Narmafotinib Earns FDA Fast Track Designation for Advanced Pancreatic Cancer

The FDA has granted fast track designation to the focal adhesion kinase (FAK) inhibitor narmafotinib (AMP945) for the treatment of patients with advanced pancreatic cancer.¹

FAK is a protein overexpressed in certain tumors, including pancreatic cancer. Narmafotinib is a highly potent and selective FAK inhibitor that has demonstrated activity in a range of preclinical studies. The agent is currently under investigation in combination with gemcitabine and nab-paclitaxel (Abraxane) as first-line therapy for patients with unresectable or metastatic pancreatic cancer in the phase 1/2 ACCENT trial (NCT05355298).

Findings from a preliminary analysis of part A of ACCENT presented at the 2024 ASCO Annual Meeting showed that narmafotinib was generally safe and well tolerated.² All patients who completed their first cycle of treatment with narmafotinib plus gemcitabine and nab-paclitaxel (n = 14) elected to remain on treatment, and 9 of these patients remained on the trial for at least 5 months. One dose-limiting toxicity of uncontrolled grade 3 nausea was reported in the cohort evaluating narmafotinib at 400 mg.

Six patients experienced partial responses with narmafotinib dosed at 400 mg (n = 4) or 200 mg (n = 2). Based on the phase 1 data, 400 mg of narmafotinib has been selected as the recommended phase 2 dose (RP2D).

“Fast track designation for narmafotinib is a significant milestone for [Amplia Therapeutics],” Chris Burns, BSc (Hons), PhD, GAICD, chief executive officer and managing director of Amplia Therapeutics, stated in a news release.¹ “With this designation, we can work more closely with the FDA to accelerate our clinical program and gather the most compelling evidence for regulatory approval in this devastating disease.”

ACCENT is an open-label, 2-part, single-arm study enrolling patients at least 18 years of age with histologically or cytologically confirmed advanced pancreatic adenocarcinoma.³ In part A, patients are required to have metastatic or not surgically resectable disease, and in part B, metastatic disease with initial diagnosis less than 6 weeks prior to enrollment is required. Other key inclusion criteria consist of measurable disease; eligibility for gemcitabine plus nab-paclitaxel; an ECOG performance status of 0 or 1; a life expectancy of more than 3 months; and adequate organ function.

Patients are being excluded if they receive any investigational medicinal product within 30 days or 5 half-lives of day –8 of ACCENT; have known brain metastases that were not previously treated or well controlled for at least 3 months; undergo major surgery within 4 weeks of day –8; have a history of chronic leukemias; have a history of interstitial lung disease; or have connective tissue disorders.

In part A, prior systemic treatment for pancreatic cancer is not allowed, except for adjuvant therapy in patients who experienced recurrence more than 6 months after completion of curative/adjuvant treatment. In part B, no prior radiotherapy, surgery, chemotherapy, or investigational therapy for metastatic disease is allowed. Adjuvant treatment with 5-fluorouracil or gemcitabine administered as a radiation sensitizer is allowed in part B, provided at least 6 months have elapsed since completion of the last dose and no lingering toxicities are present; however, no prior cytotoxic doses of gemcitabine or any other chemotherapy in the adjuvant setting are allowed.

The part A dose-escalation portion of the study includes cohorts where narmafotinib is being administered at 100 mg, 200 mg, or 400 mg, in combination with gemcitabine plus nab-paclitaxel.^1,2 Part B is examining the RP2D of narmafotinib in combination with the standard-of-care chemotherapy regimen.³

The incidence of treatment-emergent adverse effects is serving as the trial’s primary end point. Determining the RP2D was also a primary end point in part A, and overall response rate per RECIST 1.1 criteria is also a primary end point in part B.

References

1. FDA fast track designation for narmafotinib in advanced pancreatic cancer. Amplia Therapeutics. September 20, 2024. Accessed September 20, 2024. https://www.ampliatx.com/blog/fda-fast-track-designation-granted-to-narmafotinib-in-pancreatic-cancer
2. Burns C, Cock T-A, Bishop A, et al. Phase 1b/2a of narmafotinib (AMP945) in combination with gemcitabine and nab-paclitaxel in first-line patients with advanced pancreatic cancer (ACCENT trial): interim analysis. J Clin Oncol. 2024;42(suppl 16):e16337. doi:10.1200/JCO.2024.42.16_suppl.e16337
3. ACCENT: AMP945 in combination with nab-paclitaxel and gemcitabine for treatment of pancreatic cancer. ClinicalTrials.gov. Updated May 6, 2024. Accessed September 20, 2024. https://clinicaltrials.gov/study/NCT05355298