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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04363801
Recruitment Status : Active, not recruiting
First Posted : April 27, 2020
Last Update Posted : January 22, 2024
Sponsor:
Collaborator:
BeiGene
Information provided by (Responsible Party):
Leap Therapeutics, Inc.

Tracking Information
First Submitted Date  ICMJE April 23, 2020
First Posted Date  ICMJE April 27, 2020
Last Update Posted Date January 22, 2024
Actual Study Start Date  ICMJE July 29, 2020
Estimated Primary Completion Date June 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 26, 2023)
  • Part A and B: Safety and Tolerability of DKN-01 in G/GEJ patients [ Time Frame: approximately 6 months ]
    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.
  • 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 [ Time Frame: approximately 12 months ]
    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
Original Primary Outcome Measures  ICMJE
 (submitted: April 23, 2020)		 Safety and Tolerability of DKN-01 in G/GEJ patients [ Time Frame: approximately 6 months ]
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 26, 2023)
  • Part A: Objective Response Rate (ORR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy [ Time Frame: approximately 6 months ]
    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).
  • Part B: Objective Response Rate (ORR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy [ Time Frame: approximately 6 months ]
    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).
  • Part A:Duration of response (DoR) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy [ Time Frame: approximately 6 months ]
    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
  • Part A:Duration of complete response (DoCR) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy [ Time Frame: approximately 6 months ]
    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
  • Part A:Progression free survival (PFS) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy [ Time Frame: approximately 6 months ]
    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
  • Part A:Overall survival (OS) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Part A:Duration of clinical benefit (DoCB) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Part A:Durable clinical benefit (DCB) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Part A:Disease control rate (DCR) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Part B:Duration of Response (DoR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy [ Time Frame: approximately 6 months ]
    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
  • Part B:Duration of complete response (DoCR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Part B:Progression free survival (PFS) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Part B:Overall survival (OS) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Part B:Duration of clinical benefit (DoCB) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Part B:Durable clinical benefit (DCB) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Part B:Disease control rate (DCR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy [ Time Frame: approximately 6 months ]
    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.
  • 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. [ Time Frame: approximately 12 months ]
    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.
  • 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. [ Time Frame: approximately 12 months ]
    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.
  • 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. [ Time Frame: approximately 12 months ]
    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.
  • 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. [ Time Frame: approximately 12 months ]
    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.
  • Part C:To characterize the frequency of toxicity ≥Grade 3 treatment-related adverse events (TRAE) associated with each of the treatment arms. [ Time Frame: approximately 12 months ]
    To characterize the frequency of toxicity ≥Grade 3 treatment-related adverse events (TRAE) associated with each of the treatment arms.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 23, 2020)
  • Objective Response Rate (ORR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy [ Time Frame: approximately 6 months ]
    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).
  • Objective Response Rate (ORR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy [ Time Frame: approximately 6 months ]
    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).
  • Duration of response (DoR) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy [ Time Frame: approximately 6 months ]
    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
  • Duration of complete response (DoCR) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy [ Time Frame: approximately 6 months ]
    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
  • Progression free survival (PFS) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy [ Time Frame: approximately 6 months ]
    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
  • Overall survival (OS) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Duration of clinical benefit (DoCB) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Durable clinical benefit (DCB) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Disease control rate (DCR) in G/GEJ patients treated with DKN-01 with tislelizumab + CAPOX as a first-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Duration of Response (DoR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy [ Time Frame: approximately 6 months ]
    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
  • Duration of complete response (DoCR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Progression free surviva (PFS) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Overall survival (OS) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Duration of clinical benefit (DoCB) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Durable clinical benefit (DCB) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy [ Time Frame: approximately 6 months ]
    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.
  • Disease control rate (DCR) in G/GEJ patients treated with DKN-01 in combination with tislelizumab as a second-line therapy [ Time Frame: approximately 6 months ]
    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.
Current Other Pre-specified Outcome Measures
 (submitted: April 23, 2020)
  • The maximum plasma concentration (C max) will be measured. [ Time Frame: Baseline to study completion (approximately 6 months) ]
    The maximum plasma concentration (C max) will be measured.
  • The time taken to reach the maximum plasma concentration (T max) will be measured. [ Time Frame: Baseline to study completion (approximately 6 months) ]
    The time taken to reach the maximum plasma concentration (T max) will be measured.
  • Area Under the Curved (AUC) will be measured. [ Time Frame: Baseline to study completion (approximately 6 months) ]
    Area Under the Curved (AUC) will be measured.
  • 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. [ Time Frame: Baseline to study completion (approximately 6 months) ]
    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.
  • 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 [ Time Frame: Baseline to study completion (approximately 6 months) ]
    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
  • 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 [ Time Frame: Baseline to study completion (approximately 6 months) ]
    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
  • 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 [ Time Frame: Baseline to study completion (approximately 6 months) ]
    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
  • Dickkopf-1 (DKK1) concentration in serum and plasma relative to safety and efficacy outcomes in G/GEJ patients [ Time Frame: Baseline to study completion (approximately 6 months) ]
    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
  • 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 [ Time Frame: Baseline to study completion (approximately 6 months) ]
    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
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE A Study of DKN-01 in Combination With Tislelizumab ± Chemotherapy in Patients With Gastric or Gastroesophageal Cancer
Official Title  ICMJE 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)
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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Gastric Cancer
  • Gastric Adenocarcinoma
  • GastroEsophageal Cancer
Intervention  ICMJE
  • Drug: DKN-01 300mg
    Administered by IV infusion
  • Drug: DKN-01 600mg
    Administered by IV infusion
  • Drug: DKN-01 400mg
    Administered by IV infusion
  • Drug: Tislelizumab 200mg
    Administered by IV infusion
  • Drug: Tislelizumab 400mg
    Administered by IV infusion
  • Drug: Oxaliplatin
    Administered by IV infusion
  • Drug: Capecitabine 1000mg/ m2 BID
    Administered orally
    Other Name: Xeloda
  • Drug: Leucovorin Calcium
    Administered by IV infusion
    Other Name: Folinic acid
  • Drug: Fluorouracil
    Administered by IV infusion
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: DKN-01 300mg
    • Drug: DKN-01 400mg
    • Drug: Tislelizumab 200mg
    • Drug: Tislelizumab 400mg
  • 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; ±HER2 therapy if applicable). Patients may have received prior neoadjuvant or adjuvant therapy.

