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

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Summary

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 ClinicalTrials.gov registry number NCT01364051.

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Acknowledgements

We acknowledge Dr Rory Smoot for his contribution to the preclinical development of this study; Dr. Andrew Ralya and Dr. Ramy Abdelrahman who contributed to the design of the early pharmacokinetics studies and analysis; and Renee McGovern, for her contribution to the development of the assays for navitoclax and sorafenib.

Funding

Supported by the Mayo Clinic U01 (CA069912), UM1 (CA186686), P30 (CA015083), and Hepatobiliary SPORE (P50 CA210964) grants.

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Author notes

  1. Joleen M. Hubbard and Brian A. Costello are co-senior authors.

Authors and Affiliations

  1. Division of Medical Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA

    Oluwadunni E. Emiloju, Andrea E. Wahner Hendrickson, Scott H. Kaufmann, Joleen M. Hubbard & Brian A. Costello

  2. Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA

    Jun Yin

  3. Department of Molecular Pharmacology and Experimental Therapeutics (MPET), Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA

    Emily Koubek, Joel M. Reid & Scott H. Kaufmann

  4. Department of Hematology and Oncology, Mayo Clinic, 5881 E. Mayo Blvd., Phoenix, AZ, 85054, USA

    Mitesh J. Borad & Mahesh Seetharam

  5. Department of Hematology & Oncology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Yanyan Lou

  6. Department of Hematology/Oncology, Fox Chase Cancer Center, Lewis Katz School of Medicine, Philadelphia, PA, 19111, USA

    Martin J. Edelman

  7. Division of Hematology/Oncology, University of Maryland School of Medicine, 22 S. Greene Street, Baltimore, MD, 21201, USA

    Edward A. Sausville & Yixing Jiang

  8. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Ahmed O. Kaseb

  9. Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    James A. Posey

  10. University of Colorado Cancer Center - Anschutz Medical Campus, 1665 Aurora Ct, Aurora, CO, 80045, USA

    Sarah L. Davis

  11. Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA

    Gregory J. Gores & Lewis R. Roberts

  12. Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute, Bethesda, MD, 20892, USA

    Naoko Takebe

  13. Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA

    Gary K. Schwartz

  14. Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, 44195, USA

    Alex A. Adjei

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  1. Oluwadunni E. Emiloju
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Contributions

O.E.- data interpretation, manuscript writing and review; J.Y.- study design, safety monitoring, data analysis and data management, manuscript review; E.K.- data analysis, writing and review of manuscript; J.R.- development of preclinical data, study design, correlative studies, manuscript review; M.E., M.B., Y.L., M.S., E.S., Y.J., A.K., J.P., S.D. were sub-Investigators at study sites, and reviewed the manuscript; N.T.- conception and design of the study, data analysis and interpretation, editing the manuscript and review the data, Final approval of the version to be published, (she was a CRADA PI for the NCI ABT263 program and submitted an IND to the FDA); G.G., L. R., G.S.- study design, manuscript review and approval of submission; A.W.H., S.K. - scientific input in trial rationale, reviewed manuscript; B.C, J.H., and A.A. - Oversight of study conduct, patient enrollment and management, Manuscript writing. All authors reviewed the manuscript.

Corresponding author

Correspondence to Brian A. Costello.

