1029P - Dazostinag (TAK-676) alone and in combination with pembrolizumab (pembro) in patients (pts) with advanced or metastatic solid tumors: Preliminary safety, PK/PD, and anti-tumor activity in a phase I dose escalation study supporting a recommended dose for expansion (RDE)

Background

Dazostinag (TAK-676) is a novel, IV, small molecule synthetic STimulator of INterferon Genes (STING) agonist, which acts as an innate immunity enhancer. In preclinical models, dazostinag induced dose-dependent cytokine production and activation/proliferation of immune cells. We present data from Part 1 of iintune-1 (NCT04420884), a phase 1 study of single agent (SA) dazostinag and combined with pembro in advanced or metastatic solid tumors.

Methods

Part 1 comprised a single-pt safety lead-in with SA dazostinag 0.1 mg IV, followed by dose escalation using Bayesian Logistic Regression Model design. Dose escalation in the combination arm began after no dose-limiting toxicities (DLTs) were seen with ≥2 SA doses. Pts receive dazostinag IV (Days 1, 8, 15) +/- pembro 200 mg IV (Day 1) in 21-day cycles.

Results

As of May 2023, 36 and 43 pts have received SA dazostinag and with pembro, respectively. There have been no DLTs up to 7 mg SA and 5 mg with pembro. The most common adverse events were fatigue (33%), nausea (29%), and pyrexia (22%). Dazostinag had linear PK across the dose range tested and was not affected by combination with pembro; elimination profile was bi-phasic with a terminal half-life of 0.5–1.7 hrs. Exposure-safety analysis indicated increasing incidence of fever or cytokine release syndrome with dazostinag Cmax. PK/PD analysis for all pts indicated dose/concentration-dependent increases in a blood 24-gene STING signature score, and plasma IFN-γ and IP-10. Dazostinag achieved a >3.5-fold induction of STING signature score across multiple dose levels. For dazostinag 5 mg with or without pembro, a >2-fold increase in IFN-γ and other cytokines (including IP-10) and increased peripheral Ki67+CD8+ T cell proliferation were observed. Three pts had objective confirmed clinical responses with dazostinag plus pembro.

Conclusions

Preliminary safety, PK/PD data, and anti-tumor activity support the declaration of the RDE of dazostinag 5 mg + pembro 200 mg. Expansion cohorts in colorectal and head and neck cancer are enrolling.

Clinical trial identification

NCT04420884.

Editorial acknowledgement

Medical writing, under the direction of the authors, was provided by Philippa Lloyd, BSc, of Ashfield MedComms, an Inizio company, funded by Takeda Pharmaceuticals, U.S.A., Inc., Lexington, MA, and complied with GPP guidelines (DeTora LM, et al. Ann Intern Med 2022 ;175:1298–1304).

Legal entity responsible for the study

Takeda Development Center Americas, Inc. (TDCA), Lexington, MA, USA.

