Updated results of the RINGSIDE phase II trial and open-label extension of AL102 for treatment of desmoid tumors

BackgroundGamma secretase inhibitors (GSIs) have shown antitumor activity against desmoid tumors (DT, aggressive fibromatosis), and AL102 is a potent, once-daily (QD), oral, selective GSI under investigation for treatment of DT.MethodsRINGSIDE Phase II is an open-label, dose-finding study in adults with progressing DT (≥10% unidimensional growth ≤18 mo or DT-related pain requiring non-opioid medication). Pts were randomized to 3 dose regimens: 1.2 mg QD, 2 mg intermittent or 4 mg intermittent (2 days on 5 days off). After selection of 1.2 mg QD for RINGSIDE phase III, all active phase II pts began receiving 1.2 mg QD in an open-label extension (OLE). We report updated RINGSIDE phase II results, including time in the OLE.ResultsPhase II enrolled 42 pts, of whom 29 (69%) entered the OLE. As of April 10, 2024, median time on treatment was 25.4 mo (range 1 – 29); 21 pts (50%) were still on treatment. Mean age was 40 yrs, 74% were women, and 69% received prior DT therapy. Best response as measured by MRI in the evaluable population by blinded independent central review (BICR) is shown in the table. The median best change in tumor volume and T2 signal intensity (reduced tumor cellularity) were -88% for the 1.2 mg QD group and -85% for all patients, and -94% and -92%, respectively. The 5 most common Grade 1-2 treatment-emergent adverse events (TEAEs) were diarrhea, nausea, fatigue, headache and dry skin. Grade 3 drug-related TEAEs were reported in 14/42 (33%) pts, the most common being skin-related. There were no Grade 4-5 or serious drug-related TEAEs. No new safety signals were observed during long-term treatment. Table: 1766P Objective response per RECIST1 in evaluable patients (n=36)2 1.2 mg QD dose (n=12) All doses 3 (n=36) Objective Response Rate (CR + PR), n (%) 9 (75%) 23 (64%) Best Overall Response, n (%) Complete Response (CR), n (%) 0 (0%) 2 (6%) Partial Response (PR), n (%) 9 (75%) 21 (58%) Stable Disease (SD), n (%) 3 (25%) 12 (33%) Progressive Disease (PD), n (%) 0 (0%) 1 (3%) Disease Control Rate (DCR), n (%) 12 (100%) 35 (97%) 1. Change from baseline in tumor shrinkage as measured on MRI by Blinded independent Central Review2. Evaluable population: patients with at least 1 post-baseline scan3. Includes 1.2 mg QD and 2 mg and 4 mg intermittent (2 days on/5 days off) ConclusionsAL102 was well tolerated with a safety profile consistent with previously reported GSI toxicities. Efficacy of the 1.2 mg QD dose was demonstrated early and continued to improve with longer time on treatment. Enrollment in the RINGSIDE phase III randomized, controlled trial of 1.2 mg QD is complete, and the study is ongoing.Clinical trial identificationNCT04871282.Editorial acknowledgementMedical writing provided by Laurie LaRusso, MS, ELS, of Chestnut Medical Communications paid for by Immunome (formerly Ayala Pharmaceuticals).Legal entity responsible for the studyImmunome, Inc. (formerly Ayala Pharmaceuticals).FundingImmunome, Inc. (formerly Ayala Pharmaceuticals).DisclosureB. Kasper: Financial Interests, Personal, Advisory Board: Bayer, Boehringer Ingelheim, Springworks Therapeutics, GSK, PharmaMar, Ayala; Financial Interests, Institutional, Coordinating PI: PharmaMar, Springworks Therapeutics, Ayala; Financial Interests, Institutional, Local PI: Cogent, Rain Therapeutics; Non-Financial Interests, Leadership Role, Past-Chair of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG): European Organisation for Research and Treatment of Cancer (EORTC). M. Gounder: Financial Interests, Personal, Financially compensated role, Honoraria: Medscape, Guidepoint Global, touchIME, Med Learning Group, Research to Practice, Great Debates and Updates, GLG, OncLive/MJH Life Sciences, MJH/PER; Financial Interests, Personal, Advisory Role: Daiichi Sankyo, Karyopharm Therapeutics, Epizyme, Bayer, Boehringer Ingelheim, Springworks Therapeutics, TYME, Rain Therapeutics, Regeneron, AADi, Ikena Oncology, Kura Oncology; Financial Interests, Personal, Advisory Role, Honoraria: Immunome (formerly Ayala); Financial Interests, Institutional, Research Funding: Immunome (formerly Ayala), AADi, Athenex, Boehringer Ingelheim, Foghorn Therapeutics, Ikena Oncology, Rain Oncology, Regeneron, SpringWorks Therapeutics, Servier, Tango Therapeutics, Kymera, Erasca, Inc; Financial Interests, Institutional, Other: GSK; Financial Interests, Personal, Licencing Fees or royalty for IP: UpToDate, GODDESS PRO Desmoid Tumor; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Epizyme; Financial Interests, Personal, Advisory Board: Desmoid Tumor Research Foundation; Non-Financial Interests, Personal, Non remunerated