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Mini oral session - Developmental therapeutics

518MO - Tolerability and preliminary clinical activity of SY-5609, a highly potent and selective oral CDK7 inhibitor, in patients with advanced solid tumors

Date

20 Sep 2021

Session

Mini oral session - Developmental therapeutics

Presenters

Manish Sharma

Citation

Annals of Oncology (2021) 32 (suppl_5): S583-S620. 10.1016/annonc/annonc699

Authors

M. Sharma1, B. Bashir2, E. Hamilton3, D. Juric4, K. Papadopoulos5, D. Richardson6, G. Shapiro7, G. Hodgson8, N. Ke8, A. D'Ippolito9, S. Henry8, L. Zhu10, M. Rosario11, H. Jolin12, D. Roth13, V. Klimek14, C. Madigan13, M. Kelly13

Author affiliations

  • 1 Clinical Research, South Texas Accelerated Research Therapeutics, 49546 - Grand Rapids/US
  • 2 Medical Oncology, Sidney Kimmel Cancer Center at Thomas Jefferson University, 19107 - Philadelphia/US
  • 3 Drug Development Unit, Sarah Cannon Research Institute / Tennessee Oncology, 37203 - Nashville/US
  • 4 Termeer Center For Targeted Therapies, Massachussetts General Hospital, 02114 - Boston/US
  • 5 Clinical Research, South Texas Accelerated Research Therapeutics, 78229 - San Antonio/US
  • 6 Division Of Gynecologic Oncology, Stephenson Cancer Center, 73104 - Oklahoma City/US
  • 7 Hematology/oncology, Dana-Farber Cancer Institute, 02215 - Boston/US
  • 8 Translational Medicine, Syros Pharmaceuticals, Cambridge/US
  • 9 Computational Biology, Syros Pharmaceuticals, Cambridge/US
  • 10 Biostatistics, Syros Pharmaceuticals, Cambridge/US
  • 11 Clinical Pharmacology, Syros Pharmaceuticals, Cambridge/US
  • 12 Clinical Science, Syros Pharmaceuticals, Cambridge/US
  • 13 Clinical Development, Syros Pharmaceuticals, Cambridge/US
  • 14 Clinical Development, Syros Pharmaceuticals, 02140 - Boston/US
More

Resources

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Abstract 518MO

Background

SY-5609 is a highly potent inhibitor of CDK7, a key regulator of cell cycle progression and transcription. Initial phase 1 results of SY-5609 in patients (pts) with advanced solid tumors reported proof of mechanism with dose-dependent effects on a pharmacodynamic (PD) gene expression marker POLR2A mRNA at 3 mg/day, the maximum tolerated dose (MTD) of the continuous daily dosing schedule. Additional data from the ongoing study, including from intermittent dosing schedules, are reported.

Methods

Doses were escalated (ongoing) above the MTD for continuous dosing in 3 schedules, each with 4-week cycles: 1) once daily (QD) dosing 5 days/week (d/wk), 2) twice daily (BID) dosing 5 d/wk, and 3) QD dosing 7 d/wk every other wk. Select cohorts were expanded to evaluate single agent SY-5609 in specific pt populations and a combination with fulvestrant in hormone receptor positive breast cancer pts. Evaluations included: safety per CTCAE v5.0; clinical activity per RECIST v1.1, tumor markers, and clinical evaluations; and PD marker POLR2A induction in peripheral blood mononuclear cells.

Results

As of 3/26/21, 51 pts enrolled, including 9 +fulvestrant. Recently, both QD intermittent dosing schedules cleared dose limiting toxicity (DLT) evaluations at 4 mg/d and 5 mg/d, with activity evaluations and escalation to higher doses ongoing. Single agent SY-5609 AEs of any causality (≥20%) included nausea, diarrhea, fatigue, decreased appetite, and thrombocytopenia; majority were low grade (1/2) and reversible. 30% (11/37) of response-evaluable pts had stable disease (SD) as best response. 6 SD pts had tumor reductions of 8.7%-18.1%, with median 198 d (range: 55-273) on treatment. 1 PDAC pt with prolonged SD (>8 months [ongoing]) had a 72% reduction of CA19-9 (5723 to 1609 U/mL), and 1 ovarian cancer pt had an 84% reduction of CA-125 (1950 to 308 U/mL). Dose dependent POLR2A induction was observed on intermittent dosing.