Funding

Takeda Development Center Americas, Inc. (TDCA), Lexington, MA, USA

Disclosure

A.J. Olszanski: Financial Interests, Personal, Advisory Board: Merck, Pfizer, BMS. J.J. Luke: Financial Interests, Personal, Other, DSMB: AbbVie, Agenus, Evaxion; Financial Interests, Personal, Funding, DSMB: Immutep; Financial Interests, Personal, Advisory Board: 7 Hills, Affivant, BioCytics, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio (stock) Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, physIQ, Pyxis, Saros, STipe, Tempest; Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy: AbbVie, Agenus, Alnylam, AstraZeneca, Atomwise, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena; Financial Interests, Institutional, Research Funding: AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Hot Spot, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar . P. Lorusso: Financial Interests, Personal, Other, Honoraria: Five Prime Therapeutics; Financial Interests, Personal, Advisory Role: AbbVie, ABL Bio, Agenus, Agios, Astellas Pharma, AstraZeneca, BAKX Therapeutics, CytomX Therapeutics, EMD Serono, Five Prime Therapeutics, Genentech, Genmab, GSK, Halozyme, I-Mab, ImCheck therapeutics, ImmunoMet, IQvia, Kineta, Kyowa Kirin International, Macrogenics, Mekanistic Therapeutics, Molecular Templates, Pfizer, QED Therapeutics, Relay Therapeutics, Roche/Genentech, Salarius Pharmaceuticals, Seagen, Shattuck Labs, Silverback Therapeutics, SK Life Sciences, Sotio, ST Cube, Stemline Therapeutics, Takeda, Trial to Reduce IDDM in the Genetically at Risk (TRIGR), TYME, Zentalis; Financial Interests, Institutional, Research Funding: Genentech; Financial Interests, Personal, Other, Travel, accommodations, expenses: Genentech. G.S. Falchook: Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Institutional, Advisory Role: AbbVie, Fujifilm, Silicon, Navire, Turning Point, Predicine, Inspirna, Regeneron, Jubilant, BostonGene, Teon, Merck; Financial Interests, Personal, Advisory Role: EMD Serono; Financial Interests, Personal, Other, Speakers honorarium for CME: Total Health Conferencing, Rocky Mountain Oncology; Financial Interests, Personal, Other, Travel (self, for work and/or research related to institution): Amgen (2022), Bristol Myers Squibb (2015), EMD Serono (2011, 2012, 2013), Fujifilm (2018), Millennium (2013), Sarah Cannon Research Institute (employer, at least once yearly), Synthorx /Sanofi (2022); Financial Interests, Institutional, Research Funding: 3-V Biosciences, Abbisko, AbbVie, ABL Bio, ADC Therapeutics, Accutar, Agenus, Aileron, American Society of Clinical Oncology, Amgen, ARMO/Eli Lilly, Artios, AstraZeneca, Bayer, BeiGene, Bioatla, Bioinvent, Biothera, Bicycle, Black Diamond, Boehringer Inge. P.L. Bedard: Financial Interests, Personal, Advisory Role: Seattle Genetics, Lilly, Amgen, Merck, Gilead Sciences, Zymeworks, Repare Therapeutics; Financial Interests, Institutional, Advisory Role: BMS, Pfizer; Financial Interests, Institutional, Research Funding: Bristol Myers Squibb, Sanofi, AstraZeneca, Genentech/Roche, GSK, Novartis, Merck, Seattle Genetics, Lilly, Amgen, Bicara, Zymeworks, Medicenna, Bayer, Takeda. R.E. Sanborn: Financial Interests, Personal, Invited Speaker: Targeted Oncology, GameOn!, OncLive; Financial Interests, Personal, Writing Engagement: EMD Serono; Financial Interests, Personal, Advisory Board: EMD Serono, Daiichi Sankyo, Lilly Oncology, Janssen Oncology, Macrogenics, Sanofi/Aventis, Regeneron, Mirati Therapeutics, GSK, Illumina, G1 Therapeutics, AstraZeneca; Financial Interests, Personal, Research Grant, Funding for investigator-initiated trials: AstraZeneca, Merck. S.P. Patel: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bristol Myers Squibb, Certis, Eli Lilly, Jazz, Genentech, Illumina, Merck, Pfizer, Rakuten, Tempus; Financial Interests, Personal, Research Grant: Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Eli Lilly, Fate Therapeutics, Gilead, Iovance, Merck, Pfizer, Roche/Genentech, SQZ Biotechnologies. J.P. Gibbs: Financial Interests, Personal, Full or part-time Employment: Takeda; Financial Interests, Personal, Stocks/Shares: Takeda. C. Li: Financial Interests, Personal, Full or part-time Employment: Takeda Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Takeda Pharmaceuticals. Y. Huang: Financial Interests, Personal, Full or part-time Employment: Takeda; Financial Interests, Personal, Stocks/Shares: Takeda. R. Gregory: Financial Interests, Personal, Full or part-time Employment: Takeda; Financial Interests, Personal, Stocks/Shares: Takeda. S. Perera: Financial Interests, Personal, Stocks/Shares: Takeda Pharmaceutical; Financial Interests, Personal, Full or part-time Employment: Takeda. R. Xu: Financial Interests, Personal, Full or part-time Employment: Takeda Development Center Americas. A. Joshi, M.Y. Lee, J. Raizer: Financial Interests, Personal, Full or part-time Employment: Takeda; Financial Interests, Personal, Stocks/Shares: Takeda. X. Gao: Financial Interests, Institutional, Principal Investigator: Arvinas, Exelixis, Pfizer, Harpoon Therapeutics, Aprea Therapeutics, Aravive, Merck, Poseida Therapeutics, TopAlliance Biosciences, Novartis, Regeneron, Bayer, ALX Oncology; Financial Interests, Personal, Advisory Board: Bayer, Guardant Health, Flare Therapeutics, Silver Therapeutics, PureTech Health, Myovant Sciences, PathAI. All other authors have declared no conflicts of interest.