activity: Foundation Medicine. R. Chugh: Financial Interests, Personal, Advisory Board: SpringWorks, Inhibrx, Jazz Pharmaceuticals; Financial Interests, Personal, Royalties: UpToDate, Inc; Financial Interests, Institutional, Local PI: Ayala, Astex Pharmaceuticals, Cogent Biosciences, Inhibrx, SpringWorks Therapeutics, GSK, Sound Biologics, Kronos Bio, PTC Therapeutics, Pfizer, PharmaMar; Financial Interests, Institutional, Coordinating PI: Janssen, Astra Zeneca. A. Singh: Financial Interests, Personal, Advisory Board, Advisory board for TGCT, GIST: Deciphera; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Aadi Biosciences, Galvanize; Financial Interests, Personal, Invited Speaker: Deciphera, Springworks; Financial Interests, Personal, Stocks/Shares, Shares in privately held company: Certis Oncology Solutions; Financial Interests, Institutional, Local PI, Ran clinical trial at UCLA: Tracon, Cogent, Boehringer Ingelheim, Deciphera, Ayala, Daiichi Sankyo. B.A. Van Tine: Financial Interests, Personal, Invited Speaker, Educational Speaker: Targeted Oncology; Financial Interests, Personal, Advisory Board, Also, Travel paid to conference to present abstract: Adaptimmune Limited; Financial Interests, Personal, Other, Consulting. Also attended and Ad Board meeting. Travel was paid to attend an Ad board meeting.: Epizyme; Financial Interests, Personal, Other, Consulting- ADRx working on a cancer project and they are requesting my expertise.: ADRx; Financial Interests, Personal, Advisory Board, tenosynovial giant cell tumors (TGCT): Ayala Pharmaceuticals; Financial Interests, Personal, Other, Consulting and Ad Board: Bayer; Financial Interests, Personal, Other, OncLive Virtual Workshop: Intellisphere LLC; Financial Interests, Personal, Advisory Board, Attended Advisory Board Meeting: Apexigen Inc; Financial Interests, Personal, Advisory Board, Attended an Advisory Board Meeting: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: PTC Therapeutics, Boehringer Ingelheim, Agenus, Regeneron Pharmaceuticals; Financial Interests, Personal, Other, Consulting: Advenchen, Deciphera Pharmaceuticals, Inc, EcoR1, Putnam, Salarius Pharm, Boxer Capital LLC, Acuta Capital Partners, LLC, Aadi; Financial Interests, Personal, Invited Speaker, Telephone interview Sarcoma Expert: Iterion Therapeutics, Inc.; Financial Interests, Personal, Invited Speaker, 2023 West Oncology Talk. Travel provided: Total Health conference; Financial Interests, Personal, Advisory Board, VISTA Ad Board: Curtis; Financial Interests, Personal, Advisory Board, Sigma-2 Receptor Ligands and Therapeutic uses therefor (006766), Modular Platform for Targeted Therapeutic Delivery (006755), Sigma-2 Receptor Ligand Drug Conjugates as Antitumor Compounds, Methods of synthesis and Uses Thereof (014229): Accuronix Therapeutics; Financial Interests, Institutional, Research Grant: Pfizer, Merck, Tracon Pharm, GSK; Financial Interests, Personal and Institutional, Research Grant, Research Grant for trial: Polaris; Non-Financial Interests, Member of Board of Directors, Non-paid: Polaris. V. Andelkovic: Financial Interests, Personal, Advisory Board, Asia-Pacific Advisory Board December 2023: Boehringer Ingelheim; Financial Interests, Personal, Stocks/Shares, Stock ownership: Moleculin Biotech. E. Choy: Financial Interests, Personal, Advisory Board: Epizyme, Adaptimmune, Bayer, Sonata Therapeutics; Financial Interests, Institutional, Local PI, Participated in RINGSIDE study as local PI. Support for the study was given to the institution.: Ayala Pharma; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Novartis; Financial Interests, Institutional, Local PI: Adaptimmune; Non-Financial Interests, Member: Connective Tissue Oncology Society, ASCO, SARC. R. Ratan: Financial Interests, Personal, Advisory Board: SpringWorks Therapeutics; Financial Interests, Institutional, Local PI: Ayala Pharmaceuticals, C4 Therapeutics; Financial Interests, Institutional, Coordinating PI: SpringWorks Therapeutics. J. Yovell: Financial Interests, Personal, Full or part-time Employment, VP clinical Development at Ayala Pharmaceuticals: Ayala Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Ayala Pharmacutical; Non-Financial Interests, Project Lead: Ayala Pharmacuticals; Non-Financial Interests, Member: ASCO. R.L. Jones: Financial Interests, Personal, Advisory Board, I worked as a consultant.: Adaptimmune, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daiichi Sankyo, Deciphera, Immunedesign, Lilly, SpringWorks, Tracon, Upto Date, PharmaMar, Astex, Immunicum, Karma Oncology, Merck, Mundipharma, Synox; Financial Interests, Institutional, Research Grant, Research grant for a clinical trial.: MSD. All other authors have declared no conflicts of interest.