FDA Grants Fast Track Designation to DKN-01 in Gastric/GEJ Adenocarcinoma

The FDA has granted a Fast Track designation to DKN-01 for the treatment of patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma whose tumors express the protein DKK1, following disease progression on or after prior treatment with fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, human epidermal receptor growth factor (HER2)/neu-targeted therapy, Leap Therapeutics announced in a press release.

DKN-01 is a humanized monoclonal antibody which blocks the activity of the DKK1 protein by binding to it. The agent is also a modulator of Wnt/Beta-catenin signaling. Previously, DKN-01 was granted an Orphan Drug designation by the FDA for the treatment of gastric and GEJ cancer.

"We are pleased with the FDA's decision to grant Fast Track designation for the development of DKN-01 to treat patients with gastric and gastroesophageal junction cancer whose tumors express high levels of DKK1," said Douglas E. Onsi, president and chief executive officer of Leap Therapeutics, in a statement. "The designation highlights the existing unmet medical need for new and effective treatments for this patient population. We believe that DKN-01 shows promise as a novel treatment option for biomarker-selected patients with these cancers, and this designation provides us with earlier and more frequent opportunities to interact with the FDA during the development of DKN-01."

In gastric and GEJ cancers, DKN-01 is currently under investigation in phase 1/2 clinical trials. These studies include the phase 2 DisTinGuish trial of DKN-01 in combination with tislelizumab, an anti–PD-1 antibody, with or without chemotherapy in patients with gastric or GEJ cancer (NCT04363801). The trial dosed its first patient in September 2020.

Data presented at the 2020 Gastrointestinal Cancer Symposium for the agent in combination with the checkpoint inhibitor pembrolizumab (Keytruda) demonstrated the clinical efficacy of the combination in gastric and GEJ cancers with high tumor DKK1 expression. The study was KEYNOTE-731 (NCT02013154), a multipart, multicenter, open-label study of DKN-01 with/without pembrolizumab.

The median progression-free survival (PFS) among patients with high DKK1 expression was 22 weeks, and the overall survival (OS) was 32 weeks. The population also had an overall response rate (ORR) of 50% and a disease control rate (DCR) of 80% in the 10 patients evaluated for response. In comparison, those with low DKK1 expression achieved a median PFS of only 6 weeks and a median OS of just 17 weeks. The low DKK1 expression group also had a 0% ORR and a DCR of 20%.

Based on these data, a multivariate analysis led to the determination that high DKK1 expression was associated with extended PFS, independent of PD-L1 expression by combined positive score.

KEYNOTE-731 is active but no longer recruiting patients. In the study, patients are assessed for the primary end point of the number of dose-limiting toxicities and the number of patients with adverse events. As secondary end points, the study is exploring clinical response to treatment, ORR, objective DCR, duration of response, duration of complete response, and OS.

Eligible patients include those with advanced esophagogastric malignancies who are at least 18 years of age with an ECOG performance status of 0 or 1, free of a secondary malignancy for over 2 years, and adequate liver, renal, hematologic, and coagulation function.

In addition to gastric and GEJ cancers, treatment with DKN-01 is being explored in gynecologic, hepatobiliary, and prostate cancers.

_References:

_{1. Leap Therapeutics announces FDA Fast Track Designation granted to DKN-01 for the treatment of gastric and gastroesophageal junction cancer. News release. Leap Therapeutics, Inc. September 24, 2020. Accessed September 24, 2020. https://bit.ly/2RX5AVc​}

_{2 Leap Therapeutics announces Orphan Drug Designation of DKN-01 for the treatment of gastric and gastroesophageal junction cancer. News release. Leap Therapeutics, Inc. June 11, 2020. Accessed September 24, 2020. https://bit.ly/330UJQF​}

_{3 Klempner SJ, Bendell JC, Villaflor VM, et al. DKN-01 in combination with pembrolizumab in patients with advanced gastroesophageal adenocarcinoma (GEA): Tumoral DKK1 expression as a predictor of response and survival. J Clin Oncol. 2020;38(suppl 4):357.}