A Study of DKN-01 in Combination With Tislelizumab ± Chemotherapy in Patients With Gastric or Gastroesophageal Cancer (DisTinGuish)

A Phase 2, Multicenter, Open-Label Study of DKN-01 in Combination With Tislelizumab ± Chemotherapy as First-Line or Second-Line Therapy in Adult Patients With Inoperable, Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (DisTinGuish)

A Phase 2, Multicenter, Open-Label Study of DKN-01 in Combination with Tislelizumab ± Chemotherapy as First-Line or Second-Line Therapy in Adult Patients with Inoperable, Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

Study Overview

• Status: Terminated
• Conditions: Gastric Cancer; Gastric Adenocarcinoma; GastroEsophageal Cancer
• Intervention / Treatment: Drug: DKN-01 300mg; Drug: Tislelizumab 200mg; Drug: DKN-01 600mg; Drug: DKN-01 400mg; Drug: Tislelizumab 400mg; Drug: Oxaliplatin; Drug: Leucovorin Calcium; Drug: Fluorouracil; Drug: Capecitabine 1000mg/ m2 twice daily (BID)

Detailed Description

This is a Phase 2 open-label, multicenter study to be conducted concurrently in 3 Parts (Parts A, B, and C). Approximately 232 patients aged 18 years or older with inoperable, histologically confirmed locally advanced or metastatic Gastric or Gastroesophageal Junction (G/GEJ) adenocarcinoma with measurable disease (RECIST v1.1) requiring therapy will be enrolled in the study. Part A and B are designed to evaluate safety, tolerability, and efficacy of the combination therapy of intravenous (IV) DKN-01 and tislelizumab ± CAPOX in G/GEJ adenocarcinoma patients. Treatment continues in repeating 21-day cycles until patient meets criteria for discontinuation or is no longer deriving clinical benefit. Two doses of DKN-01 will be evaluated in Part B (Part B1 and Part B2). Part C is the open-label, randomized, controlled, 2-arm portion of the study to evaluate the efficacy and safety of tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) ± DKN-01 in adult patients with inoperable, histologically confirmed locally advanced or metastatic G/GEJ adenocarcinoma with measurable disease (RECIST v1.1) requiring therapy. Approximately 160 patients will be randomized in a 1:1 ratio to receive either DKN-01 in combination with tislelizumab and chemotherapy regimen (CAPOX or mFOLFOX6) (n=80) or tislelizumab in combination with chemotherapy regimen (CAPOX or mFOLFOX6) (n=80).

• Study Type: Interventional
• Enrollment (Actual): 247
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Charite Universitatsmedizin Berlin
  • Frankfurt, Germany, 60488
    • Institut Fur Klinisch Onkologische Forschung Am Krankenhaus Nordwest
  • Hamburg, Germany, 20249
    • Hamatologisch-Onkologische Praxis Eppendorf (HOPE)
  • Heidelberg, Germany, 69120
    • Universitatsklinikum Heidelberg
  • Heilbronn, Germany, 74078
    • Slk-Kliniken
  • Ravensburg, Germany, 88212
    • Studienzentrum Onkologie Ravensburg
  • Saarbrücken, Germany, 66113
    • Caritas Klinikum Saarbrucken St. Theresia
• South Korea
  • Ansan-si, South Korea, 15355
    • Korea University Ansan Hospital
  • Anyang, South Korea, 14068
    • Hallym University Sacred Heart Hospital
  • Busan, South Korea, 49201
    • Dong-A University Hospital
  • Goyang, South Korea, 10408
    • National Cancer Center
  • Incheon, South Korea, 21565
    • Gachon University Gil Medical Center
  • Incheon, South Korea, 22332
    • Inha University Hospital
  • Seongnam, South Korea, 13620
    • Seoul National University Bundang Hospital
  • Seoul, South Korea, 05505
    • Asan Medical Center
  • Seoul, South Korea, 3080
    • Seoul National University Hospital
  • Seoul, South Korea, 02841
    • Korea University Anam Hospital
  • Seoul, South Korea, 08308
    • Korea University Guro Hospital
  • Seoul, South Korea, 6351
    • Samsung Medical Center
  • Seoul, South Korea, 04763
    • Hanyang University Hospital
  • Seoul, South Korea, 07061
    • Boramae Hospital SNU
  • Seoul, South Korea, 3722
    • Severance Hospital, Yonsei University Health System
  • Seoul, South Korea, 6591
    • The Catholic University of Korea St. Mary's Hospital
  • Suwon, South Korea, 16247
    • The Catholic University of Korea St. Vincent's Hospital
  • Gyeonggi-do
    • Seongnam-si, Gyeonggi-do, South Korea, 13520
      • CHA Bundang Medical Center
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Cancer Center
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • Los Angeles, California, United States, 90095
      • UCLA
    • Los Angeles, California, United States, 90025
      • The Angeles Clinic Research Institute - A Cedars-Sinai Affiliate
    • Newport Beach, California, United States, 92663
      • Hoag Memorial Hospital Presbyterian
    • Orange, California, United States, 92868
      • Chao Family Comprehensive Cancer Center, University of California, Irvine
    • San Francisco, California, United States, 94158
      • University of California San Francisco
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
    • Orlando, Florida, United States, 32804
      • AdventHealth Cancer Institute
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60611
      • Northwestern University Robert H. Lurie Comprehensive Cancer Center
  • Louisiana
    • Covington, Louisiana, United States, 70433
      • Pontchartrain Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Carbone Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion:

