A phase I study of birinapant (TL32711) combined with multiple chemotherapies evaluating tolerability and clinical activity for solid tumor patients.

Developmental Therapeutics - Clinical Pharmacology and Experimental Therapeutics
Session Type and Session Title: 
Oral Abstract Session, Developmental Therapeutics - Clinical Pharmacology and Experimental Therapeutics
Abstract Number: 
J Clin Oncol 31, 2013 (suppl; abstr 2504)
Ravi K. Amaravadi, Neil N. Senzer, Lainie P. Martin, Russell J. Schilder, Patricia LoRusso, Kyriakos P. Papadopoulos, David Edward Weng, Martin Graham, Alex A. Adjei; Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA; Mary Crowley Cancer Research Center, Dallas, TX; Fox Chase Cancer Center, Philadelphia, PA; Karmanos Cancer Institute, Wayne State University, Detroit, MI; START Center for Cancer Care, San Antonio, TX; TetraLogic Pharmaceuticals, Malvern, PA; Roswell Park Cancer Institute, Buffalo, NY

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Abstract Disclosures


Background: Birinapant (B) is a SMAC-mimetic that inhibits IAPs with excellent tolerability, drug exposure, target suppression and apoptotic pathway activation in clinical studies. Preclinical studies demonstrate potent anti-tumor synergy when B is combined with TNFa-inducing chemotherapies (CT). Methods: Escalating doses of B were combined with CT in a 5-arm 3+3 phase 1 study for adults (pts) with relapsed/refractory solid tumors to determine maximum tolerated dose (MTD), pharmacokinetics (PK), and efficacy to identify indications for further studies. The arms included carboplatin/paclitaxel (CP), irinotecan (I), docetaxel (D), gemcitabine (G), and liposomal doxorubicin (LD). Results: 124 pts were treated with B at doses of 2.8 to 47 mg/m2. The MTD of B for each arm was CP (47 mg/m2); I (22 mg/m2); D (47 mg/m2). The proposed G regimen could not be administered in heavily pretreated pts and B could not be evaluated for dose escalation; this arm was discontinued and no dose-limiting toxicities (DLT) occurred. LD drug shortage prevented dose escalation for B > 35mg/m2 (MTD not reached). B did not limit CT administration for CP, I, D, LD, supporting tolerable combination of B with CT. B-associated toxicity of Bell’s palsy (Grade 2) was considered a DLT and noted at higher dose levels for I, D, and LD, but not CP. This unusual reversible toxicity occurred during cycle 1 in 7 pts. Six of these pts continued therapy without recurrence. PK studies demonstrated no effect of B on CT. Except for CP, CT did not change the PK of B. CP increased plasma PK for B, possibly due to OATP1B3 transporter effects, but without increased B toxicities. 11 pts had a partial response, 61 pts had stable disease (>2 cycles, median 4.6 mo) and 37 pts had progressive disease as their best response, with clinical benefit (CR+PR+SD) of 58%. Conclusions: B can be combined with excellent tolerability with multiple CT at standard dosing. B plus CT demonstrated clinical benefit in many tumor types. Notable clinical activity occurred with I + B in pts who had failed prior I. These results support planning for further clinical studies of the I + B, and support the hypothesis for TNFa-mediated I + B synergy. Clinical trial information: NCT01188499.