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.

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.

Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients.

This study aims at establishing relationships between genetic and non-genetic factors of variation of the pharmacokinetics of irinotecan and its metabolites; and also at establishing relationships between the pharmacokinetic or metabolic parameters and the efficacy and toxicity of irinotecan. We included 49 patients treated for metastatic colorectal cancer with a combination of 5-fluorouracil and irinotecan; a polymorphism in the UGT1A1 gene (TA repeat in the TATA box) and one in the CES2 gene promoter (830C>G) were studied as potential markers for SN-38 glucuronidation and irinotecan activation, respectively; and the potential activity of CYP3A4 was estimated from cortisol biotransformation into 6beta-hydroxycortisol. No pharmacokinetic parameter was directly predictive of clinical outcome or toxicity. The AUCs of three important metabolites of irinotecan, SN-38, SN-38 glucuronide and APC, were tentatively correlated with patients' pretreatment biological parameters related to drug metabolism (plasma creatinine, bilirubin and liver enzymes, and blood leukocytes). SN-38 AUC was significantly correlated with blood leukocytes number and SN-38G AUC was significantly correlated with plasma creatinine, whereas APC AUC was significantly correlated with plasma liver enzymes. The relative extent of irinotecan activation was inversely correlated with SN-38 glucuronidation. The TATA box polymorphism of UGT1A1 was significantly associated with plasma bilirubin levels and behaved as a significant predictor for neutropoenia. The level of cortisol 6beta-hydroxylation predicted for the occurrence of diarrhoea. All these observations may improve the routine use of irinotecan in colorectal cancer patients. UGT1A1 genotyping plus cortisol 6beta-hydroxylation determination could help to determine the optimal dose of irinotecan.