FDA Grants Fast Track Designation to AL1010 for Adenoid Cystic Carcinoma Indication

The FDA has granted Fast Track Designation to AL101, an injectable small molecule gamma secretase inhibitor, as treatment of patients with recurrent or metastatic adenoid cystic carcinoma (ACC). The designation follows an Orphan Drug Designation granted in May of 2019 for treatment of ACC, Ayala Pharmaceuticals, Inc. announced in a press release.¹

The agent is currently being evaluated in the phase II ACCURACY study. Data for ACCURACY were presented at the European Society for Medical Oncology (ESMO) 2019 Congress in Barcelona, Spain.

ACCURACY, an open-label, single-arm, multicenter study followed a Simon optimal design. Twelve patients with ACC harboringNOTCH1/2/3/4 activating mutations were eligible to be treated with AL101 in stage 1; given 2 or more patients responded to the therapy, an additional 24 patients were enrolled in stage 2. If 6 or more out of 36 patients responded, the trial was considered positive. The trial design yields 80% power and 5% type I error rate, if the objective response rate (ORR) is 25%.²

At ESMO, Renata Ferrarotto, MD, reported that 12 patients were being treated in stage 1 with a median of 1.5 cycles of AL101 as of May 2019. The majority of patients were men with an ECOG performance status of 0 and withNOTCHmutations in the PEST domain. In a press release corresponding with the ESMO presentation, Ayala Pharmaceuticals reported that there was a 22% response rate and 61% disease control observed in the study.³

AL101 at 4 mg intravenously once weekly was administered to patients in the study. The primary end point was ORR per RECIST v1.1 by an independent review committee (IRC), and the secondary end points were ORR by investigator review (IR), duration of response by IRC and IR, progression-free survival by IRC, overall survival, and safety.

The study included patients with confirmed ACC with knownNOTCH1/2/3/4activating mutations that is recurrent or metastatic, not amenable to potentially curative surgery or radiotherapy, and with evidence of radiographic or clinical disease progression within 6 months of giving informed consent. Patients were required to have Formalin-fixed, Paraffin-embedded tissue available for testing, and have at least 1 target measurable lesion if they have nodal or have visceral metastasis. Patients were excluded from the study if they had been diagnosed with a malignancy other than ACC in the past 2 years, have uncontrolled or active infection, a gastrointestinal disease with increased risk of diarrhea, symptomatic central nervous system metastases, an unstable or severe uncontrolled medical condition, or abnormal organ and marrow function. Patients with an ECOG performance status of 2 or higher were ineligible for the study.

“Receiving Fast Track designation from the FDA underscores the urgent need for a targeted therapy to address the devastating nature of ACC, a rare disease for which no standard drug therapy currently exists,” Roni Mamluk, PhD, Chief Executive Officer of Ayala, said in a statement. “We are pleased with the initial data from our phase II ACCURACY clinical trial, demonstrating that AL101 has been well tolerated and has shown encouraging preliminary signs of activity in this extremely difficult-to-treat patient population. We look forward to continuing discussions with the FDA in our effort to develop a novel treatment for patients in need.”

The ACCURACY trial is ongoing and actively recruiting patients with recurrent or metastatic ACC. The prospective completion date of the study in July of 2021. With a Fast Track Designation, the development of AL101 can be expedited for review by the FDA. A rolling review of a New Drug Application for AL101 may be allowed if the relevant criteria are met.

References

1. Ayala Pharmaceuticals granted U.S. FDA fast track designation for AL101 for the treatment of recurrent or metastatic adenoid cystic carcinoma [new release]. Rehovot, Israel and Wilmington, DE: Ayala Pharmaceuticals, Inc.; March 3, 2020.https://bwnews.pr/38ltSy1. Accessed March 3, 2020.
2. Ferrato R, Ho A, Wirth LJ, et al. ACCURACY a phase (P) II trial of AL101, a pan-Notch inhibitor, in recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) patients (pts) with Notch activating mutations (Notch act mut): Preliminary safety and efficacy data.Annals of Oncol. 2019;30(suppl 5):v465-v466. doi: 10.1093/annonc/mdz252.040.
3. Ayala Pharmaceuticals presents encouraging preliminary safety and efficacy data in patients with recurrent/metastatic adenoid cystic carcinoma with progressing disease and notch activating mutations from ongoing phase 2 clinical trial at ESMO [news release]. Rehovot, Israel and Wilmington, DE: Ayala Pharmaceuticals, Inc.; September 30, 2019.https://bit.ly/2PH7Qzp. Accessed March 3, 2020.