713TiP - A phase I study of PRT3789, a potent and selective degrader of SMARCA2 in patients with advanced or metastatic solid tumors and a SMARCA4 mutation

Background

Genes encoding subunits of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex are often mutated in cancer, occurring in 20% of all human cancers (Shain PLOS One 2013 ; Fernando Nat Commun 2020 ). The SWI/SNF complex contains 1 of 2 mutually exclusive ATP catalytic enzymatic subunits, SMARCA2 (BRM) or SMARCA4 (BRG1). Cells with SMARCA4 loss rely on its paralog, SMARCA2, making it an attractive therapeutic target (Helming Cancer Cell 2014 ; Hoffman PNAS 2014 ; Oike Cancer Res 2013 ). Multiple tumor types have SMARCA4 mutations, including thoracic sarcomas, lymphomas, and cancers of the lung, ovaries, and skin ( Shain 2013 ; Fernando 2020 ). PRT3789 induces proteosome-dependent degradation of SMARCA2. Preclinical data indicate that PRT3789 is a potent and selective degrader of SMARCA2, which induces robust synthetic lethality in SMARCA4-deficient cancers.

Trial design

This phase 1 (NCT05639751), open label, multicenter, dose-finding study evaluates the safety, tolerability, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of PRT3789. Adults with advanced or metastatic solid tumors with a SMARCA4 mutation, who have progressed on, or are intolerant to, standard therapy are eligible to enroll. Other key eligibility criteria include measurable disease by RECIST v1.1 or nonmeasurable (but evaluable) disease, ECOG PS 0–1, and resolved acute effects of prior therapy. Successive cohorts will receive escalating doses of intravenous PRT3789 once weekly for 3 weeks (1 cycle). PRT3789 treatment will continue until disease progression or unacceptable toxicity, whichever occurs first. A Bayesian optimal interval method will inform dose escalation, de-escalation, or maintenance based on the number of patients with dose-limiting toxicities (DLTs), until the maximum tolerated dose and recommended phase 2 dose (RP2D) are determined. The primary endpoints are safety, tolerability, DLTs, and RP2D. Secondary endpoints include objective response rate, progression-free survival, duration of response, disease control rate, and PK and PD profiles of PRT3789. The study began enrolling patients in January 2023.

Clinical trial identification

NCT05639751.

Editorial acknowledgement

Editorial support was provided by Miriam Cohen, PhD, ISMPP CMPP, of Team9Science, a Vaniam Group Company (Chicago, IL, USA).

Legal entity responsible for the study

Prelude Therapeutics.

Funding

Prelude Therapeutics.