Part A & C:

1. No previous therapy for cancer. Patients may have received prior neoadjuvant or adjuvant therapy as long it was completed without disease recurrence for at least 6 months since last treatment.

   Part B Only:

2. Disease progression during first-line therapy or within 4 months after the last dose of first-line therapy.

3. Documentation of elevated Dickkopf-1 (DKK1) messenger ribonucleic acid (mRNA) expression from a fresh tumor biopsy or a biopsy obtained within the 6 months of screening.

   Part C Only:

4. Documentation of programmed cell death protein ligand-1 (PD-L1) combined positive score (CPS) by immunohistochemistry (IHC) and DKK1 mRNA expression in tumor cells by ISH from a fresh tumor biopsy (preferred) or archived tumor biopsy specimen conducted in a Sponsor designated central laboratory.

   General:

5. Able to provide written informed consent prior to any study-specific procedures.
6. Age ≥18 years on the day of signing the informed consent (exception: ≥19 years in the Republic of Korea).
7. Confirmed diagnosis of gastric adenocarcinoma or gastroesophageal junction (GEJ) adenocarcinoma.
8. One or more tumors measurable on radiographic imaging as defined by Response Evaluation Criteria in Solid Tumor (RECIST) 1.1.
9. Tumor tissue for mandatory pre-treatment evaluation (fresh biopsy [preferred] or archived specimen).
10. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 within 7 days of first dose of study drug
11. Acceptable liver, renal, hematologic, and coagulation function
12. Females of childbearing potential and male partners of female patients must agree to use adequate contraception during the study and for 6 months after their last dose of study drug.
13. Non-sterile males must be willing to use a highly effective method of birth control for the duration of the study and for at least 6 months after the last dose of study drugs.

Exclusion:

Part A & C Only:

1. Diagnosis of HER2-positive G/GEJ adenocarcinoma.
2. Unable to swallow capsules or disease significantly affected gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction (for those receiving CAPOX in Part C).

3. Prior therapy with an anti-programmed cell death protein 1 (PD-1) or anti-PD-L1 antibody.

   Part B Only:

4. Major surgery or chemotherapy within 21 days of first dose of study drug.

   General:

