January 4, 2021 — The pivotal phase 2/3 RINGSIDE trial, which is evaluating the potent, selective oral gamma secretase inhibitor AL102, has been permitted to proceed and can potentially be used as a registrational study for adolescent and adult patients with desmoid tumors.
The pivotal phase 2/3 RINGSIDE trial, which is evaluating the potent, selective oral gamma secretase inhibitor AL102, has been permitted to proceed and can potentially be used as a registrational study for adolescent and adult patients with desmoid tumors, according to Ayala Pharmaceuticals following the completion of its end-of-phase 1 meeting with the FDA on the agent.
The agreement was based on findings from the AL101 and AL102 studies, which demonstrated durable responses with the agent in this patient population. Ayala Pharmaceuticals, the developer of AL102, stated that the RINGSIDE study is expected to initiate in the first half of 2021.
“This exciting news of entering into a potentially registration-enabling pivotal trial, earlier than expected, represents an important step for Ayala as we are able to accelerate the development of AL102 for the treatment of desmoid tumors based on positive and encouraging feedback from the FDA following our end-of-phase 1 meeting,” said Roni Mamluk, PhD, chief executive officer of Ayala. “Desmoid tumors are a rare, debilitating and often disfiguring class of soft-tissue tumors for which there are currently no approved therapies. We believe AL102 is well positioned to potentially provide effective systemic treatment based on the body of data conducted by [Bristol Myers Squibb] in patients with desmoid tumors implicating the role of Notch pathway in activating aberrant growth pathways contributing to desmoid tumor growth.”
Desmoid tumors are rare connective tissue tumors that typically arise in the upper and lower extremities, abdominal wall, head and neck area, and mesenteric root and chest wall, and can appear in additional areas. While these tumors do not metastasize, desmoid tumors often and aggressively infiltrate neurovascular structures and vital organs.
Patients with desmoid tumors often have a challenging daily life and experience chronic pain, functional deficits, general decrease in their quality of life and organ dysfunction. The incidence of desmoid tumors is approximately 1700 patients in the United States and typically occur in patients aged between 15 and 60 years, most commonly in those between 30 and 40 years old and in females.
There are currently no FDA-approved systemic therapies for the treatment of patients with unresectable, recurrent or progressive desmoid tumors.
AL102 is currently being developed for the treatment of patients with desmoid tumors, as well as in combination with BCMA-targeting agents in multiple myeloma.
In the phase 2/3 RINGSIDE trial, investigators are evaluating the efficacy, safety, and tolerability of AL102 in adult and adolescent patients with desmoid tumors. In part 1 of the trial, which will be an open-label design, up to 36 patients with progressive desmoid tumors will be enrolled. There will be 3 study arms across 3 AL102 doses: 1.2 mg daily, 2 mg twice weekly, and 4 mg twice weekly, with initial follow up of safety, tolerability and tumor volume by magnetic resonance imaging after 16 weeks so optimal dose can be determined. Following the end of part 1, all patients will be eligible to enroll into an open-label extension study at the selected dose, and long-term efficacy and safety will be monitored.
Part 2 will comprise a double-blind, placebo-controlled study of up to 156 patients with progressive disease, who will be randomized 2:1 to receive AL102 or placebo.
The primary end point will be progression-free survival (PFS); secondary endpoints include objective response rate (ORR), duration of response (DOR), and patient-reported quality of life (QOL) measures.
Read-outs of initial interim data from part 1 and dose selection will be expected by the middle of 2022, and part 2 of the study will begin immediately following that read-out.