PharmaMar Clinical R and D

Colmenar Viejo, Spain

PharmaMar Clinical R and D

Colmenar Viejo, Spain
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Pardo B.,Lhospitalet Of Llobregat | Salazar R.,Lhospitalet Of Llobregat | Ciruelos E.,Hospital Universitario 12 Of Octubre | Cortes-Funes H.,Hospital Universitario 12 Of Octubre | And 9 more authors.
Medical Oncology | Year: 2012

Maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics (PK) were evaluated for trabectedin 3-h every-3-weeks schedule in 33 cancer patients stratified according to liver dysfunction degree as per baseline alkaline phosphatase (AP). Stratification was as follows: stratum I [upper limit of normal (ULN) < AP ≤1.5 × ULN; n = 16], stratum II [1.5 × ULN < AP ≤2.5 × ULN; n = 12], and stratum III [AP >2.5 × ULN; n = 5] (bilirubin <2.5 × ULN for all 3 strata). In each stratum, patients were treated in sequential cohorts at escalating doses. Dose-limiting toxicities (DLTs) were grade 3 transaminase increases not recovering baseline values on day 21, febrile neutropenia/grade 4 neutropenia lasting >5 days and AP increase more than twice over baseline. The MTD and RD for stratum I (mild baseline AP) was 1.3 mg/m2. Recruitment was stopped early in strata II/III (moderate/severe baseline AP) without reaching the MTD due to slow accrual and difficulty in finding patients. Biochemical parameters other than AP (bilirubin, AST or ALT) were similar between strata. No relevant PK differences were found between strata. In conclusion, the MTD and RD (1.3 mg/m2) were confirmed only for stratum I. Stratification criteria based on baseline AP apparently did not segregate the patients according to their liver dysfunction degree. Antitumor activity was found in patients with pretreated ovarian cancer. Copyright © Springer Science+Business Media, LLC 2011.


Chu Q.,Cancer Therapy and Research Center | Mita A.,Cancer Therapy and Research Center | Forouzesh B.,Cancer Therapy and Research Center | Tolcher A.W.,Cancer Therapy and Research Center | And 6 more authors.
Clinical Cancer Research | Year: 2010

Purpose: This phase I study evaluated the feasibility, safety, pharmacokinetics (PK), and preliminary evidence of anticancer activity of the sequential administration of paclitaxel and trabectedin on an every-2-week schedule in patients with refractory solid malignancies. The study also sought to determine the maximum tolerated dose (MTD) level on this schedule, as well as to recommend doses for diseasedirected studies. Experimental Design: Twenty-seven patients were treated with paclitaxel (80-120 mg/m2; 1-hour i.v. infusion, day 1) and trabectedin (0.525-0.775 mg/m2; 3-hour i.v. infusion, day 2) with doses increased in successive cohorts. Blood sampling for PK and drug-drug interaction studies was done. Results: Neutropenia, which resulted in treatment delay exceeding 1 week, was the principal doselimiting toxicity for this paclitaxel-trabectedin regimen and precluded dose escalation above 120 mg/m2 paclitaxel and 0.650 mg/m2 trabectedin. At the MTD (120 mg/m2 paclitaxel and 0.650 mg/m2 trabectedin), the safety profile was favorable in patients receiving cumulative treatment. Relevant drug-drug PK interactions between paclitaxel and trabectedin were not identified. A patient with soft tissue sarcoma had a complete response and several patients with various refractory solid malignancies showed protracted stable disease as their best response. Conclusions: The MTD level of sequential paclitaxel 1-hour infusion (day 1) and trabectedin 3-hour infusion (day 2) administered every 2 weeks is 120 and 0.650 mg/m2, respectively. The manageable toxicities at the MTD, preliminary evidence of antitumor activity, and lack of notable PK drug-drug interactions warrant further disease-directed studies of this regimen in relevant tumor types and settings. ©2010 AACR.

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