On June 5, 2023 Ayala Pharmaceuticals, Inc. (OTCQX: ADXS), a clinical-stage oncology company, reported further results from the Phase 2 (Part A) segment of the RINGSIDE study evaluating AL102 in desmoid tumors (Press release, Ayala Pharmaceuticals, JUN 5, 2023, View Source [SID1234632461]). The results were presented in a Poster Discussion Session at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on Saturday, June 3. AL102 is a once-daily, potent, selective, oral gamma-secretase inhibitor (GSI).

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"Gamma secretase inhibitors are emerging as a promising new drug class for the management of desmoid tumors with the potential for tumor regression, good tolerability, and symptomatic improvement," said Dr. Mrinal M. Gounder, Medical Oncologist at Memorial Sloan Kettering Cancer Center in New York. "These latest data from the Phase 2 segment of RINGSIDE demonstrate that AL102 is active in desmoid tumors. Responses to treatment were seen in all dose groups, with a higher and more rapid response in the 1.2 mg once-daily dosing group. Most responses were maintained and deepened with time across all the parameters measured, including centrally determined volume, T2 and RECIST-criteria, with a manageable safety profile that is typical for the class. AL102 has potential to be a valuable addition to our treatment armamentarium for desmoid tumor patients," he concluded.

RINGSIDE Poster Highlights

The ongoing Phase 2/3 RINGSIDE clinical trial is a randomized, global multi-center study evaluating AL102 in patients with progressing desmoid tumors. The study consists of two parts: Phase 2 (Part A) is an open-label, dose regimen-finding study; Phase 3 (Part B) is a double blind, placebo-controlled study utilizing the 1.2 mg once daily dose regimen selected based on data from Phase 2. The study also includes an open label extension enrolling patients who were on active drug at the end of Phase 2, as well as crossover patients from Phase 3.

In the Phase 2 segment of RINGSIDE, Patients were randomized to one of three dose regimens of AL102 (n=14 each): either 1.2 mg once-daily (QD), 4 mg twice a week (BIW) or 2 mg BIW. Enrollment of all 42 patients into Phase 2 was completed as of March 2022. As of January 3, 2023, median time on study was 10.3 months (range 0.8 – 14.7) and 30 patients were still on study,10 of whom rolled over to the open label extension.

Efficacy Results

Best overall responses for the three dose arms, as determined by per blinded independent central review (BICR), are summarized in the table below:

Evaluable population

1.2 mg QD 4 mg BIW 2 mg BIW
(n= 12) (n=13) (n=11)
ORR (CR + PR), n (%) 6 (50) 3 (23.1) 5 (45.5)
Complete Response (CR) 0 0 0
Partial Response (PR) 6 (50) 3 (23.1) 5 (45.5)
Stable Disease (SD) 6 (50) 10 (76.9) 4 (36.4)
Progressive Disease (PD) 0 0 2 (18.1)
Disease Control Rate 100% 100% 81.90%
Time to objective response (months), median (range)

6.7 9.8 9.2
(3.8-9.4) (9.0-12.3) (6.4-9.2)
In the intention-to-treat (ITT) population, partial responses were observed in 43% of patients (i.e., 6/14) in the 1.2 mg QD group, 21.4% of patients (3/14) in the 4 mg BIW group, and 36% (5/14) in the 2 mg BIW group.

As shown in the next table, there was a consistent pattern of deeper, more rapid and persistent tumor responses as measured by volume reduction, T2W signal intensity and RECIST with AL102 1.2 mg daily than with intermittent doses. The decrease in T2W, as measured by MRI, reflects a decrease in tumor cellularity and is considered a strong indicator of anti-tumor activity in desmoid tumors. Tumor volume shrinkage consistently deepens over time and some patients who may not have had PRs by RECIST early in treatment may evolve to PRs with longer follow-up.