Conclusions

Intermittent dosing of SY-5609 is tolerable above the MTD for continuous dosing with evidence of dose dependent PD effects observed. Early evidence of clinical activity, with durable SD and reduction in tumor size and markers, supports continued dose escalation with intermittent dosing.

Clinical trial identification

NCT04247126; first posted January 29, 2020.

Editorial acknowledgement

Legal entity responsible for the study

Syros Pharmaceuticals, Inc.

Funding

Syros Pharmaceuticals, Inc.

Disclosure

M. Sharma: Financial Interests, Institutional, Principal Investigator: Alexo; Financial Interests, Institutional, Principal Investigator: Alpine; Financial Interests, Institutional, Principal Investigator: Amgen; Financial Interests, Institutional, Principal Investigator: Apexian; Financial Interests, Institutional, Principal Investigator: Arrys; Financial Interests, Institutional, Principal Investigator: Asana; Financial Interests, Institutional, Principal Investigator: Ascentage; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Beigene; Financial Interests, Institutional, Principal Investigator: Bristol-Myers Squibb; Financial Interests, Institutional, Principal Investigator: Bolt; Financial Interests, Institutional, Principal Investigator: Cardiff; Financial Interests, Institutional, Principal Investigator: Celgene; Financial Interests, Institutional, Principal Investigator: Compugen; Financial Interests, Institutional, Principal Investigator: Coordination; Financial Interests, Institutional, Principal Investigator: Constellation; Financial Interests, Institutional, Principal Investigator: CytomX; Financial Interests, Institutional, Principal Investigator: eFFECTOR; Financial Interests, Institutional, Principal Investigator: Eli Lilly; Financial Interests, Institutional, Principal Investigator: Epizyme; Financial Interests, Institutional, Principal Investigator: Exelixis; Financial Interests, Institutional, Principal Investigator: Formation Biologics; Financial Interests, Institutional, Principal Investigator: Forty Seven; Financial Interests, Institutional, Principal Investigator: Genmab; Financial Interests, Institutional, Principal Investigator: GlaxoSmithKline; Financial Interests, Institutional, Principal Investigator: Helsinn; Financial Interests, Institutional, Principal Investigator: Ikena; Financial Interests, Institutional, Principal Investigator: Innovent; Financial Interests, Institutional, Principal Investigator: InhibRx; Financial Interests, Institutional, Principal Investigator: Incyte; Financial Interests, Institutional, Principal Investigator: Ipsen; Financial Interests, Institutional, Principal Investigator: Jounce; Financial Interests, Institutional, Principal Investigator: KLUS Pharma; Financial Interests, Institutional, Principal Investigator: Lexicon; Financial Interests, Institutional, Principal Investigator: LOXO; Financial Interests, Institutional, Principal Investigator: Livzon; Financial Interests, Institutional, Principal Investigator: Macrogenics; Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Institutional, Principal Investigator: Mersana; Financial Interests, Institutional, Principal Investigator: NGMBio; Financial Interests, Institutional, Principal Investigator: Northern; Financial Interests, Institutional, Principal Investigator: NovoCure; Financial Interests, Institutional, Principal Investigator: Odonate; Financial Interests, Institutional, Principal Investigator: Pfizer; Financial Interests, Institutional, Principal Investigator: PureTech; Financial Interests, Institutional, Principal Investigator: Regeneron; Financial Interests, Institutional, Principal Investigator: Samumed; Financial Interests, Institutional, Principal Investigator: Sapience; Financial Interests, Institutional, Principal Investigator: Seagen; Financial Interests, Institutional, Principal Investigator: Shattuck; Financial Interests, Institutional, Principal Investigator: Symphogen; Financial Interests, Institutional, Principal Investigator: Syros Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: