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

Gastric Cancer Clinical Trial

— DisTinGuish  

Official title:

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04363801
• Other study ID #: DEK-DKK1-P205
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: July 29, 2020
• Est. completion date: December 2025

Study information

• Verified date: January 2024
• Source: Leap Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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 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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 232
• Est. completion date: December 2025
• Est. primary completion date: June 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Adenocarcinoma
• Gastric Adenocarcinoma
• Gastric Cancer
• GastroEsophageal Cancer
• Stomach Neoplasms

Intervention

Drug:
• DKN-01 300mg
Administered by IV infusion
• DKN-01 600mg
Administered by IV infusion
• DKN-01 400mg
Administered by IV infusion
• Tislelizumab 200mg
Administered by IV infusion
• Tislelizumab 400mg
Administered by IV infusion
• Oxaliplatin
Administered by IV infusion
• Capecitabine 1000mg/ m2 BID
Administered orally
• Leucovorin Calcium
Administered by IV infusion
• Fluorouracil
Administered by IV infusion

Locations

Country	Name	City	State
Germany	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
Korea, Republic of	Korea University Ansan Hospital	Ansan-si
Korea, Republic of	Hallym University Sacred Heart Hospital	Anyang
Korea, Republic of	Dong-A University Hospital	Busan
Korea, Republic of	National Cancer Center	Goyang
Korea, Republic of	Gachon University Gil Medical Center	Incheon
Korea, Republic of	Inha University Hospital	Incheon
Korea, Republic of	CHA Bundang Medical Center	Seongnam	Gyeonggi-do
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Boramae Hospital SNU	Seoul
Korea, Republic of	Hanyang University Hospital	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Korea University Guro Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Korea, Republic of	The Catholic University of Korea St. Mary's Hospital	Seoul
Korea, Republic of	The Catholic University of Korea St. Vincent's Hospital	Suwon
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
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	City of Hope	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic Florida	Jacksonville	Florida
United States	The Angeles Clinic Research Institute - A Cedars-Sinai Affiliate	Los Angeles	California
United States	UCLA	Los Angeles	California
United States	University of Southern California	Los Angeles	California
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Columbia University Irving Medical Center	New York	New York
United States	Hoag Memorial Hospital Presbyterian	Newport Beach	California
United States	Chao Family Comprehensive Cancer Center, University of California, Irvine	Orange	California
United States	AdventHealth Cancer Institute	Orlando	Florida
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Mayo Clinic Cancer Center	Phoenix	Arizona
United States	Rhode Island Hospital	Providence	Rhode Island
United States	University of California San Francisco	San Francisco	California
United States	University of Arizona	Tucson	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
Leap Therapeutics, Inc.	BeiGene

Countries where clinical trial is conducted

United States,  Germany,  Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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)
Other	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)
Other	Area Under the Curved (AUC) will be measured.	Area Under the Curved (AUC) will be measured.	Baseline to study completion (approximately 6 months)
Other	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)
Other	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)
Other	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)
Other	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)
Other	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)
Other	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)
Primary	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 6 months
Primary	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	To assess whether the addition of DKN-01 to the combination of tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6 [leucovorin calcium, fluorouracil, and oxaliplatin]) improves PFS according to the RECIST v1.1 as assessed by the Investigator, in advanced DKK1-high and overall G/GEJ adenocarcinoma compared to tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) as a first-line therapy	approximately 12 months
Secondary	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) in inoperable, locally advanced or metastatic G/GEJ patients treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy as assessed with Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).	approximately 6 months
Secondary	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) in inoperable, locally advanced or metastatic DKK1-high G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy as assessed with Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).	approximately 6 months
Secondary	Part A:Duration of response (DoR) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy	Duration of Response (DoR) in inoperable, locally advanced or metastatic G/GEJ patients treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy	approximately 6 months
Secondary	Part A:Duration of complete response (DoCR) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy	Duration of complete response (DoCR) in inoperable, locally advanced or metastatic G/GEJ patients treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy	approximately 6 months
Secondary	Part A:Progression free survival (PFS) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy	Progression free survival (PFS) in inoperable, locally advanced or metastatic G/GEJ patients treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy	approximately 6 months
Secondary	Part A:Overall survival (OS) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy	Overall survival (OS) in inoperable, locally advanced or metastatic G/GEJ patients treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy.	approximately 6 months
Secondary	Part A:Duration of clinical benefit (DoCB) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy	Duration of clinical benefit (DoCB) in inoperable, locally advanced or metastatic G/GEJ patients treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy.	approximately 6 months
Secondary	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) in inoperable, locally advanced or metastatic G/GEJ patients treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy.	approximately 6 months
Secondary	Part A:Disease control rate (DCR) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy	Disease control rate (DCR) in inoperable, locally advanced or metastatic G/GEJ patients treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy.	approximately 6 months
Secondary	Part B:Duration of Response (DoR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy	Duration of Response (DoR) in inoperable, locally advanced or metastatic DKK1-high G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy	approximately 6 months
Secondary	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) in inoperable, locally advanced or metastatic DKK1-high G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy.	approximately 6 months
Secondary	Part B:Progression free survival (PFS) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy	Progression free survival (PFS) in inoperable, locally advanced or metastatic DKK1-high G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy.	approximately 6 months
Secondary	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) in inoperable, locally advanced or metastatic DKK1-high G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy.	approximately 6 months
Secondary	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) in inoperable, locally advanced or metastatic DKK1-high G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy.	approximately 6 months
Secondary	Part B:Durable clinical benefit (DCB) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy	Durable clinical benefit (DCB) in inoperable, locally advanced or metastatic DKK1-high G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy.	approximately 6 months
Secondary	Part B:Disease control rate (DCR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy	Disease control rate (DCR) in inoperable, locally advanced or metastatic DKK1-high G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy.	approximately 6 months
Secondary	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.	To estimate the objective response rate (ORR), according to RECIST v1.1, as assessed by the Investigator, the duration of response (DoR) and overall survival (OS) in advanced DKK1-high and overall G/GEJ adenocarcinoma patients treated with DKN-01 in combination with tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) compared to tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) as a first-line therapy.	approximately 12 months
Secondary	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.	To estimate the objective response rate (ORR), according to RECIST v1.1, as assessed by the Investigator, the duration of response (DoR) and overall survival (OS) in advanced DKK1-high and overall G/GEJ adenocarcinoma patients treated with DKN-01 in combination with tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) compared to tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) as a first-line therapy.	approximately 12 months
Secondary	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.	To estimate the objective response rate (ORR), according to RECIST v1.1, as assessed by the Investigator, the duration of response (DoR) and overall survival (OS) in advanced DKK1-high and overall G/GEJ adenocarcinoma patients treated with DKN-01 in combination with tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) compared to tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) as a first-line therapy.	approximately 12 months
Secondary	Part C:To assess whether the addition of DKN-01 with tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) improves PFS and ORR in patients with CPS =5 or CPS <5 advanced DKK1-high and overall G/GEJ adenocarcinoma as a first-line therapy.	To assess whether the addition of DKN-01 to the combination of tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) improves PFS and ORR, according to RECIST v1.1, as assessed by the Investigator, in patients with CPS =5 or CPS <5 advanced DKK1-high and overall G/GEJ adenocarcinoma compared to tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) as a first-line therapy.	approximately 12 months
Secondary	Part C:To characterize the frequency of 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 of the treatment arms.	approximately 12 months