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

NCT ID: NCT04363801

Last Updated: 2025-10-09

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 247 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-07-29
• Study Completion Date: 2025-03-31

Brief Summary

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

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).

Conditions

Gastric Cancer; Gastric Adenocarcinoma; GastroEsophageal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

DKN-01 300mg

Intervention Type: DRUG

Administered by IV infusion

DKN-01 400mg

Intervention Type: DRUG

Administered by IV infusion

Tislelizumab 200mg

Intervention Type: DRUG

Administered by IV infusion

Tislelizumab 400mg

Intervention Type: DRUG

Administered by IV infusion

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.

Group Type: EXPERIMENTAL

DKN-01 300mg

Intervention Type: DRUG

Administered by IV infusion

DKN-01 400mg

Intervention Type: DRUG

Administered by IV infusion

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.

Group Type: EXPERIMENTAL

DKN-01 600mg

Intervention Type: DRUG

Administered by IV infusion

DKN-01 400mg

Intervention Type: DRUG

Administered by IV infusion

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.

Group Type: ACTIVE_COMPARATOR

Tislelizumab 200mg

Intervention Type: DRUG

Administered by IV infusion

Tislelizumab 400mg

Intervention Type: DRUG

Administered by IV infusion

Oxaliplatin

Intervention Type: DRUG

Administered by IV infusion

Capecitabine 1000mg/ m2 twice daily (BID)

Intervention Type: DRUG

Administered orally

Leucovorin Calcium

Intervention Type: DRUG

Administered by IV infusion

Fluorouracil

Intervention Type: DRUG

Administered by IV infusion

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.

Group Type: EXPERIMENTAL

DKN-01 600mg

Intervention Type: DRUG

Administered by IV infusion

DKN-01 400mg

Intervention Type: DRUG

Administered by IV infusion

Tislelizumab 200mg

Intervention Type: DRUG

Administered by IV infusion

Tislelizumab 400mg

Intervention Type: DRUG

Administered by IV infusion

Oxaliplatin

Intervention Type: DRUG

Administered by IV infusion

Capecitabine 1000mg/ m2 twice daily (BID)

Intervention Type: DRUG

Administered orally

Leucovorin Calcium

Intervention Type: DRUG

Administered by IV infusion

Fluorouracil

Intervention Type: DRUG

Administered by IV infusion

Interventions

DKN-01 300mg

Administered by IV infusion

Intervention Type: DRUG

DKN-01 600mg

Administered by IV infusion

Intervention Type: DRUG

DKN-01 400mg

Administered by IV infusion

Intervention Type: DRUG

Tislelizumab 200mg

Administered by IV infusion

Intervention Type: DRUG

Tislelizumab 400mg

Administered by IV infusion

Intervention Type: DRUG

Oxaliplatin

Administered by IV infusion

Intervention Type: DRUG

Capecitabine 1000mg/ m2 twice daily (BID)

Administered orally

Intervention Type: DRUG

Leucovorin Calcium

Administered by IV infusion

Intervention Type: DRUG

Fluorouracil

Administered by IV infusion

Intervention Type: DRUG

Other Intervention Names

Experimental; Experimental; Experimental; humanized IgG4 anti-PD-1 monoclonal antibody; Tevimbra; humanized IgG4 anti-PD-1 monoclonal antibody; Tevimbra; Eloxatin; Xeloda; Folinic acid; 5-FU

Eligibility Criteria

Inclusion Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

BeiGene

INDUSTRY

Sponsor Role: collaborator

Leap Therapeutics, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Cynthia Sirard, MD

Role: STUDY_DIRECTOR

Chief Medical Officer

Locations

Mayo Clinic Cancer Center

Phoenix, Arizona, United States

University of Arizona

Tucson, Arizona, United States

City of Hope

Duarte, California, United States

The Angeles Clinic Research Institute - A Cedars-Sinai Affiliate

Los Angeles, California, United States

University of Southern California

Los Angeles, California, United States

UCLA

Los Angeles, California, United States

Hoag Memorial Hospital Presbyterian

Newport Beach, California, United States

Chao Family Comprehensive Cancer Center, University of California, Irvine

Orange, California, United States

University of California San Francisco

San Francisco, California, United States

Mayo Clinic Florida

Jacksonville, Florida, United States

AdventHealth Cancer Institute

Orlando, Florida, United States

Northwestern University Robert H. Lurie Comprehensive Cancer Center

Chicago, Illinois, United States

University of Chicago

Chicago, Illinois, United States

Pontchartrain Cancer Center

Covington, Louisiana, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Columbia University Irving Medical Center

New York, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

Rhode Island Hospital

Providence, Rhode Island, United States

MD Anderson Cancer Center

Houston, Texas, United States

University of Wisconsin Carbone Cancer Center

Madison, Wisconsin, United States

Charité Universitätsmedizin Berlin

Berlin, , Germany

Institut Fur Klinisch Onkologische Forschung Am Krankenhaus Nordwest

Frankfurt, , Germany

Hämatologisch-Onkologische Praxis Eppendorf (HOPE)

Hamburg, , Germany

Universitatsklinikum Heidelberg

Heidelberg, , Germany

Slk-Kliniken

Heilbronn, , Germany

Studienzentrum Onkologie Ravensburg

Ravensburg, , Germany

Caritas Klinikum Saarbrücken St. Theresia

Saarbrücken, , Germany

CHA Bundang Medical Center

Seongnam-si, Gyeonggi-do, South Korea

Korea University Ansan Hospital

Ansan-si, , South Korea

Hallym University Sacred Heart Hospital

Anyang, , South Korea

Dong-A University Hospital

Busan, , South Korea

National Cancer Center

Goyang, , South Korea

Gachon University Gil Medical Center

Incheon, , South Korea

Inha University Hospital

Incheon, , South Korea

Seoul National University Bundang Hospital

Seongnam, , South Korea

Korea University Anam Hospital

Seoul, , South Korea

Hanyang University Hospital

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Boramae Hospital SNU

Seoul, , South Korea

Korea University Guro Hospital

Seoul, , South Korea

Seoul National University Hospital

Seoul, , South Korea

Severance Hospital, Yonsei University Health System

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

The Catholic University of Korea St. Mary's Hospital

Seoul, , South Korea

The Catholic University of Korea St. Vincent's Hospital

Suwon, , South Korea

Countries

United States; Germany; South Korea

References

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.

Reference Type: DERIVED

PMID: 39432867 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan: SAP Part A+B

View Document

Document Type: Statistical Analysis Plan: SAP Part C

View Document

Other Identifiers

DEK-DKK1-P205

Identifier Type: -

Identifier Source: org_study_id