5. Squamous cell or undifferentiated or other histological type of gastric cancer.
6. Prior therapy with an anti-PD-L2 or any other antibody or drug specifically targeting T-cell co-stimulation or co-inhibitory checkpoint pathways in any treatment setting (including adjuvant/neoadjuvant) or prior therapy with an anti-DKK1 agent.
7. Patients with active autoimmune diseases or history of autoimmune diseases that may relapse.
8. Any condition that required treatment with steroids or any other immune suppressive drugs within 14 days prior to first dose of study drug.
9. Active leptomeningeal disease or uncontrolled brain metastases.
10. Any active cancer ≤ 2 years before first dose of study drug with the exception of cancer for this study.
11. Uncontrolled diabetes or >Grade 1 laboratory test abnormalities in potassium, sodium, or corrected calcium despite standard medical management or ≥Grade 3 hypoalbuminemia within 14 days before first dose of study drug.
12. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage within 7 days prior to first dose of study drug.
13. Clinically significant anorexia within 7 days prior to first dose of study drug.
14. History of interstitial lung disease, non-infectious pneumonitis, pulmonary fibrosis, acute lung disease, or uncontrolled systemic diseases.
15. Active, uncontrolled bacterial, viral, or fungal infections, within 14 days of study entry requiring systemic therapy.
16. Prior allogeneic stem cell transplantation or organ transplantation.
17. History of severe hypersensitivity reactions to other monoclonal antibodies or any components of study treatment.
18. Known dihydropyrimidine dehydrogenase deficiency.
19. New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, or unstable arrhythmia.
20. Fridericia-corrected QT interval (QTcF) > 470 msec (female) or history of congenital long QT syndrome.
21. Known to be human immunodeficiency virus (HIV) positive.
22. Serious nonmalignant disease
23. History of osteonecrosis of the hip or have evidence of structural bone abnormalities in the proximal femur on magnetic resonance imaging (MRI) scan that are symptomatic and clinically significant.
24. Known osteoblastic bony metastasis.
25. History of gastrointestinal perforation and/or fistulae within 6 months prior to first dose of study drug.
26. Major surgery 28 days prior to study entry.
27. Serious psychiatric or medical conditions that could interfere with treatment.
28. Toxicities (as a result of prior anticancer therapy) that have not recovered to baseline or stabilized, except for Adverse Events (AEs) not considered a likely safety risk (e.g., alopecia, neuropathy, and specific laboratory abnormalities).
29. Administration of a live vaccine within 28 days before first dose of study drug.
30. Active substance abuse.
31. Pregnant or nursing.
32. Concurrent participation in another therapeutic clinical study.
33. Prior radiation therapy within 14 days prior to study entry.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A First Line Treatment; Part A patients will receive IV DKN-01 (300 mg) on Days 1 and 15, IV tislelizumab (200 mg) on Day 1, IV oxaliplatin (130 mg/m2) on Day 1, and oral capecitabine (1000 mg/m2 twice daily [BID]) on Days 1-15 of each 21-day cycle. Part A is restricted to patients who have not had prior systemic therapy for locally advanced or metastatic disease. Patients may have received prior neoadjuvant or adjuvant therapy as long as it was completed without disease recurrence for at least 6 months.	Drug: DKN-01 300mg; Administered by IV infusion; Other Names: Experimental; Drug: Tislelizumab 200mg; Administered by IV infusion; Other Names: Tevimbra; humanized IgG4 anti-PD-1 monoclonal antibody; Drug: DKN-01 400mg; Administered by IV infusion; Other Names: Experimental; Drug: Tislelizumab 400mg; Administered by IV infusion; Other Names: Tevimbra; humanized IgG4 anti-PD-1 monoclonal antibody
Experimental: Part B2 Second Line Treatment; Part B patients will receive IV DKN-01 (600 mg) on Days 1 and 15 and IV tislelizumab (200 mg) on Day 1 of each 21-day cycle. Patients enrolled in Part B are required to have DKK1-high (H-score ≥ 35) G/GEJ adenocarcinoma (pre-screen biopsy) and must have had only 1 prior systemic therapy for locally advanced/metastatic disease (platinum + fluoropyrimidine-based therapy; ±HER2 therapy if applicable). Patients may have received prior neoadjuvant or adjuvant therapy.	Drug: DKN-01 600mg; Administered by IV infusion; Other Names: Experimental; Drug: DKN-01 400mg; Administered by IV infusion; Other Names: Experimental
Active Comparator: Part C Control First Line Treatment; Part C control patients will receive only tislelizumab in combination with chemotherapy regimen (CAPOX or mFOLFOX6). Part C is restricted to patients who have not had prior systemic therapy for locally advanced or metastatic disease. Patients may have received prior neoadjuvant or adjuvant therapy as long as it was completed without disease recurrence for at least 6 months.	Drug: Tislelizumab 200mg; Administered by IV infusion; Other Names: Tevimbra; humanized IgG4 anti-PD-1 monoclonal antibody; Drug: Tislelizumab 400mg; Administered by IV infusion; Other Names: Tevimbra; humanized IgG4 anti-PD-1 monoclonal antibody; Drug: Oxaliplatin; Administered by IV infusion; Other Names: Eloxatin; Drug: Leucovorin Calcium; Administered by IV infusion; Other Names: Folinic acid; Drug: Fluorouracil; Administered by IV infusion; Other Names: 5-FU; Drug: Capecitabine 1000mg/ m2 twice daily (BID); Administered orally; Other Names: Xeloda
Experimental: Part C Experimental First Line Treatment; Part C experimental patients will receive DKN-01 in combination with tislelizumab and chemotherapy regimen (CAPOX or mFOLFOX6). Part C is restricted to patients who have not had prior systemic therapy for locally advanced or metastatic disease. Patients may have received prior neoadjuvant or adjuvant therapy as long as it was completed without disease recurrence for at least 6 months.	Drug: Tislelizumab 200mg; Administered by IV infusion; Other Names: Tevimbra; humanized IgG4 anti-PD-1 monoclonal antibody; Drug: DKN-01 600mg; Administered by IV infusion; Other Names: Experimental; Drug: DKN-01 400mg; Administered by IV infusion; Other Names: Experimental; Drug: Tislelizumab 400mg; Administered by IV infusion; Other Names: Tevimbra; humanized IgG4 anti-PD-1 monoclonal antibody; Drug: Oxaliplatin; Administered by IV infusion; Other Names: Eloxatin; Drug: Leucovorin Calcium; Administered by IV infusion; Other Names: Folinic acid; Drug: Fluorouracil; Administered by IV infusion; Other Names: 5-FU; Drug: Capecitabine 1000mg/ m2 twice daily (BID); Administered orally; Other Names: Xeloda
Experimental: Part B1 Second Line Treatment; Part B patients will receive IV DKN-01 (300 mg) on Days 1 and 15 and IV tislelizumab (200 mg) on Day 1 of each 21-day cycle. Patients enrolled in Part B are required to have DKK1-high (H-score ≥ 35) G/GEJ adenocarcinoma (pre-screen biopsy) and must have had only 1 prior systemic therapy for locally advanced/metastatic disease (platinum + fluoropyrimidine-based therapy; ±Human Epidermal growth factor Receptor 2 [HER2] therapy if applicable). Patients may have received prior neoadjuvant or adjuvant therapy.	Drug: DKN-01 300mg; Administered by IV infusion; Other Names: Experimental; Drug: DKN-01 400mg; Administered by IV infusion; Other Names: Experimental

