Abstract C2: Clinical safety, pharmacokinetics and early evidence of activity of the oral IAPs inhibitor Debio 1143 in combination with carboplatin and paclitaxel: a phase Ib study
Authors: Ray-Coquard Isabelle , Le Tourneau Christophe , Isambert Nicolas , Gomez-Roca Carlos A. , Cassier Philippe , Sablin Marie Paule , Gavillet Bruno , Purcea Daniela , Rouits Elisabeth , Schusterbauer Claudia , Zanna Claudio , Fumoleau Pierre , Delord Jean-Pierre 
Published: May 2016

Abstract
Background: Resistance to apoptosis is a typical hallmark of cancer. Inhibitor of Apoptosis Proteins (IAPs) block caspase activation, modulate NF-kB signaling pathways, and are involved in resistance to standard chemo and radiation therapies. As such, IAPs antagonism represents an attractive target for therapeutic intervention. Debio 1143 is a potent orally-available monovalent SMAC mimetic antagonist of IAPs currently in clinical development. A previous phase I study showed Debio 1143 was well tolerated up to 900 mg QD as a single agent, with strong evidence of pharmacodynamic (PD) activity and appropriate pharmacokinetic (PK) disposition at doses ≥ 120 mg. [1] This Phase I study defined the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, PK, and PD of Debio 1143 in combination with carboplatin and paclitaxel.
Methods: Treatment-naïve and previously treated patients with squamous non-small cell lung cancer (NSCLC), and previously treated patients with triple negative breast cancer (TNBC) and platinum-resistant epithelial ovarian cancer (EOC) were treated with carboplatin (AUC 6) and paclitaxel 175 mg/m2 on day 1 of every 21-day-cycle up to a maximum of 6 cycles, combined with escalating doses of Debio 1143, administered once daily on days 1-5 of every 21-day cycle. The starting dose of Debio 1143 was 200 mg QD.
Results: Thirty-one patients were included in the study. Four patients are still on treatment. Hematological DLTs were observed in 2/4 patients in the first two dose levels despite the reduction of Debio 1143 dose to 100 mg. PK data suggested a PK interaction between Debio 1143 and paclitaxel. The study protocol was amended to reduce the doses of carboplatin to AUC 5 and paclitaxel to 135 mg/m2. Afterwards, patients received Debio 1143 doses of 100 mg (n = 2), 125 mg (n = 2), 175 mg (n = 2), 200 mg (n = 7), 225 mg (n = 5), 250 mg (n = 9). DLTs were febrile neutropenia (n = 2) and G3 ALT increase (n = 1). The MTD of Debio 1143 to be combined with carboplatin (AUC 5) and paclitaxel (135 mg/m2) is 250 mg QD. Most common treatment-related AEs reported in ≥ 15% of patients were asthenia (n = 13), decreased appetite (n = 11), diarrhea (n = 9), neutropenia (n = 9), thrombocytopenia (n = 8), anemia (n = 8), nausea (n = 7), fatigue (n = 7), vomiting (n = 4), AST increase (n = 4), hypomagnesaemia (n = 4), myalgia (n = 4),and epistaxis (n = 4). Paclitaxel exposure in patients dosed at 135 mg/m2 in combination with Debio 1143 was similar to historical control dosed at 175 mg/m2 due to a 25 to 40% reduction in clearance. Preliminary evaluation of PD endpoints confirmed Debio 1143-induced cIAP1 degradation in PBMCs at doses starting from 100mg. In line with the expected mechanism of action, modulation of serum PD markers of NF-kB signaling pathways and epithelial apoptosis was also observed during treatment. Twenty-three patients were evaluable for response. Partial responses by RECIST have been observed in 7 patients with EOC (6/17) and TNBC (1/5).
Conclusions: The combination of Debio 1143 with carboplatin and paclitaxel is well tolerated, with significant PD activity and hints of activity. The clinical PK interaction between Debio 1143 and paclitaxel is well-controlled and managed in the patients. These findings support a further Phase II program.
[1] HI Hurwitz et al., Cancer Chemother Pharmacol (2015) 75:851
Citation Format: Isabelle Ray-Coquard, Christophe Le Tourneau, Nicolas Isambert, Carlos A. Gomez-Roca, Philippe Cassier, Marie Paule Sablin, Bruno Gavillet, Daniela Purcea, Elisabeth Rouits, Claudia Schusterbauer, Claudio Zanna, Pierre Fumoleau, Jean-Pierre Delord. Clinical safety, pharmacokinetics and early evidence of activity of the oral IAPs inhibitor Debio 1143 in combination with carboplatin and paclitaxel: a phase Ib study. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C2.