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Clinical and pharmacological phase I study with accelerated titration design of a daily times five schedule of BBR3464, a novel cationic triplatinum complex (2000)

Sessa, C. ; Capri, G. ; Gianni, L. ; [et al.]

Springer

Annals of oncology 11 (2000), S. 977-983

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ISSN: 1569-8041

Keywords: BBR3464 ; phase I ; platinum analog ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Objectives:To define the maximum tolerated dose (MTD), thetoxicity and pharmacokinetic profile of BBR3464, a novel triplatinum complex. Patients and methods:Fourteen patients with advanced solid tumorsnot responsive to previous antitumor treatments received BBR 3464 on a daily× 5 schedule every twenty-eighth day. The drug was given as a one-hourinfusion with pre-and post-treatment hydration (500 ml in one hour) and noantiemetic prophylaxis. The starting dose was 0.03 mg/m2/day. Amodified accelerated titration escalation design was used. Total and freeplatinum (Pt) concentrations in plasma and urine were assessed by ICP-MS ondays 1 and 5 of the first cycle. Results:Dose was escalated four times up to 0.17mg/m2/day. Short-lasting neutropenia and diarrhea of late onsetwere dose-limiting and defined the MTD at 0.12 mg/m2. Nausea andvomiting were rare, neither neuro- nor renal toxic effects were observed.BBR3464 showed a rapid distribution phase of 1 hour and a terminal half-lifeof several days. At 0.17 mg/m2 plasma Cmax and AUC on day 5 werehigher than on day 1, indicating drug accumulation. Approximately 10%of the equivalent dose of BBR3464 (2.2%–13.4%) wasrecovered in a 24-hour urine collection. Conclusions:The higher than expected incidence of neutropenia andGI toxicity might be related to the prolonged half-life and accumulation oftotal and free Pt after daily administrations. Lack of nephrotoxicity and thelow urinary excretion support the use of the drug without hydration. Thesingle intermittent schedule has been selected for clinical development.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1008302309734

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Phase I clinical and pharmacokinetic study of the oral platinum analogue JM216 given daily for 14 days (1998)

Sessa, C. ; Minoia, C. ; Ronchi, A. ; [et al.]

Springer

Annals of oncology 9 (1998), S. 1315-1322

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ISSN: 1569-8041

Keywords: oral chemotherapy ; oral platinum analogue ; phase I

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Background: The oral bis (acetate) ammine dichloro cyclohexylamine platinum (i.v.) analogue (BMS-182751) was brought into clinical development because it was shown to be cytotoxic against some human tumour cell lines and to have an antitumor activity in murine tumours at least comparable to that of parenteral cisplatin and carboplatin. In early clinical studies in which the optimal schedule of treatment was daily for five consecutive days, dose-dependent nausea and vomiting occurred in about two-thirds of patients. Patients and methods: To evaluate if the use of lower daily doses for longer periods of time could result in a better tolerability, JM216 was given once daily for 14 consecutive days every four to five weeks to adult patients with solid tumors. Oral antiemetics were given prophylactically only at the highest doses. The pharmacokinetics of total and ultrafiltrable platinum were studied on days 1 and 14 of the first cycle by Inductively Coupled-Mass-Spectrometry (ICP-MS). Results: Forty-six patients were treated at doses ranging from 10 mg/m2/d to 50 mg/m2/d and 39 were evaluable for hematologic toxicity over 74 cycles. MTDs were reached at 45 mg/m2/d and 50 mg/m2/d × 14 repeated every five weeks in patients with extensive, or limited/no prior treatment, respectively. The dose-limiting toxicity was neutropenia which was delayed and variable among patients. Other non-hematological toxicities were severe vomiting (22% of cycles), diarrhea (28% of cycles) and drug-associated fever (32% of patients), controlled with paracetamol. Subjective improvement with disappearance of tumour-related pain was observed in one patient with chemotherapy-resistant metastatic prostate cancer and in one previously untreated patient with malignant mesothelioma. Cmax and AUC values of both total and ultrafiltrable platinum on days 1 and 14 were highly variable among patients. Only Cmax on day 1 was linearly related to the dose. Total and ultrafiltrable platinum were still detectable two weeks after the last dose. No relationship could be established between AUC values and toxicities. Conclusions: Daily doses of JM216 of 40 mg/m2 and 45 mg/m2 for 14 consecutive days every five weeks with oral antiemetic prophylaxis are selected for phase II evaluation of single agent in patients with extensive or limited/no prior treatment, respectively. The administration of JM216 on a day × 14 schedule produced nausea and vomiting comparable to that observed with the day × 5 regimen but of longer duration. The variability of pharmacokinetics and pharmacodynamics, even though limited at the doses proposed for phase II evaluation of JM216 as single agent, recommend a careful monitoring of the patients.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1008441416790

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Clinical and pharmacokinetic phase I trial of oral dimethylaminoetoposide (NK611) administered for 21 days every 35 days (1996)

Raßmann, I. ; Schrödel, H. ; Schilling, T. ; [et al.]

Springer

Investigational new drugs 14 (1996), S. 379-386

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ISSN: 1573-0646

Keywords: NK611 ; dimethylaminoetoposide ; phase I ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Summary We have conducted a clinical and pharmacokinetic trial of the novel podophyllotoxin derivative NK611 administered orally for 21 consecutive days. The treatment was repeated every 35 days. Eighteen patients were included into the study, all of whom were eligible. Due to early progression of tumor disease in two patients, 16 patients were évaluable for toxicity [7 female, 9 male, median age 64 years (range: 44 to 73)]. Dose escalation steps were 5 mg/day [105 mg per cycle (pc)], 10 mg/day (210 mg pc), 12.5 mg/day (265 mg pc) and 15 mg/day (315 mg pc). A total of 37 courses was administered. Toxicity was evaluated using NCI-CTC criteria. Granulocytopenia was the main hematologic toxicity. Other hematologic toxicities were sporadic. Non-hematologic toxicities were mild and consisted of grade 1 nausea and grade 2 alopecia. Pharmacokinetic analyses were performed in six patients each treated with 10 mg/day and 12.5 mg per day, and in one patient treated with 15 mg/day. Using a two-compartment model, t1/2α ranged from 0.47 to 1.54 h and t1/2β from 2.0–11.6 h. Mean values for C max and AUC were 1.47 ± 0.331 μg/ml and 13.67±3.81 μg/ml·h. No objective tumor responses were observed. However, one patient with metastatic breast cancer had stable disease for twelve months. We conclude that the Maximum Tolerated Dose of NK611 administered daily for 21 consecutive days is 12.5 mg/day. The Dose-Limiting Toxicity is granulocytopenia. The recommended dose for further clinical Phase II studies is 10 mg/day.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00180814

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