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A and B: Safety and Tolerability of DKN-01 in G/GEJ Patients	Number of subjects with adverse drug reactions and toxicities as assessed by CTCAE v5.0 CAPOX (capecitabine + oxaliplatin) in patients with inoperable, locally advanced or metastatic G/GEJ adenocarcinoma.	approximately 28 months
Part C: Progression Free Survival (PFS) in G/GEJ DKK1 High and Overall Patients Treated With DKN-01 in Combination With Tislelizumab and Chemotherapy vs Tislelizumab and Chemotherapy as a First-line Therapy	PFS was measured from the date of randomization to the date of documented disease progression, based on investigator assessed radiologic review using RECIST v1.1, or death due to any cause, whichever occurred first. If the patient had not died, but there was no radiographic post-baseline tumor assessment, PFS was censored at the date of randomization. If there were radiographic post-baseline tumor assessments that verified lack of disease progression, PFS was censored at the most recent tumor assessment before the data cut-off or study withdrawal, whichever occurred first.	approximately 30 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Objective Response Rate (ORR) in G/GEJ Patients Treated With DKN-01 in Combination With Tislelizumab + CAPOX as a First-line Therapy	Objective Response Rate (ORR) is defined as the proportion of patients achieving best overall response of Complete Response (CR) or Partial Response (PR) through radiological assessment of tumor response, based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Investigators were urged to have the same radiographic imaging modality used throughout the study for each subject (at baseline and at subsequent assessments) in order to provide uniformity of radiographic assessments.	approximately 28 months
Part B: Objective Response Rate (ORR) in G/GEJ Patients Treated With DKN-01 in Combination With Tislelizumab as a Second-line Therapy	Objective Response Rate (ORR) is defined as the proportion of patients achieving best overall response of Complete Response (CR) or Partial Response (PR) as assessed with Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).	approximately 28 months
Part A: Duration of Response (DoR) in G/GEJ Patients Treated With DKN-01 With Tislelizumab + CAPOX as a First-line Therapy	DoR is defined only for responders (patients with BOR of CR or PR) as the time from initial response until radiographically documented progressive disease or death due to any cause, whichever is earlier.	approximately 28 months
Part A: Duration of Complete Response (DoCR) in G/GEJ Patients Treated With DKN-01 With Tislelizumab + CAPOX as a First-line Therapy	DoCR is defined as the time from initial complete response (CR) until radiographically documented progressive disease or death due to any cause, whichever is first.	approximately 28 months
Part A: Progression Free Survival (PFS) in G/GEJ Patients Treated With DKN-01 With Tislelizumab + CAPOX as a First-line Therapy	For RECIST, PFS is defined as the time from first study drug dose (i.e., C1D1) to first radiographically documented progressive disease or death due to any cause.	approximately 28 months
Part A: Overall Survival (OS) in G/GEJ Patients Treated With DKN-01 With Tislelizumab + CAPOX as a First-line Therapy	Overall survival (OS) is defined as the time from first study drug dose (i.e., C1D1) to first radiographically documented progressive disease or death due to any cause.	approximately 28 months
Part A: Duration of Clinical Benefit (DoCB) in G/GEJ Patients Treated With DKN-01 With Tislelizumab + CAPOX as a First-line Therapy	DoCB is defined as the time from the initiation of DKN-01 to the time of progressive disease or death due to any cause, whichever occurs first, for patients who had a BOR of CR, PR, or SD of ≥6 weeks.	approximately 28 months
Part A: Durable Clinical Benefit (DCB) in G/GEJ Patients Treated With DKN-01 With Tislelizumab + CAPOX as a First-line Therapy	Durable clinical benefit (DCB) is defined as the proportion of patients presenting a Duration of clinical benefit (DoCB) for ≥180 days from initiation of DKN-01. Patients who have a best overall response of PD or those with clinical benefit lasting <180 days are not included.	approximately 28 months
Part A: Disease Control Rate (DCR) in G/GEJ Patients Treated With DKN-01 With Tislelizumab + CAPOX as a First-line Therapy	DCR is defined as the proportion of patients presenting with a best overall response (BOR) of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) for a duration of at least 6 weeks from initiation of DKN-01, as assessed by the Investigator using RECIST v1.1.	approximately 28 months
