DisTinGuish Trial Doses First Patient With Investigational Dickkopf-1 Antibody DKN-01 Plus Tislelizumab in Gastric/GEJ Cancer

The first patient has officially been dosed with investigational anti-Dickkopf-1 antibody (DKN-01) plus tislelizumab (BGB-A317) with or without chemotherapy as part of the ongoing phase 2a DisTinGuish study (NCT04363801) in patients with gastric or gastroesophageal junction (GEJ) cancer.¹

"Dosing of the first patient in the DisTinGuish study is a key milestone for the DKN-01 development program," said Cynthia Sirard, MD, chief medical officer of Leap Therapeutics the developer of DKN-01. "We are excited to have the opportunity to combine DKN-01 with tislelizumab due to the promising signals in a DKK1 biomarker-defined population of esophagogastric cancer patients. We look forward to working closely alongside BeiGene to evaluate this potential new combination therapy for a patient population with a high global unmet medical need."

DKN-01 was most recently given a fast track designation by the FDA in September 2020 for the treatment of patients with gastric and GEJ adenocarcinoma with a high-risk of DKK1 tumor expression, as well as those who have progressed following fluoropyrimidine- and platinum-containing chemotherapy, and HER2/neu targeted therapy.² Previous data showed that in the phase 1/2 P102/KEYNOTE-731 trial, DKN-01 plus pembrolizumab demonstrated a median PFS of more than 22 weeks in 10 evaluable patients, while the median OS was approximately 32 weeks. Additionally, the ORR was 50% and the DCR was 80%. In low DKK1-expressing patients, the median PFS was 6 weeks, and the median OS and DCR rate was was 17 weeks and 20%, respectively.

Thenonrandomized, open-label, multicenter phase 2a, study is examining the combination of DKN-01 and tislelizumab with or without chemotherapy as either a first- or second-line treatment in patients with inoperable, locally advanced gastric or GEJ adenocarcinoma.³

The study is conducted in 2 parts—parts A and B, both of which will be enrolled concurrently—accruing up to 72 patients aged 18 years or older with measurable disease. In part A of the study, patients will receive a frontline treatment consisting of 300 mg of intravenous DKN-01 on days 1 and 15, 200 mg of tislelizumab on day 1, 130 mg/m2 of oxaliplatin on day 1, and oral capecitabine (Xeloda; 1000 mg/m2) on days 1 to 15 of each 21-day cycle.

In order to be eligible for this portion of the trial, patients could not have undergone prior systemic therapy for locally advanced or metastatic disease. That being said, prior adjuvant or neoadjuvant therapy was permitted, provided that the treatment was completed without disease recurrence for a minimum of 6 months.

In both parts of the study, the safety, tolerability, and efficacy of the combination will be evaluated. The combination will be administered in repeating 21-day cycles until those enrolled on the trial either meet the criteria for discontinuation of treatment or are no longer receiving clinical benefit from the regimen.

Part B focuses on treatment in the second-line setting, with 1 cohort of patients receiving 300 mg of DKN-01 on days 1 and 15 and 200 mg of tislelizumab on day 1 of each 21-day cycle, while a second cohort received a 600 mg dose of DKN-01. In this part of the trial, patients arerequired to have a DKK1-high disease of ≥35 and could have received 1 prior systemic therapy for locally advanced or metastatic disease. Much like part A, neoadjuvant and adjuvant therapy were allowed.

The primary end point of the study is safety and tolerability, with key secondary end points consisting of ORR, duration of response, progression-free survival (PFS), OS, duration of clinical benefit, DCR, and duration of response.

References

1. 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. Nasdaq Investors. September 21, 2020. Accessed September 21, 2020. https://bit.ly/33ERZIZ.
2. Leap Therapeutics Announces FDA Fast Track Designation granted to DKN-01 for the treatment of gastric and gastroesophageal junction cancer. News release. Leap Therapeutics. September 24, 2020. Accessed October 7, 2020. https://bit.ly/2HvLvU8.
3. 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 October 7, 2020. https://bit.ly/2F9zK4P.