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

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 DKK1 mRNA expression from a fresh tumor biopsy or a biopsy obtained within the 6 months of screening.

Part C Only:

4. Documentation of PD-L1 CPS by 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 GEJ adenocarcinoma.

8. One or more tumors measurable on radiographic imaging as defined by RECIST 1.1.

9. Tumor tissue for mandatory pre-treatment evaluation (fresh biopsy [preferred] or archived specimen).

10. 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 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 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.