TaiRx; Financial Interests, Institutional, Principal Investigator: Tesaro; Financial Interests, Institutional, Principal Investigator: Treadwell; Financial Interests, Institutional, Principal Investigator: QED. B. Bashir: Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Bicycle Therapeutics; Financial Interests, Institutional, Research Grant: Ikena Oncology; Financial Interests, Institutional, Principal Investigator: Syros Pharmaceuticals; Financial Interests, Institutional, Research Grant: Kahr Medical. E. Hamilton: Financial Interests, Institutional, Research Grant: OncoMed; Financial Interests, Institutional, Research Grant: Genentech/Roche; Financial Interests, Institutional, Research Grant: Zymeworks; Financial Interests, Institutional, Research Grant: Rgenix; Financial Interests, Institutional, Research Grant: ArQule; Financial Interests, Institutional, Research Grant: Clovis; Financial Interests, Institutional, Research Grant: Silverback Therapeutics; Financial Interests, Institutional, Research Grant: Millennium; Financial Interests, Institutional, Research Grant: Acerta Pharma; Financial Interests, Institutional, Research Grant: Sermonix Pharmaceuticals; Financial Interests, Institutional, Research Grant: Torque; Financial Interests, Institutional, Research Grant: Black Diamond; Financial Interests, Institutional, Research Grant: Karyopharm; Financial Interests, Institutional, Research Grant: Infinity Pharmaceuticals; Financial Interests, Institutional, Research Grant: Curis; Financial Interests, Institutional, Research Grant: Syndax; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Immunomedics; Financial Interests, Institutional, Research Grant: FujiFilm; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Institutional, Research Grant: Deciphera; Financial Interests, Institutional, Research Grant: Fochon; Financial Interests, Institutional, Research Grant: Molecular Templates; Financial Interests, Institutional, Research Grant: Onconova Therapeutics; Financial Interests, Institutional, Research Grant: Dana Farber Cancer Hospital; Financial Interests, Institutional, Research Grant: Hutchinson MediPharma; Financial Interests, Institutional, Research Grant: MedImmune; Financial Interests, Institutional, Research Grant: SeaGen; Financial Interests, Institutional, Research Grant: Puma Biotechnology; Financial Interests, Institutional, Research Grant: Compugen; Financial Interests, Institutional, Research Grant: TapImmune; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: H3 Biomedicine; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Institutional, Research Grant: Merus; Financial Interests, Institutional, Research Grant: Regeneron; Financial Interests, Institutional, Research Grant: Arvinas; Financial Interests, Institutional, Research Grant: StemCentRx; Financial Interests, Institutional, Research Grant: Verastem; Financial Interests, Institutional, Research Grant: eFFECTOR Therapeutics; Financial Interests, Institutional, Research Grant: CytomX; Financial Interests, Institutional, Research Grant: InventisBio; Financial Interests, Institutional, Research Grant: Lycera; Financial Interests, Institutional, Research Grant: Mersana; Financial Interests, Institutional, Research Grant: Radius Health; Financial Interests, Institutional, Research Grant: Abbvie; Financial Interests, Institutional, Research Grant: Nucana; Financial Interests, Institutional, Research Grant: Leap Therapeutics; Financial Interests, Institutional, Research Grant: Zenith Epigenetics; Financial Interests, Institutional, Research Grant: Zenith Epigenetics; Financial Interests, Institutional, Research Grant: Harpoon; Financial Interests, Institutional, Research Grant: Orinove; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Tesaro; Financial Interests, Institutional, Research Grant: Macrogenics; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Syros Pharmaceuticals; Financial Interests, Institutional, Research Grant: Sutro; Financial Interests, Institutional, Research Grant: G1 Therapeutics; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: