First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies.

Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-escalation study, in which CRLX101 was administered intravenously over 60 min among two dosing schedules, initially weekly at 6, 12, and 18 mg/m(2) and later bi-weekly at 12, 15, and 18 mg/m(2). The maximum tolerated dose (MTD) was determined at 15 mg/m(2) bi-weekly, and an expansion phase 2a study was completed. Patient samples were obtained for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Response was evaluated per RECIST criteria v1.0 every 8 weeks. Sixty-two patients (31 male; median age 63 years, range 39-79) received treatment. Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting toxicity. Among all phase 1/2a patients receiving the MTD (n = 44), most common grade 3/4 adverse events were neutropenia and fatigue. Evidence of systemic plasma exposure to both the polymer-conjugated and unconjugated CPT was observed in all treated patients. Mean elimination unconjugated CPT Tmax values ranged from 17.7 to 24.5 h, and maximum plasma concentrations and areas under the curve were generally proportional to dose for both polymer-conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 %) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC patients was 4.4 months. These combined phase 1/2a data demonstrate encouraging safety, pharmacokinetic, and efficacy results. Multinational phase 2 clinical development of CRLX101 across multiple tumor types is ongoing.

Phase 2 trials: the missing link in new drug development?

El objetivo de los programas de desarrollo de drogas anticancer es producir agentes con eficacia contra tumores en humanos. La Fase 2 es la primera investigación diseñada específicamente para probar la eficacia antineoplásica. Podría condiserarse el componente más importante de un programa de desarrollo de drogas, pero tradicionalmente, ha sido quizás el eslabón más débil. Los estudios Fase 2 están destinados a rastrear nuevos agentes y determinar su actividad contra una variedad de diferentes tipos de tumores. También ofrecen al paciente la oportunidad de un tratamiento mejor que aquel disponible atualmente. Los pacientes que particpan en los estudios Fase 2 no deben tener cánceres avanzados o refractarios. Esta ha sido una área deficiente en estudio Fase 2 anteriores. Hay poca posibilidad de que pacientes que anteriormente hayan sido objeto de un tratamiento intensivo repsondan a un agente antineoplástico no importa cuan efectivo haya sido éste en pacientes que no hayan recibido terapia previa contra el cáncer. El objetivo final del estudio 2 es determinar la respuesta del tumor. Es la responsabilidad del investigador clínico asegurar que drogas Fase 2 sean ofrecidas a pacientes de cáncer en un ambiente en el que tanto el paciente con el agente tengan la mayor opoetunidad de éxito