1929P - phase II results from the RINGSIDE phase II/III trial of AL102 for treatment of desmoid tumors

Background

There is an unmet need for more effective and well tolerated systemic therapy for desmoid tumors (DT, aggressive fibromatosis). Gamma secretase inhibitors (GSIs) have shown antitumor activity against DT. AL102 is a potent, oral, selective GSI under investigation for treatment of DT.

Methods

RINGSIDE is a phase 2/3 study for pts with progressing DT. In the open-label phase 2 study, adults with progressing DT (≥10% unidimensional growth ≤18 mo or DT-related pain requiring non-opioid medication) were randomized to 3 dose regimens: 1.2 mg QD (once daily), 2 mg intermittent BIW (2 days on 5 days off), or 4 mg intermittent BIW. RINGSIDE phase 3 is a double-blind, placebo-controlled study evaluating the chosen dose regimen from phase 2 (1.2 mg QD). We report updated efficacy and safety results from RINGSIDE phase 2.

Results

All 42 phase 2 pts enrolled as of Mar 2022. As of Jan 3, 2023, median time on study was 10.5 mo (range 0.8 – 14.7) and 30 pts (71%) were still on study, 10 (24%) of whom rolled over to an open-label extension. Mean age was 40 yrs, 74% were women, and 69% had received prior DT therapy. The best response in the evaluable population by blinded independent central review (BICR) was partial response in 6/12 pts (50%) for 1.2 mg QD, 3/13 pts (23%) for 4 mg BIW, and 5/11 pts (46%) for 2 mg BIW. Disease control rate was 100%, 91%, and 97%, respectively. Deeper, more rapid and maintained response was observed with 1.2 mg QD. Median volume change (BICR) from baseline was -52% for 1.2 mg QD, -10% for 4 mg BIW, and -15% for 2 mg BIW at Week 16 and -76%, -36%, and -52%, respectively, at Week 28, with similar patterns for T2 signal intensity (reduced tumor cellularity). The 5 most common Grade 1-2 treatment-emergent adverse events (TEAE) were diarrhea, nausea, fatigue, alopecia, and dry skin. Grade 3 drug-related TEAE were reported in 10/42 (24%) pts. There were no Grade 4-5 or serious drug-related TEAE and no new safety signals. Final phase 2 data will be reported.

Conclusions

AL102 was well tolerated with a safety profile consistent with other GSIs. Tumor response, volume reduction and T2 signal reduction were observed earlier with 1.2 mg QD, with deeper and maintained treatment responses. This dose was selected for RINGSIDE phase 3 (currently enrolling).

Clinical trial identification

NCT04871282.

Editorial acknowledgement

Medical writing support provided by Laurie LaRusso, MS, ELS, Chestnut Medical Communications, paid for by Ayala Pharmaceuticals.

Legal entity responsible for the study

Ayala Pharmaceuticals, Inc.

Funding

Ayala Pharmaceuticals, Inc.

Disclosure

B. Kasper: Financial Interests, Personal, Advisory Board: Bayer, Blueprint, Boehringer Ingelheim, Springworks, GSK, PharmaMar, Ayala; Financial Interests, Institutional, Coordinating PI: PharmaMar, Springworks, Ayala; Non-Financial Interests, Leadership Role, 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, Other, Honoraria: Flatiron Health, PER, Medscape, Guidepoint Global, touchIME, MedLearning Group, More Health; Financial Interests, Personal, Advisory Role: Daiichi Sankyo, Karyopharm Therapeutics, Epizyme, Bayer, Springworks Therapeutics, Boehringer Ingelheim, TYME, Ayala Pharma, Rain Therapeutics, Regeneron; Financial Interests, Personal, Speaker’s Bureau: Amgen, Karyopharm Therapeutics, Boehringer Ingelheim; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Royalties: GODDESS PRO Desmoid Tumor; Financial Interests, Personal, Other, Travel Accommodations: Epizyme; Other, Other: Desmoid Tumor Research Foundation; Non-Financial Interests, Personal, Non remunerated activity: Foundation Medicine, Athenex. R. Chugh: Financial Interests, Personal, Advisory Role: Springworks Therapeutics, Jazz Pharmaceuticals; Financial Interests, Institutional, Research Funding: Ayala, Cogent, AstraZeneca, Advenchen, Epizyme, Pfizer, Plexxikon, Springworks, Mundipharma, Glaxxo Smith Kline, Sound Biologics, Janssen, Cornerstone, PTC Therapeutics. M. Agulnik: Financial Interests, Personal, Speaker, Consultant, Advisor Boehringer Ingelheim, Deciphera, Aadi Bioscience, Blueprint Medicine, Bayer, Genzyme, Daiichi Sankyo, Eli Lilly. 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, Advisory Board: PTC Therapeutics, Boehringer Ingelheim, Agenus, Regeneron Pharmaceuticals; 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, Other, Consulting: Advenchen; Financial Interests, Institutional, Research Grant: Tracon Pharm, Pfizer, Merck, GSK; 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; Non-Financial Interests, Member of Board of Directors, Non-paid: Polaris. E. Choy: Financial Interests, Personal, Advisory Board: Epizyme, Adaptimmune, Bayer; Financial Interests, Institutional, Local PI, Participated in RINGSIDE study as local PI. Support for the study was given to the institution: Ayala Pharma; 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. G. Gordon: Financial Interests, Personal, Advisory Role: Ayala Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Ayala Pharmaceuticals. 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. A. Gutierrez: Financial Interests, Personal, Full or part-time Employment: Ayala. 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.