FDA Grants ADP-A2M4 RMAT Designation for Synovial Sarcoma

The FDA has granted a Regenerative Medicine Advanced Therapy (RMAT) designation to ADP-A2M4 (MAGE-A4) as a treatment for patients with synovial sarcoma.¹

The RMAT designation was based on updated data from a phase I trial that was presented at the 2019 CTOS Annual Meeting, in which 50% of patients achieved clinical responses with ADP-A2M4. The agent is a genetically engineered autologous-specific peptide-enhanced affinity receptor (SPEAR) T cell.

The phase I dose-escalation trial assessed safety, tolerability, and antitumor activity of the agent in 14 patients with synovial sarcoma. The median age of patients was 54 years old, and patients previously received a median of 2 lines of systemic therapy. The median dose of ADP-A2M4 given was 9.7 x 10⁹ (4.49-9.98 x 10⁹).

The best overall response rate in the 12 patients assessed in the expansion phase of the trial was 58%, which included both confirmed and unconfirmed partial responses (PRs). ADP-A2M4 had a disease control rate of 93%, which was defined by the objective overall response and stable disease (SD).

Eleven out of 12 patients demonstrated clinical benefit in post-baseline scans, including 7 patients with either a confirmed or unconfirmed PR and 4 patients with SD. There were 5 confirmed PRs according to RECIST criteria, while 3 patients remained ongoing at the time of cutoff and 2 patients developed progressive disease. Two unconfirmed PRs remain ongoing at data cutoff.

No dose-limiting toxicities were reported, and ADP-A2M4 appeared well-tolerated in patients with synovial sarcoma. Adverse events appeared consistent with what is expected with chemotherapy and other immunotherapies. There was 1 case of fatal aplastic anemia, which was described and reported to the FDA.²

To be eligible for enrollment, patients had to be ≥18 years old with a histologically confirmed diagnosis of synovial sarcoma, or 1 of the other following cancers: urothelial carcinoma, melanoma, squamous cell carcinoma of the head and neck, ovarian cancer, non—small cell lung cancer, esophageal or gastric cancer, or myxoid/round call liposarcoma.

All subjects had to be HLA-A*02-positive with expression of the MAGE-A4 RNA or protein on their tumor. Patients had to have measurable disease according to RECIST v1.1 criteria prior to lymphodepletion. The anticipated life expectancy of the patient also had to be > 6 months prior to leukapheresis and >3 months prior to lymphodepletion.

Patients were excluded from the trial if they had HLA-A*02:05 positive in either allele, HLA-A*02:07 as the sole HLA-A*02 allele, or any A*02 null allele as the sole HLA-A*02 allele. Additionally, patients were excluded if they had symptomatic CNS metastasesm any other malignancy besides the tumor within 3 years prior to screening, uncontrolled incurrent illness, active infection with HIV, HBV, HCV, or HTLV, or is pregnant/breastfeeding.

"RMAT designation is another important step in bringing our ADP-A2M4 therapy to market in 2022 for patients with synovial sarcoma. We have compelling data with ADP-A2M4 for the treatment of synovial sarcoma and are eager to make this therapy available to patients who have few other treatment options," said Elliot Norry, acting chief medical of Adaptimmune Therapeutics, the developers of the agent, in a press release. "We are screening and enrolling patients with sarcoma in our phase II SPEARHEAD-1 trial."

The RMAT designation is designed to expedite drug development and review processes. To be eligible for the RMAT designation, a drug must be a regenerative medicine intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition. Preliminary clinical evidence must demonstrate the drug's ability to address an unmet medical need. With the RMAT designation, ADP-A2M4 will receive incentives for Breakthrough Therapy designations, such as additional interaction and guidance from the FDA, the potential for accelerated approval, and potential priority review of the biologics license application, as well as other opportunities to expedite the development.

ADP-A2M4 has previously received an Orphan Drug Designation from the FDA for the treatment of patients with soft tissue sarcomas. Adaptimmune Therapeutics expect that the RMAT designation will expedite the development of the CAR T cell therapy with a goal of commercialization in 2022 for patients with synovial sarcoma.

References

1. Regenerative Medicine Advanced Therapy Designation Granted by FDA to ADP‑A2M4 for the Treatment of Synovial Sarcoma [press release]. Philadelphia, Pennsylvania and Oxfordshire, United Kingdom: Adatimmune Therapuetics plc. https://bit.ly/2PfYN7c. Accessed December 4, 2019.
2. Updated Data from Phase 1 ADP-A2M4 Trial Demonstrating Continued Clinical Benefit for People with Synovial Sarcoma. Adaptimmune. https://bit.ly/388crlu. Published November 16, 2019. Accessed December 4, 2019.