Clinical trial NCT04363801: A Study of DKN-01 in Combination With Tislelizumab ± Chemotherapy in Patients With Gastric or Gastroesophageal Cancer
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Gastric Cancer
Gastric Adenocarcinoma
GastroEsophageal Cancer
Keywords: Gastric cancer
Gastroesophageal junction
cancer
adenocarcinoma
DKK1
Tislelizumab
DKN-01
Lead sponsor: Leap Therapeutics, Inc.
Sponsor class: INDUSTRY
Collaborators: name: BeiGene
First posted: 2020-04-27
Enrollment: 232
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 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).

Eligibility criteria: 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.

Primary outcomes:
measure: Part A and B: Safety and Tolerability of DKN-01 in G/GEJ patients
timeFrame: approximately 6 months
measure: 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
timeFrame: approximately 12 months
Secondary outcomes:
measure: Part A: Objective Response Rate (ORR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy
timeFrame: approximately 6 months
measure: Part B: Objective Response Rate (ORR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy
timeFrame: approximately 6 months
measure: Part A:Duration of response (DoR) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy
timeFrame: approximately 6 months
measure: Part A:Duration of complete response (DoCR) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy
timeFrame: approximately 6 months
measure: Part A:Progression free survival (PFS) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy
timeFrame: approximately 6 months
measure: Part A:Overall survival (OS) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy
timeFrame: approximately 6 months
measure: Part A:Duration of clinical benefit (DoCB) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy
timeFrame: approximately 6 months
measure: Part A:Durable clinical benefit (DCB) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy
timeFrame: approximately 6 months
measure: Part A:Disease control rate (DCR) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy
timeFrame: approximately 6 months
measure: Part B:Duration of Response (DoR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy
timeFrame: approximately 6 months
measure: Part B:Duration of complete response (DoCR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy
timeFrame: approximately 6 months
measure: Part B:Progression free survival (PFS) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy
timeFrame: approximately 6 months
measure: Part B:Overall survival (OS) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy
timeFrame: approximately 6 months
measure: Part B:Duration of clinical benefit (DoCB) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy
timeFrame: approximately 6 months
measure: Part B:Durable clinical benefit (DCB) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy
timeFrame: approximately 6 months
measure: Part B:Disease control rate (DCR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy
timeFrame: approximately 6 months
measure: 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.
timeFrame: approximately 12 months
measure: 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.
timeFrame: approximately 12 months
measure: 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.
timeFrame: approximately 12 months
measure: 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.
timeFrame: approximately 12 months
measure: Part C:To characterize the frequency of toxicity ≥Grade 3 treatment-related adverse events (TRAE) associated with each of the treatment arms.
timeFrame: approximately 12 months
Other outcomes:
measure: The maximum plasma concentration (C max) will be measured.
timeFrame: Baseline to study completion (approximately 6 months)
measure: The time taken to reach the maximum plasma concentration (T max) will be measured.
timeFrame: Baseline to study completion (approximately 6 months)
measure: Area Under the Curved (AUC) will be measured.
timeFrame: Baseline to study completion (approximately 6 months)
measure: 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.
timeFrame: Baseline to study completion (approximately 6 months)
measure: 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
timeFrame: Baseline to study completion (approximately 6 months)
measure: 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
timeFrame: Baseline to study completion (approximately 6 months)
measure: 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
timeFrame: Baseline to study completion (approximately 6 months)
measure: Dickkopf-1 (DKK1) concentration in serum and plasma relative to safety and efficacy outcomes in G/GEJ patients
timeFrame: Baseline to study completion (approximately 6 months)
measure: 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
timeFrame: Baseline to study completion (approximately 6 months)
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Cancer Center
state: Arizona
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: The Angeles Clinic Research Institute - A Cedars-Sinai Affiliate
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Newport Beach
country: United States
facility: Hoag Memorial Hospital Presbyterian
state: California
city: Orange
country: United States
facility: Chao Family Comprehensive Cancer Center, University of California, Irvine
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Orlando
country: United States
facility: AdventHealth Cancer Institute
state: Florida
city: Chicago
country: United States
facility: Northwestern University Robert H. Lurie Comprehensive Cancer Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Covington
country: United States
facility: Pontchartrain Cancer Center
state: Louisiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center
state: Wisconsin
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Frankfurt
country: Germany
facility: Institut Fur Klinisch Onkologische Forschung Am Krankenhaus Nordwest
city: Hamburg
country: Germany
facility: Hämatologisch-Onkologische Praxis Eppendorf (HOPE)
city: Heidelberg
country: Germany
facility: Universitatsklinikum Heidelberg
city: Heilbronn
country: Germany
facility: Slk-Kliniken
city: Ravensburg
country: Germany
facility: Studienzentrum Onkologie Ravensburg
city: Saarbrücken
country: Germany
facility: Caritas Klinikum Saarbrücken St. Theresia
city: Seongnam
country: Korea, Republic of
facility: CHA Bundang Medical Center
state: Gyeonggi-do
city: Ansan-si
country: Korea, Republic of
facility: Korea University Ansan Hospital
city: Anyang
country: Korea, Republic of
facility: Hallym University Sacred Heart Hospital
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital
city: Goyang
country: Korea, Republic of
facility: National Cancer Center
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Hanyang University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Boramae Hospital SNU
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea St. Mary's Hospital
city: Suwon
country: Korea, Republic of
facility: The Catholic University of Korea St. Vincent's Hospital
Study officials:
affiliation: Chief Medical Officer
name: Cynthia Sirard, MD
role: STUDY_DIRECTOR
References: