Phase Ib study of chidamide (CS055), a new subtype-selective oral histone deacetylase inhibitor, in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer.

Abstract

e19075 Background: Chidamide (CS055) is a new benzamide type of histone deacetylase (HDAC) inhibitor with subtype selective activity against HDAC1, 2, 3 and 10. Synergistic effect of chidamide combined with paclitaxel and carboplatin (PC) have been demonstrated in various in vitro studies. Chidamide has shown well-tolerated and favorable PK profiles in patients (pts) with advanced solid tumors and lymphomas.This phase Ib study was designed to assess the safety and pharmacokinetics of chidamide plus PC in pts with advanced non-small cell lung cancer (NSCLC). Methods: Chemonaive pts with stage IIIb or IV NSCLC were treated with the escalating doses of chidamide (20, 25, and 30mg) plus PC. Chidamide was oral administered twice per week. Paclitaxel (175 mg/m2) and carboplatin (AUC 5 mg·min/mL) were given both on day 1 every 3 weeks. Pts with response or stable disease after four cycles maintained single chidamide therapy until disease progression or unacceptable toxicity. Results: No DLT was observed in the 20 mg (n=3) and 25 mg (n=3) cohorts. 2 DLTs occurred in the 30 mg cohort (n=4), where 1 pt experienced grade 4 thrombocytopenia at the end of the first cycle, and the other developed grade 3 neutropenia and grade 2 thrombocytopenia resulting in the delay of the 2nd treatment cycle for > 14 days. Therefore, chidamide in 25 mg was determined to be the MTD with this combination regimen. ≥ Grade 3 toxicities were thrombocytopenia (n=3) and neutropenia (n=1). 1 pt experienced grade 1 prolonged QTc. Co-administration had no significant effect on clearance of either chidamide or paclitaxel. 1 pt in the 20 mg cohort had confirmed partial response. Of 5 pts with brain metastases, 2 of them had complete disappearance of brain tumors after 4-cycle treatment. Conclusions: Chidamide plus PC was safe and well tolerated, with no apparent chidamide-paclitaxel pharmacokinetic interaction. Preliminary efficacy results suggest that chidamide combined with PC could provide benefit to NSCLC pts, with a potential interest of further observation of brain metastasis control in NSCLC with this regimen. Clinical trial information: ChiCTR-ONC-12002283.