Part B: Duration of Response (DoR) in G/GEJ Patients Treated With DKN-01 in Combination With Tislelizumab as a Second-line Therapy	DoR is defined only for responders (patients with BOR of CR or PR) as the time from initial response until radiographically documented progressive disease or death due to any cause, whichever is earlier.	approximately 28 months
Part B: Duration of Complete Response (DoCR) in G/GEJ Patients Treated With DKN-01 in Combination With Tislelizumab as a Second-line Therapy	Duration of complete response (DoCR) is defined as the time from initial CR until radiographically documented progressive disease or death due to any cause, whichever is first. No patients had a complete response (CR); therefore, the DoCR was not applicable.	approximately 28 months
Part B: Progression Free Survival (PFS) in G/GEJ Patients Treated With DKN-01 in Combination With Tislelizumab as a Second-line Therapy	For RECIST, PFS is defined as the time from first study drug dose (i.e., C1D1) to first radiographically documented progressive disease or death due to any cause.	approximately 28 months
Part B: Overall Survival (OS) in G/GEJ Patients Treated With DKN-01 in Combination With Tislelizumab as a Second-line Therapy	Overall survival (OS) is defined as the time from first study drug dose (i.e., C1D1) to first radiographically documented progressive disease or death due to any cause.	approximately 28 months
Part B: Duration of Clinical Benefit (DoCB) in G/GEJ Patients Treated With DKN-01 in Combination With Tislelizumab as a Second-line Therapy	Duration of clinical benefit (DoCB) is defined as the time from the initiation of DKN-01 to the time of progressive disease or death due to any cause, whichever occurs first, for patients who had a BOR of CR, PR, or SD of ≥6 weeks.	approximately 28 months
Part B: Durable Clinical Benefit (DCB) in G/GEJ Patients Treated With DKN-01 in Combination With Tislelizumab as a Second-line Therapy	DCB rate is defined as the proportion of patients presenting a DoCB (Duration of clinical benefit) for ≥ 180 days from initiation of DKN-01, Patients who have a best overall response of PD or those with clinical benefit lasting <180 days will not be included.	approximately 28 months
Part B: Disease Control Rate (DCR) in G/GEJ Patients Treated With DKN-01 in Combination With Tislelizumab as a Second-line Therapy	DCR is defined as the proportion of patients presenting with a best overall response (BOR) of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) for a duration of at least 6 weeks from initiation of DKN-01, as assessed by the Investigator using RECIST v1.1.	approximately 28 months
Part C: To Estimate the Objective Response Rate (ORR) in DKK1-high G/GEJ Adenocarcinoma Patients Treated With DKN-01 in Combination With Tislelizumab + Chemotherapy Regimen (CAPOX or mFOLFOX6) as a First-line Therapy.	Objective Response Rate (ORR) is defined as the proportion of patients achieving best overall response of Complete Response (CR) or Partial Response (PR) as assessed by the investigator using RECIST v1.1. Experimental group: Sirexatamab + tislelizumab + CAPOX/FOLFOX, Control group: Tislelizumab + CAPOX/FOLFOX	approximately 30 months
Part C: To Estimate the Duration of Response (DoR) in DKK1-high G/GEJ Adenocarcinoma Patients Treated With DKN-01 in Combination With Tislelizumab + Chemotherapy Regimen (CAPOX or mFOLFOX6) as a First-line Therapy.	The duration of response (DoR) is defined only for responders (patients with a BOR of CR or PR) at the time from initial response (CR or PR) until radiographically documented progressive disease or death due to any cause, whichever is earlier. For ORR patient without PD or death, DoR is censored at the most recent tumor assessment before the data cutoff or study withdrawal, whichever occurs first.	approximately 30 months
Part C: To Estimate the Overall Survival (OS) in DKK1-high G/GEJ Adenocarcinoma Patients Treated With DKN-01 in Combination With Tislelizumab + Chemotherapy Regimen (CAPOX or mFOLFOX6) as a First-line Therapy.	Overall survival (OS) OS is defined as the time from the date of randomization to death due to any cause. For a patient who is not known to have died by the end of study follow-up, observation of OS is censored at the date the patient was last known to be alive (i.e., date of last contact). Patients lacking data beyond the day of randomization is censored at the date of randomization (i.e., OS duration of 1 day).	approximately 30 months
