FDA Grants Orphan Drug Designation to AL102 in Desmoid Tumors
Data from the phase 2 of the RINGSIDE trial have led the FDA to grant an orphan drug designation to AL102 as a potential therapeutic option for patients with desmoid tumors.
- AL102 is a potent, orally available, selective gamma secretase inhibitor (GSI).
- AL102 is currently being explored in the phase 2/3 RINGSIDE trial (NCT04871282) for patients with progressing desmoid tumors.
- In the phase 2 study, AL102 was safe and generally well-tolerated across all doses.
The FDA granted an orphan drug designation to AL102, a GSI, for the treatment of patients with desmoid tumors, according to Ayala Pharmaceuticals.1
According to findings from the phase 2 portion of the phase 2/3 RINGSIDE study which were presented at the 2023 ASCO Annual Meeting, AL102 was well-tolerated among patients treated across all doses. Though there were no complete responses observed, the gamma secretase inhibitor produced partial responses across all doses.2
For AL102 at a dose of 1.2 mg once per day (n = 12), the overall response rate (ORR) was 50%, 50% of patients had stable disease (SD), and the median time to response (TTR) was 6.7 months (range, 3.8-9.4). Among the 13 patients treated with AL102 at 4 mg twice per week, the ORR was 23.1%, the SD rate was 76.9%, and the median TTR in this group was 9.8 months (range, 9.0-12.3). Additionally, at a dose of 2 mg twice per week (n = 11), AL102 elicited an ORR of 45.5%, a SD rate of 36.4%, a progressive disease rate of 18.1%, and a median TTR of 9.1 months (range, 6.4-9.2).
cancer cell: © vitanovski - stock.adobe.com
“Receiving FDA orphan drug status for AL102 underscores the significant unmet need for novel treatment options for people living with desmoid tumors. We look forward to continuing to work closely with regulators, clinical investigators, patients, and their families to advance this potentially important medicine and make it available to those who may benefit from it,” said Kenneth A. Berlin, president and chief executive officer of Ayala Pharmaceuticals, in a press release.1
In the phase 2 portion of the RINGSIDE trial, patients aged 18 years and older with relapsed/refractory or treatment-naive desmoid tumors with tumor growth of at least 10% of the sum of largest diameters within the past 18 months were eligible for enrollment. Patients with desmoid tumor-related pain that was not adequately controlled with non-opioid medication were also eligible for enrollment in the trial, and patients were required to have a measurable lesion on MRI.2,3
Once enrolled, patients were randomized to 1 of 3 treatment arms which consisted of AL102 at 1.2 mg once daily, AL102 at 2 mg on a 2-days-on/5-days-off schedule, or AL102 at 4 mg on a 2-days-on/5-days-off schedule. In the open-label extension of the trial, patients received AL102 at 1.2 mg per day. The primary end point of phase 2 was safety, and tumor volume reduction was a secondary end point.
Forty-two patients were enrolled in phase 2 and their mean age was 39.9 years (range, 19-72).3 Most patients were female (73.8%), had extra abdominal desmoid tumors (73.8%), and received prior therapy for desmoid tumors (69.0%), including chemotherapy (47.6%), a targeted small molecule (28.6%), and hormonal therapy (21.4%). The median tumor size was 61.0 mm (range, 0-169). Further, 47.6% of patients underwent prior surgery for desmoid tumors, and 9.5% received prior radiotherapy.
Additional data from RINGSIDE revealed that the disease control rate in the 1.2, 4, and 2 mg groups were 100%, 91%, and 97% in these groups, respectively. The median change in tumor volume from baseline in the 1.2 mg arm was –51.9% at week 16, –76.4% at week 28, and –75.9% at week 40. For the median change in TW2 signal intensity, similar patterns were observed with –58.4%, –77.8%, and –85.2% at weeks 16, 28, and 40, respectively. The median change in the sum of diameters per RECIST v1.1 criteria was –13.3%, –29.4%, and –22.8% at weeks 16, 28, and 40, respectively.
In the 4 mg arm, the median change in tumor volume from baseline was –9.5% at week 16, –35.5% at week 28, and –63.4% at week 40. The median change in TW2 signal intensity was –37.9% at 16 weeks, –42.1% at 28 weeks, and –56.6% at 40 weeks, respectively. The median change in the sum of diameters per RECIST v1.1 criteria was 1.7%, –9.6%, and –16.7% at weeks 16, 28, and 40, respectively.
Further, in the 2 mg of AL102 twice per week group, the median change in tumor volume from baseline was –15.2% at week 16, –51.2% at week 28, and –61.2% at week 40. At weeks 16, 28, and 40, the median change in TW2 signal intensity was –28.2%, –50.2%, and –54.9%, respectively, and the median change in the sum of diameters per RECIST v1.1 criteria at these times were –7.2%, –7.1%, and –22.0%.
Looking at safety, most adverse events (AEs) were grade 1 or grade 2 and no grade 4, grade 5, or serious treatment-emergent AEs (TEAEs) were seen. The most common grade 1-2 TEAEs included diarrhea, nausea, fatigue, alopecia, and dry skin. Across all doses, grade 3 drug-related TEAEs were seen in 26.2% of patients.
As tumor response, volume reduction, and T2 signal reduction were observed earlier in patients treated in the 1.2 mg group, this dose was selected to be studied in phase 3 of the trial. Enrollment is ongoing for this phase 3 portion.
References
Ayala Pharmaceuticals announces AL102 receives orphan drug designation for desmoid tumors. News release. Ayala Pharmaceuticals. November 6, 2023. Accessed November 7, 2023. https://tinyurl.com/2hh86vpt
Gounder MM, Jones RL, Chugh R, et al. RINGSIDE phase 2/3 trial of AL102 for treatment of desmoid tumors (DT): Phase 2 results. J Clin Oncol. 2023;41(suppl 16):11515. doi:10.1200/JCO.2023.41.16_suppl.11515
A study of AL102 in patients with progressing desmoid tumors (RINGSIDE). ClinicalTrials.gov. Updated August 30, 2023. Accessed November 7, 2023. https://tinyurl.com/453hfa2a
