Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study

Herbert I Hurwitz, David C Smith, Henry C Pitot, Jeffrey M Brill, Rashmi Chugh, Elisabeth Rouits, Joseph Rubin, John Strickler, Gregoire Vuagniaux, J Mel Sorensen, Claudio Zanna, Herbert I Hurwitz, David C Smith, Henry C Pitot, Jeffrey M Brill, Rashmi Chugh, Elisabeth Rouits, Joseph Rubin, John Strickler, Gregoire Vuagniaux, J Mel Sorensen, Claudio Zanna

Abstract

Purpose: To assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of DEBIO1143, an antagonist of inhibitor apoptosis proteins.

Methods: This first-in-man study in patients with advanced cancer used an accelerated dose titration design. DEBIO1143 was given orally once daily on days 1-5 every 2 or 3 weeks until disease progressed or patients dropped out. The starting dose of 5 mg was escalated by 100% in single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of three and subsequently six patients and reduction in dose increments to 50%. Maximum tolerated dose (MTD) was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken.

Results: Thirty-one patients received doses from 5 to 900 mg. Only one DLT was reported at 180 mg. No MTD was found. Most common adverse drug reactions were fatigue (26%), nausea (23%), and vomiting (13%). Average t max and T 1/2 was about 1 and 6 h, respectively. Exposure increased proportionally with doses from 80 to 900 mg, without accumulation over 5 days. Plasma CCL2 increased at 3-6 h postdose and epithelial apoptosis marker M30 on day 5; cIAP-1 levels in PBMCs decreased at all doses >80 mg. Five patients (17%) had stable disease as the best treatment response.

Conclusion: DEBIO1143 was well tolerated at doses up to 900 mg and elicited PD effects at doses greater 80 mg. Limited antitumor activity may suggest development rather as adjunct treatment.

Trial registration: ClinicalTrials.gov NCT01078649.

Figures

Fig. 1
Fig. 1
Patient flowchart according to CONSORT. DP disease progression (second line: duration of stable disease); UPR upon patient request
Fig. 2
Fig. 2
Dose proportionality of Cmax and AUCinf
Fig. 3
Fig. 3
Expression of cIAP. a in skin biopsies of 12 patients (H-scores; on the top). b in PBMC (quantitative Western blot results as % from baseline) across doses (on the bottom; for results per dose see Suppl. 2)
Fig. 4
Fig. 4
Pharmacodynamic measurements

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