Phase I trial of temsirolimus (TEM) plus sorafenib (SOR) in advanced hepatocellular carcinoma (HCC) with pharmacokinetic (PK) and biomarker correlates.

Abstract

4102 Background: Mammalian target of rapamycin inhibitors added to SOR augment antitumor effect in HCC models. We developed a phase 1 trial to determine maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of TEM plus SOR in HCC patients (pts). The study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support from Pfizer, Inc., and conducted at 2 NCCN centers. Methods: Eligibility: ≥1 measurable site. No prior systemic therapy (Tx). ECOG ≤2, Child Pugh ≤7, bilirubin ≤2 mg/dL, platelets (PLT) ≥75,000/mcL. Design: 3+3 escalation. Dose-limiting toxicity (DLT) window 28 days. MTD expansion cohort of 9 pts for PK and biomarkers. Endpoints: 1°: MTD, RP2D. 2°: Safety, toxicity, PK for TEM. Exploratory: Tumor necrosis, alpha fetoprotein (AFP)-L3, des-γ-carboxyprothrombin, and circulating tumor cells (CTC) by slide-based assay. Results: 21 pts enrolled. Median age: 60 (47-77). Male/Female: 15/6. Etiology: HCV 9 (43%), HBV 4 (19%), HBV+HCV 2 (10%), ETOH 2 (10%), unknown 4 (19%). Toxicity: DL1: 1 DLT Grade (Gr) 3 PLT. All pts required reductions for adverse events (AE); de-escalated to DL-1 for intolerability. DL-1: 1 DLT Gr3 hand-foot syndrome (HFS). Most common related ≥Gr 3 AE: HypoPO4 (52%); PLT (24%); transaminitis (19%); diarrhea, fatigue, HFS (10% each). Possibly related serious AE (SAE): Gr4 tumor rupture, Gr4 urosepsis, Gr3 dental infection with Gr2 ANC, Gr2 pneumonia (1 pt, 5% each). Best response: Confirmed partial response (PR) 2/21 (10%), stable disease (SD) 11/21 (52%), progression 1/21 (5%), 7/21 (33%) not evaluable. Time on study: Range <1 to 19+ months; median 3+ months for pts who completed ≥1 cycle (16/21). 16/21 (76%) had baseline elevated AFP ≥20; 8/16 (50%) had >50% decline. CTC were detected in 5/5 of tested samples. Decreased tumor enhancement on Tx was seen. Conclusions: DL-1 is MTD and RP2D, lower than a prior trial in pts without HCC; tolerability may be impacted by cirrhosis. Encouraging durable radiographic and AFP responses occurred. [Table: see text]