FDA Grants Fast Track Status to DKN-01 for Gastric and GEJ Cancer

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 have high DKK1 expression, who have progressed on or after a fluoropyrimidine- and platinum-containing chemotherapy, and HER2/neu targeted therapy, if appropriate, according to Leap Therapeutics, Inc.¹

“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 GEJ cancer whose tumor express high levels of DKK1,” Douglas E. Onsi, president and chief executive officer of Leap Therapeutics, Inc, stated in a press release. “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.”

DKN-01 is a humanized monoclonal antibody that was developed to blind to and block the activity of the DKK1 protein, which serves as a modulator of the Wnt/Beta-catenin signaling pathway that is frequently involved in tumorigenesis and immune system suppression. 

In the phase 1/2 P102/KEYNOTE-731 trial (NCT02013154) of DKN-01, investigators examined the agent as a monotherapy and in combination regimens in previously treated patients with advanced esophagogastric cancer.² Participants were given single-agent DKN-01, DKN-01 plus paclitaxel, or DKN-01 plus pembrolizumab (Keytruda).

In the trial, the combination of DKN-01 and pembrolizumab resulted in favorable outcomes for patients with gastric/GEJ tumors that had high DKK1 expression and who had not received previous treatment with a PD-1 or PD-L1 inhibitor.

Specifically, results showed that the median progression-free survival (PFS) with the combination in 10 evaluable patients was over 22 weeks, while the median overall survival (OS) was almost 32 weeks. The objective response rate (ORR) elicited with the combination was 50% in these patients, and the disease control rate (DCR) was 80%. Moreover, in patients with low DKK1 expression, the median PFS with the combination was approximately 6 weeks, the median OS was over 17 weeks, and the DCR was 20%.

Additionally, no correlation between PD-L1 expression as measured by combined positive score (CPS) and efficacy with the combination regimen was observed. However, high expression of DKK1 was linked with longer PFS independent of PD-L1 CPS level, according to data from a multivariate analysis.

More recently, in September 2020, the biotechnology company announced that the first patient had been dosed in the phase 2a DisTinGuish study (NCT04363801), which is examining DKN-01 in combination with tislelizumab (BGB-A317) with or without chemotherapy as a first- or second-line treatment in adult patients with inoperable, locally advanced gastric/GEJ adenocarcinoma.³

The nonrandomized, open-label, multicenter trial will be conducted in 2 parts. Part A will be comprised of 24 patients with gastric/GEJ adenocarcinoma who have not previously received systemic treatment in the locally advanced/metastatic setting. Part B will include up to 48 participants with previously treated, inoperable, locally advanced or metastatic gastric/GEJ adenocarcinoma with high DKK1 expression as second-line treatment.

The objective of the trial is to examine the efficacy, safety, and tolerability of DKN-01 administered intravenously in combination with tislelizumab with or without capecitabine plus oxaliplatin in this population. In part A, patients will receive intravenous (IV) DKN-01 at a dose of 300 mg on days 1 and 15, intravenous tislelizumab at a dose of 200 mg on day 1, IV oxaliplatin at 130 mg/m² on day 1, and oral capecitabine at 1000 mg/m² twice daily on days 1 through 15 of each 21-day treatment cycle.⁴ In part B, patients will receive IV DKN-01 on days 1 and 15 and IV tislelizumab on day 1 of each 21-day cycle. Both parts of the trial will be conducted simultaneously.

DKN-01 was granted an orphan drug designation by the FDA in June 2020 for the treatment of patients with gastric cancer or GEJ cancer. The agent is currently under exploration in clinical trials for gastroesophageal, 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/2HvLvU8.
2. Leap Therapeutics presents updated data at the ASCO 2020 Gastrointestinal Cancers Symposium (ASCO GI) Global Meeting. News release. Leap Therapeutics, Inc. January 23, 2020. Accessed September 24, 2020. https://bit.ly/2N4woRf.
3. Leap Therapeutics and BeiGene announce first patient dosed in study of DKN-01 in combination with tislelizumab for the treatment of metastatic gastric or gastroesophageal junction cancer. News release.Leap Therapeutics, Inc. September 21, 2020. Accessed September 24, 2020. https://prn.to/3csjwjH.
4. A study of DKN-01 in combination with tislelizumab +/- chemotherapy in patients with gastric or gastroesophageal cancer (DisTinGuish). ClinicalTrials.gov. Updated August 25, 2020. Accessed September 24, 2020. https://clinicaltrials.gov/ct2/show/NCT04363801.