Part C: Assess Whether the Addition of DKN-01 With Tislelizumab + Chemotherapy Regimen (CAPOX or mFOLFOX6) Improves PFS in Patients w/ Combined Positive Score (CPS) ≥5 or CPS <5 Advanced DKK1-high and Overall G/GEJ Adenocarcinoma as a First-line Therapy.	PFS was measured from the date of randomization to the date of documented disease progression, based on investigator assessed radiologic review using RECIST v1.1, or death due to any cause, whichever occurred first. If the patient had not died, but there was no radiographic post-baseline tumor assessment, PFS was censored at the date of randomization. If there were radiographic post-baseline tumor assessments that verified lack of disease progression, PFS was censored at the most recent tumor assessment before the data cut-off or study withdrawal, whichever occurred first.	approximately 30 months
Part C: To Assess Whether the Addition of DKN-01 With Tislelizumab + Chemotherapy Regimen (CAPOX or mFOLFOX6) Improves ORR in Patients With CPS ≥5 or CPS <5 Advanced DKK1-high and Overall G/GEJ Adenocarcinoma as a First-line Therapy.	Objective Response Rate (ORR) is defined as the proportion of patients achieving best overall response of Complete Response (CR) or Partial Response (PR) as assessed by the investigator using RECIST v1.1. Risk difference (RD)(%) or ORR: Positive RD implies the exposure is associated with a higher probability of the outcome occurring. Negative RD indicates the exposure is associated with a lower probability of the outcome occurring.	approximately 30 months
Part C: Number of Patients With Toxicity ≥Grade 3 Treatment-related Adverse Events (TRAE) Associated With Each of the Treatment Arms.	To characterize the frequency of toxicity ≥Grade 3 treatment-related adverse events (TRAE) associated with each treatment arm: Control (tislelizumab in combination with chemotherapy regimen (CAPOX or mFOLFOX6) and Experimental (DKN-01 in combination with tislelizumab and chemotherapy regimen (CAPOX or mFOLFOX6))	approximately 30 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The maximum plasma concentration (C max) will be measured.	The maximum plasma concentration (C max) will be measured.	Baseline to study completion (approximately 6 months)
The time taken to reach the maximum plasma concentration (T max) will be measured.	The time taken to reach the maximum plasma concentration (T max) will be measured.	Baseline to study completion (approximately 6 months)
Area Under the Curved (AUC) will be measured.	Area Under the Curved (AUC) will be measured.	Baseline to study completion (approximately 6 months)
Concentration of anti-DKN-01 antibodies in human serum in G/GEJ patients treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy.	Concentration of anti-DKN-01 antibodies in human serum in patients with inoperable, locally advanced or metastatic G/GEJ treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy.	Baseline to study completion (approximately 6 months)
Concentration of anti-DKN-01 antibodies in human serum in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy	Concentration of anti-DKN-01 antibodies in human serum in patients with inoperable, locally advanced or metastatic DKK1-high G/GEJ treated with DKN-01 in combination with tislelizumab as a second-line therapy	Baseline to study completion (approximately 6 months)
Concentration of anti-tislelizumab antibodies in human serum in G/GEJ patients treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy	Concentration of anti-tislelizumab antibodies in human serum in patients with inoperable, locally advanced or metastatic G/GEJ treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy	Baseline to study completion (approximately 6 months)
Concentration of anti-tislelizumab antibodies in human serum in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy	Concentration of anti-tislelizumab antibodies in human serum in patients with inoperable, locally advanced or metastatic DKK1-high G/GEJ treated with DKN-01 in combination with tislelizumab as a second-line therapy	Baseline to study completion (approximately 6 months)
Dickkopf-1 (DKK1) concentration in serum and plasma relative to safety and efficacy outcomes in G/GEJ patients	Dickkopf-1 (DKK1) concentration in serum and plasma relative to safety and efficacy outcomes in patients with inoperable, locally advanced or metastatic G/GEJ treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy	Baseline to study completion (approximately 6 months)
Dickkopf-1 (DKK1) concentration in serum and plasma relative to safety and efficacy outcomes in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy	Dickkopf-1 (DKK1) concentration in serum and plasma relative to safety and efficacy outcomes in patients with inoperable, locally advanced or metastatic DKK1-high G/GEJ treated with DKN-01 in combination with tislelizumab as a second-line therapy	Baseline to study completion (approximately 6 months)

