Phase II study of 9-aminocamptothecin in previously treated lymphomas: results of Cancer and Leukemia Group B 9551

Abstract

Purpose To evaluate the efficacy and toxicity of the topoisomerase I inhibitor, 9-aminocamptothecin (9-AC), in patients with relapsed lymphoma and to correlate 9-AC plasma concentrations with response and toxicity. Methods Eligible patients had relapsed Hodgkin lymphoma (HL) treated with one or two prior regimens, low grade non-Hodgkin’s lymphoma (NHL) treated with one or two prior regimens, or aggressive NHL treated with one prior regimen. The first nine patients received 9-AC dimethylacetamide 0.85 mg/m2 per day intravenously over 72 h every 2 weeks and the remaining 27 patients received 9-AC/colloidal dispersion 1.1 mg/m2 per day. Patients received a minimum of three cycles unless progression or intolerable toxicity occurred. Responding patients received two cycles past best response with a minimum of six cycles. Results CALGB 9551 accrued 37 patients from April 1996 through October 2000; one patient with HD, 18 patients with indolent lymphoma, and 17 patients with aggressive lymphoma. The overall response rate was 17%, with response rates of 11% (2 partial responses) in patients with indolent histologies and 23% (1 complete response, 3 partial responses) in patients with aggressive histologies. The patient with HD did not respond. Response rates were similar for both drug formulations. The median remission duration for the six responders was 6.5 months, with one remission lasting longer than 12 months. Significant grade 3 and 4 toxicities included neutropenia (66%), anemia (31%), and thrombocytopenia (36%), with 20% of patients experiencing grade 3 or 4 infection. No treatment related deaths occurred. Steady state serum concentrations did not correlate with patient response or toxicity. Conclusion Single agent 9-AC has modest activity in aggressive non-Hodgkin’s lymphoma

Physicochemical Characterization of 9-Aminocamptothecin in Aqueous Solutions

“…Various types of drug delivery systems tested in phases I and II clinical studies were developed aiming to improve the pharmacokinetics of 9AC and unleash its therapeutic potential (10)(11)(12)(13)(14). Like other CPT analogs, 9AC also suffers from drawbacks of low solubility and hydrolytic instability at physiological pH but, to our knowledge, no comprehensive thermodynamic studies have ever been published in the literature.…”

Antitumor Efficacy of Colon‐Specific HPMA Copolymer/9‐Aminocamptothecin Conjugates in Mice Bearing Human‐Colon Carcinoma Xenografts

“…The dose of 9‐AC/CD was 1.1 mg · m −2 per day (total dose 3.3 mg · m −2 ) as a continuous intravenous infusion on days 1–3 and repeated every 2 weeks. The dose of 9‐AC/CD is nearly 30% higher than that for 9‐AC/DMA with a similar toxicity profile 29. Unfortunately, 9‐AC in both formulations failed to demonstrate antitumor activity in clinical trials because of dose‐limited toxicity.…”

Desmoplastic small round cell tumor (DSRCT) xenografts and tissue culture lines: Establishment and initial characterization

“…DSRCT is significantly less common than the remaining tumors of the family, but have the worst prognosis. DSRCTs have been demonstrated to be refractory to chemotherapy and almost uniformly fatal (9), however, the tumors may respond well to camptothecin compounds, which have been identified to have a certain effectiveness against indolent tumors (15,16). …”