PharmaMar; Financial Interests, Institutional, Research Grant: Olema; Financial Interests, Institutional, Research Grant: Polyphor; Financial Interests, Institutional, Research Grant: Immunogen; Financial Interests, Institutional, Research Grant: Plexxicon; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Akesobio Australia; Financial Interests, Institutional, Research Grant: Shattuck Labs; Financial Interests, Institutional, Advisory Role: Boehringer Ingelheim; Financial Interests, Institutional, Advisory Role: Novartis; Financial Interests, Institutional, Advisory Role: Dantari; Financial Interests, Institutional, Advisory Role: Lilly; Financial Interests, Institutional, Advisory Role: Merck; Financial Interests, Institutional, Advisory Role: Puma Biotechnology; Financial Interests, Institutional, Advisory Role: Silverback Therapeutics; Financial Interests, Institutional, Advisory Role: CytomX; Financial Interests, Institutional, Advisory Role: Pfizer; Financial Interests, Institutional, Advisory Role: Mersana; Financial Interests, Institutional, Advisory Role: Black Diamond; Financial Interests, Institutional, Advisory Role: H3 Biomedicine; Financial Interests, Institutional, Advisory Role: Daiichi Sankyo; Financial Interests, Institutional, Advisory Role: AstraZenica; Financial Interests, Institutional, Advisory Role: Arvinas; Financial Interests, Institutional, Advisory Role: Deciphera Pharmaceuticals; Financial Interests, Institutional, Advisory Role: Eisai; Financial Interests, Institutional, Advisory Role: Seagen; Financial Interests, Institutional, Advisory Role: Genentech/Roche. D. Juric: Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Ibsen; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Guardant; Financial Interests, Personal, Advisory Board: Petra Pharma; Financial Interests, Personal, Advisory Board: Mapkure; Financial Interests, Personal, Advisory Board: Vibliome Therapeutics; Financial Interests, Personal, Advisory Board: Relay Therapeutics; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Genentech; Financial Interests, Institutional, Funding: EMD Serono; Financial Interests, Institutional, Funding: Eisai; Financial Interests, Institutional, Funding: Takeda; Financial Interests, Institutional, Funding: Placon Therapeutics; Financial Interests, Institutional, Funding: Syros; Financial Interests, Institutional, Funding: Ribon Therapeutics; Financial Interests, Institutional, Funding: Infinity Pharmaceuticals; Financial Interests, Institutional, Funding: InventisBio; Financial Interests, Institutional, Funding: Amgen. K. Papadopoulos: Financial Interests, Personal, Advisory Role: Basilia; Financial Interests, Personal, Advisory Role: Turning Point Therapeutics; Financial Interests, Personal, Advisory Role: Bicycle Therapeutics; Financial Interests, Institutional, Research Grant: Abbvie; Financial Interests, Institutional, Research Grant: MedImmune; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Regeneron; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Calithera Biosciences; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Peloton Therapeutics; Financial Interests, Institutional, Research Grant: ADC Therapeutics; Financial Interests, Institutional, Research Grant: 3D Medicines; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Syros Pharmaceuticals; Financial Interests, Institutional, Research Grant: Mersana; Financial Interests, Institutional, Research Grant: MabSpace Biosciences; Financial Interests, Institutional, Research Grant: Jounce Therapeutics; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Anheart; Financial Interests, Institutional, Research Grant: F-star; Financial Interests, Institutional, Research Grant: Linnaeus; Financial Interests, Institutional, Research Grant: Mirati; Financial Interests, Institutional, Research Grant: Tempest Therapeutics; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Treadwell Therapeutics; Financial Interests, Institutional, Research Grant: Pfizer. D. Richardson: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Role: