Comentaré brevemente los 2 abstracts que THLD presenta en ASCO (no veo ninguno de páncreas, pero juraría haberlo visto en alguna parte).
El de leucemias:
Phase I study of TH-302, a hypoxia-activated cytotoxic prodrug, in subjects with advanced leukemias.
Category: Leukemia, Myelodysplasia, and Transplantation
Abstract No: 6585
Citation: J Clin Oncol 30, 2012 (suppl; abstr 6585)
Author(s): Marina Konopleva, Damian Handisides, Gustavo A. Lorente, Juliana M. Benito, Mary Ann Richie, Gautam Borthakur, Elias Jabbour, Stefan Faderl, Jorge E. Cortes, Stewart Kroll, Michael Andreeff, Hagop Kantarjian, Deborah A. Thomas; University of Texas M. D. Anderson Cancer Center, Houston, TX; Threshold Pharmaceuticals, South San Francisco, CA
Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard designed to be selectively activated in hypoxic conditions. Preclinical data in mice with ALL have demonstrated marked expansion of hypoxia in areas of marrow leukemia infiltrates (Benito et al., PlosOne, in press). TH-302 also exhibited specific hypoxia-dependent cytotoxicity when tested against primary ALL and AML samples in vitro. Based on these findings, a phase 1 study of TH-302 was designed for advanced leukemias. Methods: Eligibility: ECOG ≤ 3, relapsed/refractory leukemias for which no standard therapy options were available, and acceptable hepatorenal function. A standard 3+3 dose escalation design was used with 40% dose increments. TH-302 was administered IV over 30-60 minutes daily on Days 1-5 of a 21-day cycle. The objectives were to determine the MTD and PK profile of TH-302 with this schedule and to assess preliminary clinical activity of TH-302. Results: 34 subjects with previously treated AML (n=26), ALL (n=6) or CML in blast phase (n=1) received TH-302 at doses of 120 (n=4), 170 (n=4), 240 (n=3), 330 (n=3), 460 (n=16) or 550 (n=4) mg/m². No skin or mucosal toxicity was noted in participants treated with TH-302 doses ≤240 mg/m2. At 330 mg/m2, grade 2 dermatological toxicities included skin ulcer (n=1) and hand/foot syndrome (n=1). Grade 2 mucositis (n=3) and grade 2 skin toxicity (e.g. skin rash, skin ulcers; n=3) were reported at 460 mg/m2; none were dose-limiting. Two of 3 evaluable subjects treated at the 550 mg/m2 cohort experienced DLTs of grade 3 esophagitis. Eight subjects had stable disease or better after 1 cycle. One ALL subject (at 120 mg/m2) cleared marrow blasts with persistent neutropenia. One AML subject (at 550 mg/m2) achieved CRp after 1 cycle with resolution of leukemia cutis. Conclusions: TH-302 administered daily for 5 consecutive days every 3 weeks is well-tolerated with increased incidence of skin and mucosal toxicity at higher dose levels. Clinical activity has been noted with a few objective responses, but majority of cytoreductions in the AML subset were transient. Clinical trials combining TH-302 with various chemotherapeutics with established efficacy in AML and ALL are planned.
Resultados alentadores, pero muy preliminares. Bien en cuanto a toxicidad/tolerancia. Es pronto para valorar eficacia que, en cualquier caso, habrá que valorar en tratamiento combinado, no único (lo normal). Tampoco era el objetivo.
pijusmagnificus ha comentado, de forma bastante optimista, que "1 de cada 4 pacientes a 550 les fue de puta madre con una respuesta completa después de un ciclo. Esto es lo que vale!!". No creo que sea lo más relevante, porque también dice que la mayoría de las respuestas (en general, no sólo a la dosis máxima ensayada) han sido transitorias; me interesa más el que 8 (de 34) hayan mostrado "enfermedad estable o mejor" tras un ciclo. Además, de los 4 tratados a 550 mg/m2 sólo 3 son "evaluables" y 2 han mostrado toxicidad (esofagitis grado 3) que ha limitado la dosis (tal vez por eso sólo son evaluables 3). En principio, eso indicaría que la dosis máxima tolerada (MTD) resultante del estudio sería 460 mg/m².
______________________________________________________________________
"Minidiccionario":
MTD = maximal tolerated dose = dosis máxima tolerada
PK = farmacocinética
ALL = leucemia linfocítica aguda
AML = leucemia mielocítica aguda
CML = leucemia mielocítica crónica
CRp = eliminación de blastos de médula ósea
DLTs = Dose limiting toxicities = toxicidad limitante de la dosis