(P 172) PHASE 2 RESULTS FROM THE RINGSIDE PHASE 2/3 TRIAL OF AL102 FOR TREATMENT OF DESMOID TUMORS

Objective: 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 patients with progressing DT. In the open-label Phase 2 study, adults with progressing DT (≥10% unidimensional growth ≤18 months 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 patients enrolled as of Mar 2022. As of Jan. 3, 2023, median time on study was 10.5 months (range 0.8 – 14.7) and 30 patients (71%) were still on study, 10 (24%) of whom rolled over to an open-label extension. Mean age was 40 years, 74% were women, and 69% had received prior DT therapy. Pharmacokinetics data showed that AL102 was rapidly absorbed at all doses and exposure was similar under fasted and fed conditions. The median tmax was 1-2 hours, the effective t1/2 was 19.4-22.4 hours and time to steady state after daily dosing was 4-5 days. The best response in the evaluable population by blinded independent central review (BICR) was partial response in 6/12 patients (50%) for 1.2 mg QD, 3/13 patients (23%) for 4 mg BIW, and 5/11 patients (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%) patients. There were no Grade 4-5 or serious drug-related TEAE and no new safety signals. Final Phase 2 data will be reported.

Conclusion: In this Phase 2 study, AL102 was safe and well tolerated across all tested doses. The safety profile was consistent with the GSI class of drugs. Tumor response, volume reduction and T2 signal reduction were observed earlier in the 1.2 mg QD group, with deeper and maintained treatment responses. This dose was selected for study in RINGSIDE Phase 3, which is currently enrolling in multiple countries.