Disclosure

I. Dagogo-Jack: Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: AstraZeneca, Xcovery, Catalyst Pharmaceuticals, Pfizer, Syros Pharmaceuticals, BostonGene, Bayer, Genentech, Sanofi, Janssen, Bristol Myers Squibb Foundation , Novocure; Financial Interests, Personal, Financially compensated role: Foundation Medicine, Aptitude Health, Creative Educational Concepts, OncLive, ASCO Post, DAVA Oncology, Medscape, Total Health, Triptych Health Partners, Research to Practice, American Academic Health System; Financial Interests, Institutional, Research Funding: Pfizer, Novartis, Genentech, Calithera Biosciences, Vivace Therapeutics; Financial Interests, Institutional, Research Funding: Array BioPharma; Financial Interests, Personal, Research Funding: Guardant Health, BostonGene, Tango Therapeutics. A. Dowlati: Financial Interests, Personal, Advisory Role: AstraZeneca, Merck, Ipsen, Amgen, Seattle Genetics, AbbVie, BMS. R. Guo: Financial Interests, Institutional, Research Funding: Merck. M.M. Awad: Financial Interests, Personal, Advisory Role, Consulting: Genentech, Bristol Myers Squibb, Merck, AstraZeneca, AbbVie, Neon, Achilles, Maverick, Blueprint Medicines, Hengrui, Syndax, Ariad, Nektar, Gritstone, ArcherDX, Mirati, NextCure, Novartis, EMD Serono, Panvaxal/NovaRx, Foundation Medicine; Financial Interests, Personal, Research Grant, : Genentech, Bristol Myers Squibb; Financial Interests, Personal, Research Grant: AstraZeneca, Lilly. A. Swalduz: Financial Interests, Personal, Financially compensated role: AstraZeneca, Janssen, Roche, Amgen, BMS; Financial Interests, Personal, Advisory Role: AstraZeneca, Janssen, Roche, Amgen, BMS, Pfizer, Lilly; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pfizer, Roche. E. Calvo: Financial Interests, Personal, Advisory Board: Adcendo, Amunix, Anaveon, AstraZeneca, BMS, Janssen, MonTa, MSD, Nanobiotix, Nouscom, Novartis, Servier, TargImmune, T-knife, Chugai, Elevation Oncology, Ellipses Pharmacy, SyneosHealth, Genmab, Diaccurate; Financial Interests, Personal, Invited Speaker: OncoDNA, PharmaMar, Roche/Genentech; Financial Interests, Personal, Full or part-time Employment, Director, Clinical Research: HM Hospitales Group; Financial Interests, Personal, Full or part-time Employment, Medical Oncologist. Clinical Investigator. Director, Clinical Research: START Madrid - CIOCC (Centro Integral Oncológico Clara Campal); Financial Interests, Personal, Member of Board of Directors, External Independent member of Board of Directors: PharmaMar; Financial Interests, Personal, Ownership Interest: START, Oncoart Associated; Financial Interests, Personal, Steering Committee Member, Member of Data Monitoring Committee: BeiGene, Sanofi, Merus; Financial Interests, Personal, Steering Committee Member: Novartis; Non-Financial Interests, Other, Non-for-profit Foundation. President and co-founder: INTHEOS (Investigational Therapeutics in Oncological Sciences) non-for-profit Foundation; Non-Financial Interests, Advisory Role: PsiOxus; Non-Financial Interests, Other, Chair of the Independent Data Monitoring Committee: EORTC IDMC; Non-Financial Interests, Member of Board of Directors, Non-for-profit Foundation, trustee member: Non-for-profit Foundation PharmaMar; Non-Financial Interests, Advisory Role, Non-for-profit foundation: CRIS Cancer Foundation, non-for-profit ; Non-Financial Interests, Member: ASCO, ESMO, SEOM, EORTC. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Local PI, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer Beigene BioInvent International AB, BMS, Boehringer Ingelheim, Boston, Celgene, Daiichi Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith: Multiple. A.A. Adjei: Financial Interests, Institutional, Coordinating PI, funding for clinical trial: Vyriad; Non-Financial Interests, Advisory Role, uncompensated Advisory Board member: Merck AG, Cagent Pharmaceuticals; Non-Financial Interests, Advisory Role, uncompensated Advisory Board Member: Zai Labs; Non-Financial Interests, Advisory Role, uncompensated Chair of Advisors: Swiss Rockets; Non-Financial Interests, Advisory Role, uncompensated advisor: Johnson and Johnson; Other, Editor-in-Chief of Journal of Thoracic Oncology and JTO CRR: International Association for the Study of Lung Cancer. P. Lorusso: Financial Interests, Personal, Advisory Board: AbbVie, Genmab, Genentech, CytomX, Takeda, Cybrexa, Agenus, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, GSK, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin, Kineta, Zentalis, Molecular Templates, ABL Bio, STCube, Bayer, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanist, Mersana, BAKX Therapeutics, Scenic Biotech, Qualigen, Roivant Sciences, NeuroTrials; Financial Interests, Personal, Other, Data Safety Monitoring Board: Agios, Five Prime, Halozyme; Financial Interests, Personal, Other, imCORE Alliance: Roche-Genentech; Financial Interests, Personal, Other, Consultant: Sotio, SK Life; Financial Interests, Personal, Other, Data Safety Monitoring Committee: Tyme; Financial Interests, Personal, Advisory Board, Advisory Board & Consultant: I-Mab; Financial Interests, Personal, Stocks/Shares: BAXK; Financial Interests, Institutional, Local PI: AbbVie, ADC Therapeutics, ALX Oncology, Astellas Pharma, Astex Pharmaceuticals, AstraZeneca, Bayer, Black Diamond, Boehringer Ingelheim, Calico Life Sciences, Corvus Pharmaceuticals, CytomX Therapeutics, Eisai Pharmaceuticals, Eli Lilly, EMD Sernono, Five Prime, FLX Bio, F-Star Delta Limited, Genentech, Genmab, Incyte, Linnaeus Therapeutics, MedImmune, Merck Sharp & Dohme, Moderna Therapeutics, NextCure, Pfizer, Ribon Therapeutics, Sotio, Stemline Therapeutics, Takeda, Tesaro, Jounce; Non-Financial Interests, Other, AACI Clinical Research Innovation Steering Committee - Member: Association of American Cancer Institutes; Non-Financial Interests, Other, AACR Methods in Clinical Cancer Research Workshop-Co-Director: American