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Competing interests

J. R.- Consulting or Advisory Role for Elucida Oncology. Y.L.- Consulting or Advisory Role for AstraZeneca, Janssen, Lilly, Turning Point Therapeutics; Research Funding to Institution from Merck, Tolero Pharmaceuticals, Blueprint Medicines, Daiichi Sankyo, Genmab, Mirati Therapeutics, Roche/Genentech. M.S.- Honoraria from Horizon CME, Daiichi Sankyo, Deciphera, AADi; Travel, Accommodations, Expenses from Horizon CME. M.E.-Consulting or Advisory Role for WindMIL, Flame Biosciences, Sanofi/Regeneron, Kanaph Therapeutics, Coherus BioSciences, GE Healthcare, BioAtla; Travel, Accommodations, Expenses from Nektar; Research Funding to institution from Bristol-Myers Squibb, Apexigen, Nektar, GlaxoSmithKline, Windmil, United Therapeutics; Patent application for radiopharmaceutical to treat small cell lung cancer by Institution; Stock and Other Ownership Interests in Biomarker Strategies, Creatv MicroTech; Other Relationship: AstraZeneca/MedImmune, Boehringer Ingelheim, Takeda, Seagen, Anheart Therapeutics. A.K.- Consulting or Advisory Role for Bayer Health, Bristol-Myers Squibb, Merck, Exelixis, Genentech/Roche, Eisai, AstraZeneca; Research Funding to institution from Bristol-Myers Squibb, Merck, Bayer/Onyx, Genentech, Adaptimmune, Hengrui Pharmaceutical; Honoraria from Merck, Exelixis, Bayer Health, Bristol-Myers Squibb, Eisai, Genentech/Roche, AstraZeneca; Travel, Accommodations, Expenses from Exelixis, Merck, Bayer/Onyx, Bristol-Myers Squibb, Eisai, Genentech/Roche, AstraZeneca. J.P.- Consulting or Advisory Role for Lilly, Seagen. S.D.- Research Funding to institution from Bristol-Myers Squibb, Merck, Boston Scientific, Symphogen, I-Mab, TriSalus Life Sciences, Tvardi Therapeutics, EMD Serono, ORIC Pharmaceuticals; Stock and Other Ownership Interests in Johnson & Johnson/MedTech. L.R- has received grant support from ARIAD Pharmaceuticals, Bayer, BTG International, Exact Sciences, Gilead Sciences, Glycotest, RedHill, Target PharmaSolutions, and Wako Diagnostics; he has provided advisory services to Bayer, Exact Sciences, Gilead Sciences, GRAIL, QED Therapeutics, and TAVEC. G.S.- Consulting or Advisory Role to Bionaut Labs, Ellipses Pharma, Gencirq, Epizyme, Array BioPharma, Apexigen, Oncogenuity, Oncusp Therapeutics, Concarlo, Shanghai Pharma, Astex Pharmaceuticals, January Therapeutics, Sellas Life Sciences, PureTech, AADi, Kirilys Therapeutics, Agenus, Boehringer Ingelheim, Ipsen; Travel, Accommodations, Expenses from Array BioPharma, Epizyme, Boehringer Ingelheim; Patents, Royalties, Other Intellectual Property by institution Companion diagnostics for CD4 inhibitors, Patent granted to develop a new technology called PNAs for cancer therapy; Stock and Other Ownership Interests in GenCirq, Bionaut Labs, January Therapeutics; Research Funding to institution from Astex Pharmaceuticals, Incyte, Calithera Biosciences, Lilly, Daiichi Sankyo, Fortress Biotech, Karyopharm Therapeutics, Oxford BioTherapeutics, Astex Pharmaceuticals, TopAlliance BioSciences Inc, Adaptimmune, SpringWorks Therapeutics, TRACON Pharma. A.WH.- Research Funding to institution from ProLynx, Amgen; Patents, Royalties, Other Intellectual Property by institution in TORL Therapeutics; Consulting or Advisory Role for Oxcia; Speakers' Bureau for OncLive. S.K.- Consulting or Advisory Role for Attivare Therapeutics; Research Funding to Institution from Takeda; Patents, Royalties, Other Intellectual Property owned by Mayo Clinic an antibody developed in the Kaufmann laboratory; Uncompensated Relationships with ProLynx. A.A.- Consulting or Advisory Role for Janssen, EMD Serono, Zai Lab, Swiss Rockets, Mirati Therapeutics; Research Funding to institution from Bayer Schering Pharma, Tesaro, I-Mab, Kura Oncology, Merck KGaA, Zai Lab, Jacobio; Uncompensated Relationships with Merck KGaA, Zai Lab, Swiss Rockets. J.H.- reports advisory funds from Bayer, Merck, BeiGene, Incyte, Taiho; and research funding to institution from Merck, Treos Bio, Senhwa pharmaceuticals, Bayer, Incyte, TriOncology, Seattle Genetics, Hutchison MediPharma, Pionyr Immunotherapeutics, Trovogene, G1 Therapeutics, Roche, Pfizer, Cardiff Oncology, Mirati Therapeutics, Xilis Inc. B.C.- Research Funding to institution from GlaxoSmithKline/Novartis; Speakers' Bureau for Clinical Care Options/NCCN.

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Emiloju, O.E., Yin, J., Koubek, E. et al. Phase 1 trial of navitoclax and sorafenib in patients with relapsed or refractory solid tumors with hepatocellular carcinoma expansion cohort. Invest New Drugs 42, 127–135 (2024). https://doi.org/10.1007/s10637-024-01420-8

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