DKN-01 Plus Bevacizumab/Chemotherapy Advances to Part B in DeFianCe Trial in Advanced CRC

Zev A. Wainberg, MD

Leap Therapeutics has launched the randomized, controlled part B of the phase 2 DeFianCe trial (NCT05480306), which will evaluate the DKK1 antibody, DKN-01, in combination with standard-of-care bevacizumab (Avastin) and chemotherapy as second-line therapy in patients with advanced colorectal cancer (CRC). Part B seeks to build on earlier positive results from part A of the study.^1,2

“Part A of the DeFianCe study enrolled an aggressive heterogenous population of [patients with] second-line CRC representative of the second-line population that we see in the clinic who have poor outcomes on standard-of-care drugs and are in need of new therapies,” Zev A. Wainberg, MD, professor of medicine at UCLA and co-director of the UCLA GI Oncology Program, said in a news release. “Exceeding a 20% overall response rate [ORR] with a high disease control rate in second-line CRC patients is a clinically meaningful efficacy signal and worthy of further exploration.”

DKN-01 is a humanized monoclonal antibody that binds to and inhibits the activity of the DKK1 protein, which plays a key role in affecting an immunosuppressive tumor microenvironment and promoting tumor growth, metastasis, and angiogenesis. Removal of free DKK1 from the tumor microenvironment leads to natural killer cell activation, immune suppressor cell depletion, and immune-mediated antitumor response stimulation.³

DeFianCe is a global, open-label, phase 2 study evaluating DKN-01 plus bevacizumab and either FOLFOX or FOLFIRI in patients with advanced CRC with radiographic progression on or after one prior systemic therapy for advanced disease.²

To be eligible for enrollment, patients must have measurable disease per RECIST v1.1 criteria, disease progression following frontline systemic therapy with any fluoropyrimidine-based regimen for advanced disease except for FOLFOXIRI, and an ECOG performance status of 0 or 1.

Part A, which completed enrollment in April 2023,³ enrolled 33 patients, including those with early progression on first-line therapy, prior exposure to bevacizumab, RAS mutations, and liver metastases. Part B will enroll an additional 130 patients and will compare the investigational regimen with bevacizumab plus FOLFIRI or FOLFOX alone.

Patients in the investigational arm will receive a loading dose of DKN-01 followed by 400 mg as a 30-minute infusion every 2 weeks.

The primary end point of the study is progression-free survival (PFS). Secondary end points include ORR, duration of response, overall survival, and incidence of grade 3 or greater treatment-related adverse effects.

The company expects enrollment to take approximately 12 months and plans to have preliminary data ready for release in late 2024.

“The study enrolled quickly and has already exceeded the 20% ORR threshold. After the planned safety review meeting with our investigators, we decided to initiate the randomized controlled study,” Cynthia Sirard, MD, chief medical officer of Leap, stated in the news release. “We continue to follow these Part A patients to assess durability of response, PFS, and to determine whether additional patients with stable disease may become responders over time. We very much look forward to presenting this maturing data set at an upcoming meeting.”

DKN-01 is also under study as first-line therapy in combination with tislelizumab and chemotherapy in patients with gastric cancer in the randomized phase 2 DisTinGuish study (NCT04363801) and in combination with pembrolizumab (Keytruda) in an investigator-sponsored phase 2 trial (NCT05761951) in advanced endometrial cancer.³

References

1. Leap Therapeutics announces initiation of randomized controlled part B of the DeFianCe study of DKN-01 in colorectal cancer patients. News release. Leap Therapeutics, Inc. July 12, 2023. Accessed July 12, 2023. https://investors.leaptx.com/news-releases/news-release-details/leap-therapeutics-announces-initiation-randomized-controlled
2. Phase 2 study of DKN-01 in colorectal cancer (DeFianCe). ClinicalTrials.gov. Updated June 5, 2023. Accessed July 12, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05480306
3. Leap Therapeutics announces completion of enrollment in part A of the DeFianCe study of DKN-01 for the treatment of colorectal cancer patients. News release. Leap Therapeutics, Inc. April 12, 2023. Accessed July 12, 2023. https://investors.leaptx.com/news-releases/news-release-details/leap-therapeutics-announces-completion-enrollment-part-defiance