Median % Change from Baseline
Study Visit

1.2 mg QD 4 mg BIW 2 mg BIW
(n= 12) (n=13) (n=11)
Tumor Volume
Week 16 -51.9 -9.5 -15.2
Week 28 -76.4 -35.5 -51.2
Week 40 -75.9 -63.4 -61.2
T2W Signal Intensity (cellularity)
Week 16 -58.4 -37.9 -28.2
Week 28 -77.8 -42.1 -50.2
Week 40 -85.2 -56.6 -54.9
RECIST (sum of diameters)
Week 16 -13.3 1.7 -7.2
Week 28 -29.4 -9.6 -7
Week 40 -22.8 -16.7 -22
Safety

AL102 was generally well tolerated with a manageable safety profile across all dose arms. The safety profile was consistent with the GSI class of drugs. Regardless of dose regimen, adverse events (AEs) were predominantly Grade 1 (~70%) or Grade 2 (~20%). There were no Grade 4 or Grade 5 related AEs. Serious AEs were reported in 6 of 42 patients (14%) and assessed as unrelated to AL102 by investigators. There were no new safety signals.

Discontinuation due to AEs occurred in 6 of 42 (14%) patients. These were due to Grade 2 rash, keratitis, stomatitis, diarrhea, ALT elevation. All occurred within 3 months of treatment initiation.

Ovarian dysfunction was reported in 11 of 23 (48%) women of childbearing potential across all dose arms, but in only 3 of 9 (33%) women who received the 1.2 mg once-daily dose.

The registration-enabling Phase 3 segment is enrolling patients globally. For more information on RINGSIDE, please visit ClinicalTrials.gov and reference Identifier NCT04871282 (RINGSIDE).

A copy of the poster can be found on the Ayala corporate website here.

Conference Call and Webcast

There will be a conference call and webcast with slides at 10:00 a.m. Eastern Time on Wednesday, June 7, during which Ayala management will discuss the latest RINGSIDE data presented at ASCO (Free ASCO Whitepaper) and respond to questions.

Investors Dial: 1-877-407-9039
Int’l Investors Dial: 1-201-689-8470
Investors in Israel Dial: 1-809-406-247
Conference ID: 13739267

Participants can use Guest dial-in numbers above and be answered by an operator OR click the Call me link for instant telephone access to the event. The Call me link will be made active 15 minutes prior to scheduled start time.

Webcast: View Source;tp_key=d058de57b1

The webcast will also be archived for a period of 90 days on the Investor Relations web pages of Ayala (View Source).

MSK Disclosure: Dr. Gounder has financial interests related to Ayala Pharmaceuticals

About Desmoid Tumors

Desmoid tumors, also called aggressive fibromatosis or desmoid-type fibromatosis, are rare connective tissue tumors that typically arise in the upper and lower extremities, abdominal wall, head and neck area, mesenteric root, and chest wall, or other parts of the body. Desmoid tumors do not metastasize, but often aggressively infiltrate neurovascular structures and vital organs. People living with desmoid tumors are often limited in their daily life due to chronic pain, functional deficits, general decrease in their quality of life and organ dysfunction. Desmoid tumors have an annual incidence of approximately 1,700 patients in the United States and typically occur in patients between the ages of 15 and 60 years. They are most commonly diagnosed in young adults between 30-40 years of age and are more prevalent in females. Today, surgery is no longer regarded as the cornerstone treatment of desmoid tumors due to surgical morbidity and a high rate of recurrence post-surgery. There are currently no FDA-approved systemic therapies for the treatment of unresectable, recurrent or progressive desmoid tumors.

About AL102

AL102 is an investigational small molecule gamma secretase inhibitor (GSI) that is designed to potently and selectively inhibit Notch 1, 2, 3 and 4, and is currently being evaluated in the Phase 2/3 RINGSIDE clinical studies in patients with progressing desmoid tumors. AL102 is designed to inhibit the expression of Notch gene targets by blocking the final cleavage step by the gamma secretase required for Notch activation. Ayala obtained an exclusive, worldwide license to develop and commercialize AL102 from Bristol-Myers Squibb Company in November 2017. AL102 was granted U.S. FDA Fast Track Designation for the treatment of DT.