1488MO - Initial results of phase II/III trial of AL102 for treatment of desmoid tumors (DT)

Background

AL102 is a potent, orally available, selective gamma secretase inhibitor (GSI) under investigation as an antineoplastic agent. GSIs have antitumor activity against DT, including AL101 (2 confirmed PRs >3.5 years and >1 year; 1 stable disease for 1 year). There remains an unmet need for effective systemic therapy in DT, associated with durable tolerability, tumor regression, and symptom improvement.

Methods

RINGSIDE is a Phase 2/3 randomized study in patients with progressing DT. Part A (Phase 2) is an open-label part with safety as the primary endpoint. Patients are randomized to three dosing regimens: 1.2 mg QD, 2 mg intermittent BIW (2 days on 5 days off), or 4 mg intermittent BIW. Part B is a Phase 3 double-blind, placebo-controlled study with PFS as primary endpoint. The dose for part B will be determined based on the totality of data collected in part A. We report descriptive statistics for Part A. A Food Effect/PK (FE) substudy was also performed.

Results

As of Feb 22, 2022, 31 patients enrolled in Part A and 30 were still on study (the first 18 patients for ≥4 weeks). Mean age was 40 years, and 74% were women. The table shows treatment-emergent adverse events (TEAEs) by dose. There were no deaths or life-threatening TEAEs. Four patients had Grade 3 TEAEs (2 study-drug related: anemia, diarrhea; 2 unrelated: vomiting, pleural effusion). Four patients had dose reductions and one discontinued AL102 due to TEAEs. One serious TEAE (pleural effusion) was unrelated to AL102 per investigator. The most common AEs were diarrhea, rash, nausea, fatigue and stomatitis. No clinically significant ECG findings were noted. The FE substudy revealed that food had no significant effect on PKs. Table: 1488MO

Summary of Treatment-emergent Adverse Events (TEAEs) by Patient

*Deemed unrelated to study drug by investigator

Conclusions

Safety findings to date show no indication for discontinuing any of the three dosing cohorts. Efficacy, patient reported outcome and additional safety data will be presented at the conference.

Clinical trial identification

NCT04871282.

Editorial acknowledgement

Professional medical writing support provided by Laurie LaRusso, MS, ELS (Walpole, MA, USA) funded by Ayala Pharmaceuticals, Inc.

Legal entity responsible for the study

Ayala Pharmaceuticals.

Funding

Ayala Pharmaceuticals.

Disclosure

M.M. Gounder: Financial Interests, Personal, Other, Honoraria: Flatiron Health, PER, Medscape, Guidepoint Global, touchIME, Med Learning Group, More Health; Financial Interests, Personal, Advisory Role: Daiichi Sankyo, Karyopharm Therapeutics, Epizyme, Bayer, Springworks Therapeutics, Boehringer Ingelheim, Ayala Pharmaceuticals, Rain Therapeutics; Financial Interests, Personal, Advisory Role, Ayala Pharmaceuticals: TYME; Financial Interests, Personal, Speaker’s Bureau: Amgen, Karyopharm Therapeutics, Boehringer Ingelheim; Financial Interests, Personal, Other, Patents, Royalties, Other Intellectual Property: UpToDate; Financial Interests, Institutional, Other, Patents, Royalties, Other Intellectual Property: GODDESS PRO Desmoid Tumor; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Epizyme; Financial Interests, Personal, Other, Other Relationship: Desmoid Tumor Research Foundation; Non-Financial Interests, Personal, Other: Foundation Medicine, Athenex. R.L. Jones: Financial Interests, Personal, Expert Testimony, I worked as a consultant: Adaptimmune, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daiichi, Deciphera, Immunedesign, Lilly, Springworks, Tracon, Upto Date, PharmaMar; Financial Interests, Personal, Advisory Board, I worked as a consultant: Athenex; Financial Interests, Institutional, Research Grant, Research grant for a clinical trial: MSD. R. Chugh: Financial Interests, Institutional, Funding, Research Funding: Ayala Pharmaceuticals, SpringWorks; Financial Interests, Personal, Advisory Board: Ipsen, Deciphera, Jazz Pharmaceuticals. M. Agulnik: Financial Interests, Personal, Advisory Board: Lilly, Adaptimmune, Regeneron, AstraZeneca; Financial Interests, Personal, Invited Speaker: Bristol-Myers Squibb, Bayer, Deciphera; Financial Interests, Institutional, Research Grant: Exelixis. A. Singh: Financial Interests, Personal, Other, Consultant: Daiichi Sankyo, Deciphera; Financial Interests, Institutional, Other, Support for Clinical Trial: Deciphera, RAIN Therapeutics, Ayala Pharmaceuticals, Tracon; Financial Interests, Personal, Member of the Board of Directors: Certis Oncology Solutions; Financial Interests, Personal, Stocks/Shares: Certis Oncology Solutions. 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, Invited Speaker, Also attended an Ad Board meeting. Travel was paid to present abstract at conference: GSK; 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/Advisor: Cytokinetics Inc; Financial Interests, Personal, Other, Consulting: Bayer; Financial Interests, Personal, Other, 60 minute interview regarding Synovial Sarcoma.: Bionest Partners; 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, Deciphera Pharmaceuticals, Inc; Financial Interests, Personal, Advisory Board, Attended an advisory board meeting: Novartis; Financial Interests, Personal, Advisory Board: lilly, PTC Therapeutics; Financial Interests, Personal, Invited Speaker, 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; Non-Financial Interests, Invited Speaker: Polaris. E. Choy: Financial Interests, Institutional, Invited Speaker, 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: Epizyme; Financial Interests, Personal, Invited Speaker: Epizyme; Financial Interests, Institutional, Invited Speaker: Ayala Pharmaceuticals, Springworks Therapeutics, C4 Therapeutics. J.B. Kaplan: Financial Interests, Personal, Full or part-time Employment: Ayala Pharmaceuticals. J. Yovell: Financial Interests, Personal, Full or part-time Employment: Ayala Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Ayala Pharmaceuticals. G. Gordon: Financial Interests, Personal, Full or part-time Employment: Ayala Pharmaceuticals. B. Kasper: Financial Interests, Personal, Advisory Board: Bayer, Blueprint, Boehringer Ingelheim, Springworks, GSK, PharmaMar, Ayala; Financial Interests, Institutional, Invited Speaker: 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). All other authors have declared no conflicts of interest.