Debio0932, a second-generation oral heat shock protein (HSP) inhibitor, in patients with advanced cancer - results of a first-in-man dose escalation study with a fixed dose extension phase.
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Date publication
février 2015
Auteurs
Membres identifiés du Cancéropôle Est :
Pr FUMOLEAU Pierre
Tous les auteurs :
Isambert N, Delord JP, Soria JC, Hollebecque A, Gomez-Roca C, Purcea D, Rouits E, Belli R, Fumoleau P
Lien Pubmed
Résumé
BACKGROUND: Objective was to determine maximum tolerated dose (MTD), recommended dose (RD) and schedule, safety, pharmacokinetic (PK) profile, pharmacodynamic (PD) effects, and anti-tumor activity of Debio0932, a new second-generation oral heat shock protein (HSP) inhibitor. PATIENTS AND METHODS: This was a multi-center, uncontrolled, open-label, non-randomized, dose-escalation study in adults with treatment-resistant advanced cancer. Groups of 3 patients received oral Debio0932 either daily or every other day. The starting dose of 50 mg was escalated until the MTD was reached, i.e. dose-limiting toxicity (DLT) occurred in >/=2 patients. Further 9 patients and an extension cohort of 30 patients were treated at the next lower dose (=RD). Adverse events (AE), tumor response, PK, and HSP70 levels in peripheral blood mononuclear cells (PBMCs) were recorded over 30 days. RESULTS: Fifty patients were treated with doses up to 1600 mg, at which level three DLT occurred (febrile neutropenia, diarrhea, asthenia). In total, 39 patients were then treated at the RD of 1000 mg daily. Most common drug-related AEs were asthenia and gastrointestinal events. No ocular toxicities were observed. Debio0932 was rapidly absorbed and metabolized. Plasma steady-state was reached within 9 days. Volume of distribution was high and elimination half-life was 9 to 11 h. Food had no effect on PK. PD showed large inter-patient variability, but no dose-effect relationship. Partial tumor response was observed in 2 patients (NSCLC and breast cancer), stable disease in 12 patients (5 of 8 NSCLC patients). In the extension cohort, 9 patients had stable disease, and one patient a partial metabolic tumor response. CONCLUSION: Debio0932 has limited clinical activity, together with manageable toxicity. Further development as adjunct treatment of NSCLC at daily doses of 1000 mg is warranted.
Référence
Ann Oncol. 2015 Feb 2. pii: mdv031.