High-dose toremifene as a cisplatin modulator in metastatic non-small cell lung cancer: targeted plasma levels are achievable clinically.

PURPOSE: The triphenylethylenes tamoxifen and toremifene have been reported to enhance the cytotoxicity of cisplatin by inhibition of protein kinase C (PKC) signal transduction pathways. However, the concentrations of tamoxifen and toremifene required for chemosensitization in preclinical models are generally > or =5 microM, at least tenfold higher than plasma levels observed in patients receiving these agents as antiestrogenic therapy. As part of a translational phase II trial investigating the efficacy and potential molecular mechanism of high-dose toremifene as a cisplatin modulator in metastatic non-small-cell lung cancer, plasma concentrations of toremifene and its active metabolite N-desmethyltoremifene were measured to determine whether targeted levels could be achieved clinically. METHODS: Treatment consisted of toremifene, 600 mg orally on days 1-7, and cisplatin, 50 mg/m2 intravenously on days 4 and 11, repeated every 28 days. Toremifene and N-desmethyltoremifene were measured by reverse-phase HPLC assay on days 4 and 11 prior to cisplatin infusion. RESULTS: In the initial 14 patients, the mean total plasma concentrations of toremifene plus its N-desmethyl metabolite on days 4 and 11 were 14.04 (+/- 8.6) microM and 9.8 (+/- 4.4) microM, respectively. Variability in concentrations achieved did not correlate with renal or hepatic function, gender, or body surface area. Levels of N-desmethyltoremifene were higher on day 11 relative to toremifene concentrations. CONCLUSIONS: We conclude that plasma levels achieved compare favorably with the levels required for cisplatin chemosensitization and PKC modulation in vitro. Targeted toremifene levels can be achieved clinically with 600 mg orally daily in combination with cisplatin and are well tolerated.

Phase I study of antilipopolysaccharide human monoclonal antibody MAB-T88.

Monoclonal antibody MAB-T88 is a human monoclonal immunoglobulin M antibody directed at the lipopolysaccharide of gram-negative bacteria. In this study, nine patients who were expected to become neutropenic from antineoplastic chemotherapy received an infusion of MAB-T88, three patients at each of three doses: 1, 4, and 8 mg/kg of body weight. MAB-T88 was shown to be safe, with an effective half-life in plasma of 25.4 h, and no patient developed immunoglobulin G antibody to MAB-T88.

Phase I study of paclitaxel with oral etoposide in advanced solid tumors.

PURPOSE: This study evaluated dose escalation of paclitaxel administered as a 3-hour infusion after a fixed oral etoposide regimen given daily for 10 days to determine an optimal dose and a toxicity profile for this combination. PATIENTS AND METHODS: Three consecutive cohorts consisting of 29 patients with measurable or assessable advanced solid tumors were treated with paclitaxel by intravenous infusion over 3 hours after receiving etoposide, 50 mg orally twice daily, for 10 days. Cycles were repeated every 28 days. Paclitaxel dose levels were: cohort 1, 135 mg/m2; cohort 2, 150 mg/m2; and cohort 3, 175 mg/m2. RESULTS: Dose-limiting toxicity was observed in cohort 3 in 5 of 12 patients (4 of 12 patients met criteria for myelosuppression and 1 of 12 experienced grade 3 mucositis). No unexpected toxicities were observed, and this regimen was well tolerated. DISCUSSION: Administration of paclitaxel in combination with a prolonged oral schedule of etoposide is feasible and toxicities are manageable. The dose-limiting toxicity of a 3-hour infusion of paclitaxel after 10 days of etoposide given orally was myelosuppression. Recommended doses of this combination for phase II studies are etoposide, 100 mg orally daily for 10 days, followed by paclitaxel at a dose of 150 mg/m2 intravenously over 3 hours, and repeated every 4 weeks.

Phase I trial of edatrexate plus carboplatin in advanced solid tumors: amelioration of dose-limiting mucositis by ice chip cryotherapy.

PURPOSE: Edatrexate (10-Edam) is a methotrexate analog with improved intracellular transport, polyglutamation, and antitumor activity compared to the parent compound. Edatrexate shows schedule-dependent synergism with platinum compounds in preclinical studies. We performed a phase I trial to determine toxicities and establish the maximum tolerated dose (MTD) of edatrexate in combination with carboplatin. Based on the short initial plasma half-life of edatrexate, prophylactic ice chip cryotherapy was used to reduce the severity of mucositis. PATIENTS AND METHODS: Forty-six chemotherapy-naive patients with advanced solid tumors were treated. Edatrexate was given weekly for 5 doses (50% on day 8), and then every other week, followed by carboplatin at a fixed dose of 350 mg/m2 on day 1 and then every 4 weeks for 8 cycles. Edatrexate dose was increased at increments of 10 mg/m2/dose level beginning at 60 mg/m2/week (range 60-120 mg/m2). RESULTS: All patients were assessable for toxicity and response analysis. The median number of cycles administered per patients was 4. This combination chemotherapy regimen was well tolerated. Using ice chip cryotherapy, no grade IV mucositis was observed. Grade III mucositis occurred in only 7/46 pts and was not dose-related. Protocol-defined dose-limiting toxicity occurred at a edatrexate dose level of 120 mg/m2, yielding an MTD of 110 mg/m2. Responding tumor types included non-small cell and small lung cancer, head and neck cancer, and bladder cancer. CONCLUSIONS: 1 ) This phase I study demonstrated the safety and tolerability of this edatrexate and carboplatin combination. 2) Dose-limiting mucositis did not occur allowing escalation of edatrexate dose above levels previously achieved with this edatrexate dose schedule. This was most likely a result of prophylactic ice chip cryotherapy. 3) An edatrexate dose of 110 mg/m2 with ice chip cryotherapy is recommended for Phase II trials of this combination.