Phase II clinical activity and tolerability of the SMAC-mimetic birinapant (TL32711) plus irinotecan in irinotecan-relapsed/refractory metastatic colorectal cancer

Autor: David Weng, Ravi K. Amaravadi, Zdenka E Segota, Kyriakos P. Papadopoulos, Lainie P. Martin, Alex A. Adjei, Neil Senzer, Martin C. Graham, Russell J. Schilder, Patricia LoRusso
Rok vydání: 2013
Předmět:
Zdroj: Journal of Clinical Oncology. 31:3621-3621
ISSN: 1527-7755
0732-183X
DOI: 10.1200/jco.2013.31.15_suppl.3621
Popis: 3621 Background: Birinapant (B) is a SMAC-mimetic that inhibits IAPs and has potent preclinical anti-tumor synergy combined with TNFa-inducing chemotherapies [i.e irinotecan (I)]. B and I combination is well-tolerated and has encouraging activity in a phase 1 study. This study tested B+I with an ascending dose strategy (ADS) of B to mitigate Bell’s palsy (BP) risk, an unusual and reversible side effect of SMAC mimetics. Methods: I at 350mg/m2 IV q3weeks was administered with B weekly (2 of 3 weeks). The dose of B was titrated incrementally during Cycle 1: C1D1 at 5.6mg/m2 and C1D8 at 11mg/m2 for ADS. For Cycle 2 (C2) and ongoing treatment, the B dose was 22mg/m2 or 35mg/m2, which were the MTD and DLT (BP) dose levels when combined with I from the Ph 1 study. Safety and clinical activity for KRAS mutant (KRAS-MT) and wild-type (KRAS-WT) were assessed in 3 cohorts: (1) at 22mg/m2 for CRC KRAS MT; (2) 22mg/m2 for CRC KRAS WT; (3) 35mg/m2 for CRC KRAS MT. Results: 51 patients (pts) with CRC had a median number of 4 prior regimens with 47 refractory/relapsed to irinotecan (92%). Tolerability was comparable to I alone. There were 2 PRs (4%), 27 SD (>2 cycles; 53%, median 4.7 mo), 17 PD (33%), and 5 non- evaluable pts (9%) for an overall clinical benefit (CR+PR+SD) rate of 57%. Median progression-free survival (PFS) was 2.1 months, and 6 mo PFS was 20%. KRAS MT CRC with prior I had a median PFS of 2.9 mo and 6 mo PFS of 25% (n=20). KRAS WT CRC with prior I had a median PFS of 1.4 mo and 6 mo PFS of 17% (n=18). The ADS seemed to reduce BP risk. No BP events occurred among 40 pts (22mg/m2 with ADS), compared to 1 of 7 pts (22mg/m2 without ADS). In the 35mg/m2 cohort, 1 BP event occurred among 12 pts (with ADS), compared to 3 of 6 (35mg/m2 without ADS). Conclusions: B + I demonstrated clinical benefit in pts refractory/relapsed to irinotecan, with greatest benefit in KRAS MT CRC. The ADS may provide a mitigation strategy for BP risk. Prior studies with I retreatment have showed no benefit in KRAS MT CRC. Comparable CRC pts with best supportive care have 6 mo PFS of 2%. Clinical activity supports the hypothesis for therapeutic synergy of B + I, with I as a TNFa-inducing agent. Further study of this combination is warranted. Clinical trial information: NCT01188499.
Databáze: OpenAIRE
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