pharmacokinetic parameters obtained after 5-day administration were similar to those recorded after single administration. Concerning treatment response, a transient but significant reduction in the number of leukemic cells was observed in one patient with adult T-cell leukemia. In this study, perioral numbness, hypotension, and hematological toxicity were concluded to be dose-limiting, with the maximal acceptable dose being 500 mg/m2. The recommended dose for a phase II study of NKT-01 against solid tumors was judged to be 400 mg/m2 given daily by 3-h infusion for 5 days, every 3 weeks. In hematological malignancies, however, higher myelosuppressive schedules of administration should be investigated.

[Clinical evaluation of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in autologous bone marrow transplantation].

We administered recombinant human granulocyte colony-stimulating factor (rhG-CSF) at 5 micrograms/kg/day by intravenous drip infusion for 21 consecutive days in autologous bone marrow transplanted patients. The period of posttransplant neutropenia was markedly shortened by the rhG-CSF treatment; mean days required for neutrophil recovery (greater than 500/mm3) of 14.3 days in the rhG-CSF group (n = 21) versus 27.8 days in the historical control group (n = 11). More importantly, the numbers of febrile days between day 15 and day 28 were found to be fewer in the rG-CSF group than in control group. These effects were obtained without delay in the recovery of other blood cell series and without any side effect. We conclude that the posttransplant use of the rhG-CSF is beneficial for prevention and treatment of infectious complications after autologous bone marrow transplantation.

[Clinical effect of recombinant human G-CSF on neutropenia induced by chemotherapy for non-Hodgkin's lymphoma].

A clinical trial of recombinant human granulocyte colony-stimulating factor (rG-CSF), produced by Chinese hamster ovary cells, was conducted in 66 patients receiving intensive chemotherapy for non-Hodgkin's lymphoma. Each patient received 2 cycles of CHOP therapy, and one cycle of them was performed with rG-CSF treatment and another one without rG-CSF treatment, in a cross-over fashion. rG-CSF (0.4, 2, 5, 10 micrograms/kg/day) was given intravenously or subcutaneously to each patient for 14 days from 2 days after initiation of the chemotherapy. rG-CSF increased the absolute neutrophil counts (ANC) at nadir, and reduced the period of neutropenia with ANC less than 1,000/mm3 and also the period for restoration to ANC greater than or equal to 2,000/mm3 after initiation of chemotherapy. These effects were remarkable at doses of more than 5 micrograms/kg/day intravenously and 2 micrograms/kg/day subcutaneously. Fourteen infective episodes were observed during the cycles of chemotherapy without rG-CSF treatment, while 7 infective episodes were observed during the cycles with rG-CSF treatment. rG-CSF was well tolerated. These results demonstrated that rG-CSF was effective in neutropenia induced by cancer chemotherapy at a intravenous dose of 5 micrograms/kg/day and a subcutaneous does of 2 micrograms/kg/day.

[Phase I study of an oral administration of VP 16-213].

A phase I study of VP-16-213 oral capsule was performed in 25 patients with various malignant tumors refractory to standard treatments. Doses were escalated from 50 mg/d to 300 mg/d by a 5-day administration. Leukopenia was dose-related and nadirs at 200 mg/d, 250 mg/d and 300 mg/d were 2,000, 1,600 and 700/cmm respectively, reaching in about 2 weeks and approximately one week was required for recovery. Thrombocytopenia was also dose-related but generally less frequent and milder than leukopenia. Gastrointestinal toxicities such as anorexia, nausea and vomiting occurred in about 20% of patients but well tolerated; alopecia was observed in 40%. The result indicated that an optimal dose of oral VP-16-213 for phase II study was daily 200 mg/d (approximately 130 mg/m2) for 5 consecutive administration in 3-week intervals.