Association for Cancer Research; Non-Financial Interests, Other, AACR Annual Report Committee-Member: American Association for Cancer Research; Non-Financial Interests, Other, Continuing Medical Education Committee-Member: American Association for Cancer Research; Non-Financial Interests, Other, Molecular Cancer Therapeutics Editorial Board-Member: American Association for Cancer Research; Non-Financial Interests, Other, ASCO Conquer Cancer Young Investigator Award Grand Selection Committee - Member: American Society of Clinical Oncology; Non-Financial Interests, Other, New Drugs in Oncology Seminar Planning Committee - Member: American Society of Clinical Oncology; Non-Financial Interests, Other, New Agents Committee: Translational Research Panel-Chair: Cancer Research Unite Kingdom; Non-Financial Interests, Other, Scientific Advisory Board-Member: Targeted Anti-Cancer Therapies; Non-Financial Interests, Other, Chair-Phase 0 Task Force: American Association of Cancer Research; Non-Financial Interests, Member: American Association for Cancer Research, ASCO; Other, Investigational Drug Steering Committee-Committee Member: National Cancer Institute; Other, Phase I Special Emphasis Panel-Grant Reviewer/Discussion Leader: National Cancer Institute; Other, NeXT Special Emphasis Panel-Grant Reviewer: National Cancer Institute/National Institute of Health; Other, Board of Scientific Counselors, Clinical Sciences & Epidemiology: National Cancer Institute; Other, Young Investigator Meeting, Cancer Therapy Evaluation Program - Professor: National Cancer Institute; Other, Academic Advisory Board SPORE GI Malignancies - Case Western Reserve University: Case Western Reserve University; Other, External Advisory Board - Member: University of Arizona; Other, External Scientific Advisory Board-Member: University of New Mexico; Other, Scientific External Advisory Board-Member: University of California at San Diego. S. Punekar: Financial Interests, Institutional, Local PI, Clinical Trial PI: Revolution Medicine, Simcere Pharmaceuticals, Astellas Pharmaceuticals, Constellation, A2Bio, Vitrac; Non-Financial Interests, Principal Investigator, Clinical Trial PI: Revolution Medicine, A2Bio, Simcere, Constellation, Vitrac, Astellas Pharmaceuticals. T.A. Leal: Financial Interests, Personal, Advisory Role: Janssen, Mirati, Merck, AstraZeneca, Daiichi-Sankyo, Takeda, EMD Serono, Eisai, Novocure, Amgen, Roche, Regeron, Jazz; Financial Interests, Institutional, Research Funding: Pfizer, Advaxis. T.A. Yap: Financial Interests, Personal, Other, Consultant: Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Clovis, Cybrexa, EMD Serono, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Schrodinger, Varian, Zai Labs, AbbVie, Acrivon, Adagene, Amphista, Artios, Athena, Avoro, Baptist Health Systems, Calithera, Beigene, Boxer, C4 Therapeutics, Cancer Research UK, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Institut Gustave Roussy, Diffusion, Idience, ImmuneSensor, Intellisphere, Kyn, MEI Pharma, Mereo, Natera, Nexys, Novocure, Pegascy, PER, Piper-Sandler, Prolynx, resTORbio, Theragnostics, Xinthera, OHSU, OncoSec, Ono Pharma, Versant, Vibliome, ZielBio, Radiopharm Theranostics, Sanofi, CUHK Committee, Pliant Therapeutics, Ellipses.Life, LRG1, Panangium, Seagen, Synthis, Tessellate Bio, TD2 Theragonostics, Tome Biosciences, Zentalis; Financial Interests, Personal, Other, University of Texas MD Anderson Cancer Center, where I am Medical Director of the Institute for Applied Cancer Science, which has a commercial interest in DDR and other inhibitors (IACS30380/ART0380 was licensed to Artios): MD Anderson Cancer Center, Institute for Applied Cancer Sciences; Financial Interests, Personal, Stocks/Shares: Seagan; Financial Interests, Institutional, Other, Grant/Research support: Bayer, Cyteir, EMD Serono, GSK, Karyopharm, Pfizer, Repare, Sanofi, Artios, AstraZeneca, Beigene, BioNTech, Blueprint, BMS, Clovis, Constellation, Eli Lilly, Forbius, F-Star, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, Ribon Therapeutics, Genentech, Novartis, KSQ, Kyowa, Merck, Mirati, Regeneron, Tesaro, Rubius, Scholar Rock, Seattle Genetics, Vivace, Acrivon, Zenith; Financial Interests, Institutional, Research Grant: Ideaya, Boundless Bio; Financial Interests, Institutional, Other, Grant/Research Support: Acrivon. A. Italiano: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Bayer, BMS, Lilly, Merck, MSD, Novartis, Parthenon, PharmaMar, Roche; Financial Interests, Personal, Advisory Role: AstraZeneca, Bayer, BMS, Lilly, Merck, MSD, Novartis, Parthenon, PharmaMar, Roche; Financial Interests, Personal, Research Funding: AstraZeneca, Bayer, BMS, Lilly, Merck, MSD, Novartis, Parthenon, PharmaMar, Roche. W. Novotny: Financial Interests, Personal, Full or part-time Employment: Prelude Therapeutics; Financial Interests, Personal, Leadership Role: Prelude Therapeutics; Financial Interests, Personal, Stocks or ownership: Prelude Therapeutics; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Prelude Therapeutics. C. Tankersley: Financial Interests, Personal, Full or part-time Employment: Prelude Therapeutics; Financial Interests, Personal, Stocks or ownership: Prelude Therapeutics; Financial Interests, Personal, Other, Travel, accommodation or paid expenses: Prelude Therapeutics. S. Rowe: Financial Interests, Personal, Full or part-time Employment: Prelude Therapeutics. W. Sun: Financial Interests, Personal, Financially compensated role: Prelude Therapeutics. A.I. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines; Financial Interests, Personal, Other, Consulting or Advisory Role / Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Local PI: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals; Financial Interests, Institutional, Research Grant: Chugai pharmaceutical, EISAI, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. All other authors have declared no conflicts of interest.