Phase I trial of temsirolimus (TEM) plus sorafenib (SOR) in advanced hepatocellular carcinoma (HCC).

Abstract

296 Background: SOR prolongs survival in patients (pts) with HCC. In preclinical studies, mammalian target of rapamycin (mTOR) inhibitors (I) impair HCC growth and angiogenesis. Adding mTOR-I to SOR augments antitumor effect. Phase I studies of mTOR-I plus SOR have shown tolerability but did not include cirrhotic pts. We developed a phase I trial of mTOR-I TEM plus SOR to determine safety, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) in pts with HCC. The study was approved and funded by the National Comprehensive Cancer Network (NCCN). Methods: Eligibility: Advanced HCC diagnosed histologically or clinically. No prior systemic therapy (Tx). Prior resection/local Tx permitted if ≥1 measurable site. ECOG score ≤2, Child-Pugh ≤7, bilirubin ≤2 mg/dL, platelets ≥75,000/mcL. Design: 3+3 escalation to MTD with dose-limiting toxicity (DLT) window 28 days; 6 pts at MTD for pharmacokinetics (PK). Endpoints: 1°: MTD, RP2D. 2°: Safety, toxicity, PK. Results: 9 pts enrolled to date: 7 at DL1, 2 at DL-1. Toxicity: DL1: 1 DLT of Gr3 thrombocytopenia. 1 pt removed for hypertensive urgency, adjudicated not Tx-related. 1 pt not evaluable due to abscess. 1 pt removed for Gr3 hypersensitivity to TEM in cycle 2. All remaining pts required reduction and/or delay for adverse events (AE). Tx-related AE at DL1 include: fatigue 57%, Gr3 11%; weight loss 22%, all Gr1; anorexia 57%, all Gr1/2; diarrhea 71%, all Gr1/2; rash/hand-foot syndrome 71%, Gr3 11%; thrombocytopenia 57%, Gr3 11%; hypophosphatemia 77%, Gr3 57%, refractory 11%. Study de-escalated to DL-1 due to non-DLT cumulative AE. DL-1: 2 pts enrolled have not had DLT nor dose reduction to date. Response: 4 of 7 pts in DL1 were evaluable. 3 of 4 had stable disease as best response. Conclusions: Tx-limiting, class-related AE occurred at DL1 of this double-biologic regimen. MTD in pts with Child-Pugh Class A cirrhosis appears lower than in pts without liver disease. Tolerability and dose delivery must be achieved to determine efficacy. A phase II study with correlative endpoints is planned at RP2D. Updated accrual and results will be presented. [Table: see text] [Table: see text]