Genentech/Roche; Financial Interests, Personal, Advisory Role: Deciphera; Financial Interests, Personal, Advisory Role: Mersana; Financial Interests, Personal, Advisory Role: Tesaro/GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Genentech/Roche; Financial Interests, Institutional, Research Grant: Mersana; Financial Interests, Institutional, Research Grant: Tesaro/GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Aravive; Financial Interests, Institutional, Research Grant: ArQule, Inc.; Financial Interests, Institutional, Research Grant: Deciphera; Financial Interests, Institutional, Research Grant: Harpoon Therapeutics; Financial Interests, Institutional, Research Grant: Innovent Biologics; Financial Interests, Institutional, Research Grant: Karyopharm; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Syros Pharmaceuticals; Financial Interests, Institutional, Research Grant: Five Prime Therapeutics; Financial Interests, Institutional, Research Grant: Hookipa Biotech; Financial Interests, Institutional, Research Grant: FujiFilm; Financial Interests, Institutional, Research Grant: Shattuck Labs; Financial Interests, Institutional, Research Grant: Plexxikon. G. Shapiro: Financial Interests, Personal, Advisory Board: Syros Pharmaceuticals; Financial Interests, Personal, Funding: Eli Lilly; Financial Interests, Personal, Funding: Merck KGaA/EMD Serono; Financial Interests, Personal, Funding: Merck; Financial Interests, Personal, Funding: Sierra Oncology; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: G1 Therapeutics; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Merck KGaA/EMD Serono; Financial Interests, Personal, Advisory Board: Sierra Oncology; Financial Interests, Personal, Advisory Board: Bicycle Therapeutics; Financial Interests, Personal, Advisory Board: Fusion Pharmaceuticals; Financial Interests, Personal, Advisory Board: Cybrexa Therapeutics; Financial Interests, Personal, Advisory Board: Astex; Financial Interests, Personal, Advisory Board: Almac; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Angiex; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: ImmunoMet; Financial Interests, Personal, Advisory Board: Asana; Financial Interests, Personal, Advisory Board: Artios; Financial Interests, Personal, Advisory Board: Atrin; Financial Interests, Personal, Advisory Board: Concarlo Holdings; Financial Interests, Personal, Advisory Board: Zentalis; Financial Interests, Personal, Advisory Board: Cytomx Therapeutics; Financial Interests, Personal, Advisory Board: Blueprint Medicines; Financial Interests, Personal, Other, Patent: Cyclacel Pharmaceuticals; Financial Interests, Personal, Other, Pending Patent: Liam Cornell. G. Hodgson: Financial Interests, Personal, Full or part-time Employment: syros pharmaceuticals; Financial Interests, Personal, Stocks/Shares: syros pharmaceuticals. N. Ke: Financial Interests, Institutional, Full or part-time Employment: Syros Pharmaceuticals. A. D'Ippolito: Financial Interests, Personal, Full or part-time Employment: Syros Pharmaceuticals. S. Henry: Financial Interests, Institutional, Full or part-time Employment: Syros Pharmaceuticals. L. Zhu: Financial Interests, Personal, Stocks/Shares: Syros Pharmaceuticals; Financial Interests, Personal, Full or part-time Employment: Curis, Inc; Financial Interests, Personal, Stocks/Shares: Incyte Incorporated. M. Rosario: Financial Interests, Personal, Full or part-time Employment: syros pharmaceuticals; Financial Interests, Personal, Stocks/Shares: syros pharmaceuticals. H. Jolin: Financial Interests, Personal, Full or part-time Employment, Former: syros pharmaceuticals. D. Roth: Financial Interests, Personal and Institutional, Officer, Employment, Stocks/Shares: Syros Pharmaceuticals. V. Klimek: Financial Interests, Personal, Full or part-time Employment: Syros. C. Madigan: Financial Interests, Personal, Full or part-time Employment: syros pharmaceuticals. M. Kelly: Financial Interests, Personal, Stocks/Shares: Syros Pharmaceuticals Inc.

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