A phase II trial of weekly i.v. KW-2170 in advanced castrate-resistant prostate cancer.

AIM: KW-2170 is a novel pyrazoloacridone derivative that intercalates nucleic acids. It has promising in vitro properties against prostate and other cancers and is active in vivo against doxorubicin-resistant cell lines. We wished to investigate its activity and toxicity profile in this Phase II trial in androgen independent prostate cancer. METHODS: Overall 44 men were recruited to this multicenter, open label, non-randomized study, with 35 evaluable for prostatic specific antigen (PSA) response. RESULTS: Five patients had a PSA fall greater than 50% (overall RR 14.3%, 95% CI 4.8-30.3%). Overall median survival was 16 months. In the evaluable group (n = 35), median survival was 18.9 months. The drug was very well tolerated, with the most common toxicities being hematological (anemia, leucopenia, thrombocytopenia), alopecia, fatigue, and nausea. However, most of these were National Cancer Institute Grade 1 or 2; Grade 3 neutropenia occurred in only 11% of patients, and there was no Grade 4 neutropenia. Quality of life as measured by the FACT-P scale was not compromised. CONCLUSION: KW-2170 is a very well tolerated chemotherapy agent. It has a relatively low PSA response rate, and did not meet the pre-specified criteria for further studies.

A phase I study of an anti-GD3 monoclonal antibody, KW-2871, in patients with metastatic melanoma.

PURPOSE: KW-2871 (IgG1 kappa chimeric antibody) targets GD3, which is upregulated in melanomas. We conducted a phase I trial of KW-2871 in patients with metastatic melanoma. METHODS: Seventeen (17) patients were enrolled and received an initial test dose (10 mg/m2) intravenously. Two 2 weeks later, patients were stratified into 4 cohorts to receive 4 doses of KW-2871 (infused over 1 hour) at 2-week intervals (20, 40, 60, and 80 mg/m2). No premedications were administered for the test or first therapeutic doses. RESULTS: Dose-limiting toxicities were Grade 3 laryngospasm and chest tightness with the initial therapeutic infusion at doses of 80 and 60 mg/m2. The maximum tolerated dose (MTD) was established at 40 mg/m2 of KW2871. The most common side-effect was urticaria (Grades 1-3) in 16 of 16 patients during an initial therapeutic infusion without premedication. The mean terminal half-life, clearance, and area under the concentration-time curve (AUC(0-t)) at a dose of 40 mg/m2 for course 1 were 146 +/- 31 hours, 28 +/- 6 ml/hour, and 1922 +/- 491 mcg*hour/mL, respectively. Anti-human chimeric antibody was not detected. Two (2) patients in the 40 mg/m2 cohort had stable disease. CONCLUSIONS: An MTD of 40 mg/m2 without premedication was established for KW-2871, with urticaria being the most common side-effect and dose-limiting anaphylactoid infusion reactions.