A Phase I Trial of the MET/

BACKGROUND

Crizotinib inhibits ALK, MET and ROS1 tyrosine kinases but the development of resistance to monotherapy is an issue. The anti-angiogenic properties of pazopanib could overcome crizotinib drug resistance. Additionally, the anti-angiogenic properties of crizotinib could augment the clinical efficacy of pazopanib.

METHODS

We evaluated the safety and responses in patients with advanced solid tumors treated with crizotinib and pazopanib.

RESULTS

Eighty-two patients (median age 53 years, range 18-78 years) were enrolled. The median number of prior systemic therapies was 3 (range, 0-8). We were able to dose escalate to dose level 8 (crizotinib 250 mg twice daily and pazopanib 800 mg daily) with no MTD identified. Grade 3 or 4 toxicities were seen in 32% of patients with the highest prevalence being fatigue (n=9, 11%), diarrhea (n=6, 7%), vomiting (n=3, 4%), anemia (n=2, 2%) and ALT increased (n=2, 2%). Of the 82 patients, 61 (74%) had measurable disease by RECISTv1.1 and reached first restaging (6 weeks). Partial response (PR) was observed in 6/61 (10%) patients, and stable disease (SD) lasting ≥6 months was observed in 10/61 patients (16%) (total = 16/61 (26%) of patients with SD ≥6 months/PR).

CONCLUSION

Dose level 6 (crizotinib 200 mg twice daily and pazopanib 600 mg daily) was the most tolerable dosing of the combination and can be used in future studies. We also observed moderate clinical activity in patients with advanced solid tumors that had received numerous prior therapies.

Informations de copyright

© 2021 Piha-Paul et al.

Déclaration de conflit d'intérêts

Dr Sarina A. Piha-Paul reports Clinical Trial Research Support (Received through the institution) from AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol Myers Squibb, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Daiichi Sankyo, Inc., Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, Gene Quantum, Genmab A/S, Glaxo SmithKline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., MedImmune, LLC., Medivation, Inc., Merck Sharp and Dohme Corp., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Principia Biopharma, Inc., Puma Biotechnology, Inc., Rapt Therapeutics, Inc., Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, Inc., TransThera Bio, Core Grant (CCSG Shared Resources Clinical Trial Research Support (Received through the institution)) from NCI/NIH P30CA016672, outside the submitted work. Dr Vivek Subbiah reports Research funding/Grant support for clinical trials (to institution): Novartis, Bayer, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, MedImmune, Altum, Dragonfly Therapeutics, Takeda, and National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning point therapeutics, Boston Pharmaceuticals. Travel funding: Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte, Ad Hoc Advisory Board: Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, QED pharma, MedImmune, Novartis, Signant Health. Dr Aung Naing reports grants from National Cancer Institute, grants from EMD Serono, grants from MedImmune, grants, non-financial support from ARMO BioSciences, grants from Karyopharm Therapeutics, grants from Incyte, grants, personal fees from Novartis, grants from Regeneron, grants from Merck, grants from Bristol-Myers Squibb, grants from Pfizer, grants, personal fees from CytomX Therapeutics, grants from Neon Therapeutics, grants from Calithera Biosciences, grants from TopAlliance Biosciences, grants from Eli Lilly, grants, personal fees from Kymab, grants from PsiOxus, grants from Arcus Biosciences, grants from NeoImmuneTech, grants from ImmuneOncia, grants from Surface Oncology, grants, personal fees from Genome & Company, grants from OncoSec KEYNOTE-695, grants from STCube Pharmaceuticals, outside the submitted work; and Spouse • Research funding: Immune Deficiency Foundation, Jeffrey Modell Foundation and chao physician-scientist, and Baxalta. • Advisory board: Takeda, CSL, Behring, Horizon, and Pharming. Dr Filip Janku reports grants from Agios, grants, personal fees from Asana, grants from Astellas, grants from Astex, grants from Bayer, grants from Bicara, grants from BioMed Valley Discoveries, grants from Bioxcel, grants from Bristol-Myers Squibb, grants, personal fees from Deciphera, grants from FujiFilm Pharma, grants from Genentech, personal fees from Ideaya, grants from JS Innopharm, grants from Lilly, grants from Merck, grants, personal fees from Novartis, grants from Novellus, grants from Plexxikon, grants from Proximagen, grants from Sanofi, grants, personal fees from Sotio, grants from SpringBank Pharmaceuticals, grants from SQZ Biotechnologies, grants, personal fees from Synlogic, grants from Synthorx, grants from Symphogen, personal fees from Bausch Health, personal fees, Ownership Interests from Cardiff Oncology, personal fees from Guardant Health, personal fees from IFM Therapeutics, personal fees from Immunomet, personal fees from Illumina, personal fees from Jazz Pharmaceuticals, personal fees from PureTech Health, Bio-Rad, Biocartis, outside the submitted work. Dr Shreyaskumar Patel reports personal fees from DAiichi SAnkyo, personal fees from Deciphera, consultant fees from Epizyme, Dova and Bayer, grants from Blueprint Medicines, Clinical Trial fees from Hutchison Medipharma, outside the submitted work. Dr David Hong reports grants from AbbVie, grants, Grant/Research Support & Consulting/Advisory Role from Adaptimmune, grants from Aldi-Norte, grants, Grant/Research Support & Consulting/Advisory Role from Amgen, grants from Astra-Zeneca, grants, Grant/Research Support, Consulting/Advisory Role, Travel, Accommodations, Expenses from Bayer, grants from BMS, grants from Daiichi-Sankyo, grants from Eisai, grants from Fate Therapeutics, grants, Grant/Research Support & Consulting/Advisory Role from Genentech, grants from Genmab, grants from Ignyta, grants, Grant/Research Support & Consulting/Advisory Role from Infinity, grants from Kite, grants from Kyowa, grants from Lily, grants, Grant/Research Support & Travel, Accommodations, Expenses from LOXO, grants from Merck, grants from MedImmune, grants from Mirati, grants, Grant/Research Support & Travel, Accommodations, Expenses from miRNA, grants from Molecular Templates, grants from Mologen, grants from NCI-CTEP, grants from Novartis, grants, Grant/Research Support & Consulting/Advisory Role from Numab, grants, Grant/Research Support & Consulting/Advisory Role from Pfizer, grants, Grant/Research Support & Consulting/Advisory Role from Seattle Genetics, Grant/Research Support & Consulting/Advisory Role from Takeda, grants from Turning Point Therapeutics, Verstatem, Consulting/Advisory Role from Alpha Insights, Acuta, Axion, Baxter, Boxer Capital, COG, ECOR1, Expert Connect, GLG, Group H, Guidepoint, H.C. Wainwright, Janssen, Merrimack, Medscape, NTRK Connect, Prime Oncology, Slingshot, Trieza Therapeutics, WebMD, Travel, Accommodations, Expenses from ASCO, AACR, SITC, Advisor from Molecular Match, Founder from OncoResponse, Advisor from Presagia, outside the submitted work. Dr Funda Meric-Bernstam reports personal fees from Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks, Immunomedics, Advisory Committee from Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Silverback Therapeutics, Spectrum Pharmaceuticals Zentalis, grants from Aileron Therapeutics, Sponsored Research from AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Millennium Pharmaceuticals, Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co., personal fees from Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey, Beth Israel Deaconess Medical Center, outside the submitted work. The authors report no other conflicts of interest in this work.