Phase 1 trial of navitoclax and sorafenib in patients with relapsed or refractory solid tumors with hepatocellular carcinoma expansion cohort

Oluwadunni E. Emiloju, Jun Yin, Emily Koubek, Joel M. Reid, Mitesh J. Borad, Yanyan Lou, Mahesh Seetharam, Martin J. Edelman, Edward A. Sausville, Yixing Jiang, Ahmed O. Kaseb, James A. Posey, Sarah L. Davis, Gregory J. Gores, Lewis R. Roberts, Naoko Takebe, Gary K. Schwartz, Andrea E.Wahner Hendrickson, Scott H. Kaufmann, Alex A. AdjeiJoleen M. Hubbard, Brian A. Costello

Research output: Contribution to journalArticlepeer-review


Navitoclax (ABT-263) is an oral BCL2 homology-3 mimetic that binds with high affinity to pro-survival BCL2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor also promotes apoptosis and inhibits tumor angiogenesis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. In this phase 1 study, we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). Maximum tolerated dose (MTD) was determined using the continual reassessment method. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. Ten patients were enrolled in the dose escalation cohort and 15 HCC patients were enrolled in the expansion cohort. Two dose levels were tested, and the MTD was navitoclax 150 mg daily plus sorafenib 400 mg twice daily. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities. Patients received a median of 2 cycles (range 1–36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, and there were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Navitoclax plus sorafenib is tolerable but showed limited efficacy in the HCC expansion cohort. These findings do not support further development of this combination for the treatment of advanced HCC. This phase I trial was conducted under registry number NCT01364051.

Original languageEnglish
Pages (from-to)127-135
Number of pages9
JournalInvestigational New Drugs
Issue number1
Early online dateDec 25 2024
StateAccepted/In press - 2024


  • Navitoclax
  • Sorafenib
  • BCL2
  • Hepatocellular carcinoma
  • ABT-263
  • Niacinamide/adverse effects
  • Sorafenib/therapeutic use
  • Aniline Compounds
  • Humans
  • Antineoplastic Combined Chemotherapy Protocols/adverse effects
  • Phenylurea Compounds/adverse effects
  • Carcinoma, Hepatocellular/drug therapy
  • Sulfonamides
  • Liver Neoplasms/drug therapy


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