First-in-human study of palcitoclax (APG-1252), a novel dual Bcl-2/Bcl-xL inhibitor, demonstrated advantages in platelet safety while maintaining anticancer effect in U.S. patients with metastatic solid tumors

Autor: Jason Chen, Nehal Lakhani, Qi Zeng, Zhiyan Liang, Drew W. Rasco, Lei Fu, Cunlin Wang, Dajun Yang, Ming Lu, Yifan Zhai, Yuefen Tang, Hengbang Wang
Rok vydání: 2020
Předmět:
Zdroj: Journal of Clinical Oncology. 38:3509-3509
ISSN: 1527-7755
0732-183X
DOI: 10.1200/jco.2020.38.15_suppl.3509
Popis: 3509 Background: Targeting Bcl-2/Bcl-xL proteins is considered as an important approach for anticancer drug development. Palcitoclax (APG-1252) was being developed to reduce on-target platelet toxicity without diminishing antitumor potency. Methods: The phase 1 study was to evaluate the safety/tolerability, pharmacokinetics (PK), and preliminary efficacy (assessed per RECIST 1.1) of palcitoclax in US patients with metastatic small-cell lung cancer (SCLC) or other solid tumors (NCT03080311). A standard “3+3” design was applied to the dose-escalation stage. Palcitoclax was administered IV infusion for 30 minutes, twice a week (BIW) or once a week (QW) for 3 weeks in a 28-day cycle. Once the maximum tolerated dose / recommended phase 2 dose (MTD/RP2D) was determined, additional patients were treated in a dose-expansion stage. Results: The dose-escalation phase has been completed with 42 patients (31 on BIW and 11 on QW) who received palcitoclax at 8 dose cohorts ranging 10 mg - 400 mg. Most adverse events (AEs) were grade 1 or 2 (G1 or G2), and 26.2% patients had ≥ G3 TRAEs. The most common TRAEs were platelet count decreased (14.3%), aspartate aminotransferase increased (9.5%), and alanine aminotransferase increased (7.1%). Rapid platelet drop was observed in patients treated at 320 mg and 400 mg, which was transient and resolved rapidly within 2-6 days. Palcitoclax at 240 mg once weekly was determined to be MTD/RP2D. Of 36 efficacy-evaluable patients, 3 patients with SCLC, neuroendocrine prostate cancer, and ovarian cancer respectively achieved partial response (PR) and 8 patients had stable disease (SD) as their best overall response. One patient with SCLC had a PR that lasted over 21 cycles. Preliminary PK analyses showed that Cmax and AUC were approximately dose proportional over the range of 10 mg to 320 mg following the IV infusion on Day 1, with a mean T1/2 of 3.0-13.0 hours. Conclusions: Palcitoclax is safe and well tolerated, with a favorable platelet toxicity profile. Its promising antitumor effect supports its further development in combination therapies for treatment of patients with SCLC and other solid tumors. Clinical trial information: NCT03080311 .
Databáze: OpenAIRE
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