Aplidin por sí sola o con dacarbazine como tratamiento de primera línea para el Melanoma Avanzado Inoperable (AUM)
Plitidepsin (APL) alone or with dacarbazine (DTIC) as first-line treatment for advanced unresectable melanoma (AUM).
Sub-category: Melanoma
Category: Melanoma/Skin Cancers
Meeting: 2010 ASCO Annual Meeting
Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr 8537)
Abstract No: 8537
Author(s): E. R. Plummer, P. Lorigan, L. Hayward, J. Jassem, L. Demidov, V. Moiseyenko, V. Soriano, E. Chmielowska, R. Prados, S. Szyldergemajn; Northern Centre For Cancer Care, Newcastle upon Tyne, United Kingdom; The Christie NHS Foundation Trust, Manchester, United Kingdom; Western General Hospital, Edinburgh, United Kingdom; Medical University of Gdansk, Gdansk, Poland; Russian Cancer Research Center, Moscow, Russia; N. N. Petrov Research Institute of Oncology, St. Petersburg, Russia; Instituto Valenciano de Oncologia, Valencia, Spain; Centrum Onkologii Prof. F. Lukaszczyka, Bydgoszcz, Poland; PharmaMar, Colmenar Viejo, Madrid, Spain
Abstract:
Background: In patients (pts) with AUM, DTIC alone is associated with response rates (RR) 8%-15%. Aplidin, a novel cytotoxic, gave a RR of 6% as second line therapy in AUM. APL+DTIC have shown additive cytotoxicity in preclinical models. In the prior dose-finding stage of this study, 16% of 19 evaluable pts had a partial response (PR). Recommended dose (RD) was APL 2.4 mg/m2/d 1, 8 and 15 + DTIC 800 mg/m2/d1 q4w (Plummer, J Clin Oncol 27:15s, 2009; abstr 9059). Methods: A randomized 2 stage phase II study aim to determine the activity of Arm A (APL3.2 mg/m2/d 1, 8 and 15 q4w) or Arm B (APL+DTIC) at their established RD was performed. If at least 2 responses were observed per arm after 17 evaluable pts, 13 more pt would be included in the second stage. Results: 20 pts were randomized to Arm A and 38 pt (2 not treated) to Arm B (ITT population). Of these, 17 and 29 pts, respectively were evaluable for efficacy (PP population). Baseline characteristics were: 52% males; median (med) age, 53 y (range: 21-78); med ECOG, 1 (0-2); and med LDH 1.2 upper limit normal (0.4-8.2). All pts had metastases, with a med of 2 sites involved (1-6). Arm A was discontinued as no responses were seen; Arm B continued to stage 2. In arm B, relative dose intensity was 67% and 99% for APL and DTIC, respectively. Most frequent reason for missing doses was grade (G) 2/3 ALT/AST increase. Common mild toxicities included nausea, vomiting, hypersensitivity (G3/4 reactions in 9%), myalgia, diarrhea, and constipation. G1/2 anemia occurred in 61% of pts, and G3/4 neutropenia or thrombocytopenia in 6 and 8% of pts respectively, with no febrile neutropenia. Antitumor activity included 1 (3%) complete response, 6 (21%) PR and 8 (28%) stabilizations (SD); disease control rate (CR+PR+SD) was 52% (PP) and 42% (ITT). As of Dec 2009, with a med follow-up of 4 months, PFS is 3 months (95%CI: 2-5) and 96% of pts are alive at 1 year (95% CI: 89-100%). Pharmacogenomic analyses are ongoing. Conclusions: Weekly APL alone showed no activity in AUM, while combined with DTIC showed encouraging activity. Toxicity was manageable and non-life threatening, but it led to frequent APL dose omissions. A biweekly schedule should undergo clinical evaluation.