Elsevier

Annals of Oncology

Volume 26, Issue 5, May 2015, Pages 1005-1011
Annals of Oncology

original articles
early drug development
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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ABSTRACT

The second-generation oral heat shock protein inhibitor Debio0932 showed almost linear pharmacokinetics and some clinical activity along with manageable toxicity, particularly in patients with NSCLC. Further development in this indication at daily doses of 1000 mg, preferentially in combination with other anticancer agents is warranted.

Background

Objective was to determine maximum tolerated dose (MTD), recommended dose (RD) and schedule, safety, pharmacokinetic (PK) profile, pharmacodynamic (PD) effects, and antitumor activity of Debio0932, a new second-generation oral heat shock protein (HSP) inhibitor.

Patients and methods

This was a multicenter, uncontrolled, open-label, nonrandomized, dose-escalation study in adults with treatment-resistant advanced cancer. Groups of three 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 (AEs), tumor response, PK, and HSP70 levels in peripheral blood mononuclear cells 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 9–11 h. Food had no effect on PK. PD showed large interpatient variability, but no dose–effect relationship. Partial tumor response was observed in 2 patients (NSCLC and breast cancer), stable disease (SD) in 12 patients (5 of 8 NSCLC patients). In the extension cohort, 9 patients had SD, and 1 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.

Clinical trial

NCT01168752.

Key words

heat shock protein
Debio0932
NSCLC
pharmacokinetic

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