Collaborators and Investigators

• Sponsor: Leap Therapeutics, Inc.
• Collaborators: BeiGene
• Investigators: Study Director: Cynthia Sirard, MD, Chief Medical Officer

Publications and helpful links

General Publications

• Klempner SJ, Sonbol MB, Wainberg ZA, Uronis HE, Chiu VK, Scott AJ, Iqbal S, Tejani MA, Chung V, Stilian MC, Thoma M, Zhang Y, Kagey MH, Baum J, Sirard CA, Altura RA, Ajani JA. DKN-01 in Combination With Tislelizumab and Chemotherapy as First-Line Therapy in Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: DisTinGuish. J Clin Oncol. 2025 Jan 20;43(3):339-349. doi: 10.1200/JCO.24.00410. Epub 2024 Oct 21.

Study record dates

Study Major Dates

• Study Start (Actual): July 29, 2020
• Primary Completion (Actual): March 31, 2025
• Study Completion (Actual): March 31, 2025

Study Registration Dates

• First Submitted: April 23, 2020
• First Submitted That Met QC Criteria: April 23, 2020
• First Posted (Actual): April 27, 2020

Study Record Updates

• Last Update Posted (Estimated): October 9, 2025
• Last Update Submitted That Met QC Criteria: September 22, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: cancer; Gastric cancer; adenocarcinoma; Tislelizumab; DKK1; DKN-01; Gastroesophageal junction
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Neoplasms, Glandular and Epithelial; Carcinoma; Neoplasms; Stomach Neoplasms; Adenocarcinoma; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Nucleic Acids, Nucleotides, and Nucleosides; Enzymes and Coenzymes; Coordination Complexes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Uracil; Pyrimidinones; Coenzymes; Deoxyribonucleosides; Capecitabine; Oxaliplatin; Fluorouracil; Leucovorin; tislelizumab
• Other Study ID Numbers: DEK-DKK1-P205

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No