    Interventions:
    • Drug: DKN-01 300mg
    • Drug: DKN-01 400mg
  • 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.

    Interventions:
    • Drug: DKN-01 600mg
    • Drug: DKN-01 400mg
  • 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.
    Interventions:
    • Drug: Tislelizumab 200mg
    • Drug: Tislelizumab 400mg
    • Drug: Oxaliplatin
    • Drug: Capecitabine 1000mg/ m2 BID
    • Drug: Leucovorin Calcium
    • Drug: Fluorouracil
  • 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.
    Interventions:
    • Drug: DKN-01 600mg
    • Drug: DKN-01 400mg
    • Drug: Tislelizumab 200mg
    • Drug: Tislelizumab 400mg
    • Drug: Oxaliplatin
    • Drug: Capecitabine 1000mg/ m2 BID
    • Drug: Leucovorin Calcium
    • Drug: Fluorouracil
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: January 4, 2023)		 232
Original Estimated Enrollment  ICMJE
 (submitted: April 23, 2020)		 72
Estimated Study Completion Date  ICMJE December 2025
Estimated Primary Completion Date June 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany,   Korea, Republic of,   United States
Removed Location Countries United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT04363801
Other Study ID Numbers  ICMJE DEK-DKK1-P205
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Leap Therapeutics, Inc.
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Leap Therapeutics, Inc.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE BeiGene
Investigators  ICMJE
Study Director: Cynthia Sirard, MD Chief Medical Officer
PRS Account Leap Therapeutics, Inc.
Verification Date January 2024

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP