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

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ClinicalTrials.gov Identifier: NCT04363801
Recruitment Status : Recruiting
First Posted : April 27, 2020
Last Update Posted : April 25, 2022
Sponsor:
Collaborator:
BeiGene
Information provided by (Responsible Party):
Leap Therapeutics, Inc.

Study Description
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Brief Summary:
A Phase 2a, 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

Condition or disease Intervention/treatment Phase
Gastric Cancer Gastric Adenocarcinoma GastroEsophageal Cancer Drug: DKN-01 300mg Drug: DKN-01 600mg Drug: Tislelizumab 200mg Drug: Oxaliplatin 130mg/m2 Drug: Capecitabine 1000mg/ m2 BID Phase 2

Detailed Description:
This is a Phase 2a nonrandomized, open-label, multicenter study to be conducted concurrently in 2 Parts (Parts A and B). Approximately 72 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. Both parts 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. Parts A and B will be enrolled concurrently. Two doses of DKN-01 will be evaluated in Part B (Part B1 and Part B2)
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2a, 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)
Actual Study Start Date : July 29, 2020
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : June 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
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.
 Drug: DKN-01 300mg
Administered by IV infusion

Drug: Tislelizumab 200mg
Administered by IV infusion

Drug: Oxaliplatin 130mg/m2
Administered by IV infusion

Drug: Capecitabine 1000mg/ m2 BID
Administered orally
Other Name: Xeloda
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.

 Drug: DKN-01 300mg
Administered by IV infusion

Drug: Tislelizumab 200mg
Administered by IV infusion
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.

 Drug: DKN-01 600mg
Administered by IV infusion

Drug: Tislelizumab 200mg
Administered by IV infusion


Outcome Measures
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Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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).

  2. 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).

  3. 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

  4. 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

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.


Other Outcome Measures:
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

  1. Part A:

    • 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.

  2. Part B:

    • Disease progression during first-line therapy or within 4 months after the last dose of first-line therapy.
    • Documentation of elevated DKK1 mRNA expression from a fresh tumor biopsy or a biopsy obtained within the 6 months of screening.
  3. Able to provide written informed consent prior to any study-specific procedures.
  4. Confirmed diagnosis of gastric adenocarcinoma or GEJ adenocarcinoma.
  5. One or more tumors measurable on radiographic imaging as defined by RECIST 1.1.
  6. ECOG performance status ≤ 1 within 7 days of first dose of study drug
  7. Acceptable liver, renal, hematologic, and coagulation function
  8. 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.

Exclusion:

  1. Part A:

    1. Diagnosis of HER2-positive G/GEJ adenocarcinoma.
    2. Unable to swallow capsules or disease significantly affected gastrointestinal function (add diseases as examples).

  2. Part B:

    a. Major surgery or chemotherapy within 21 days of first dose of study drug.

  3. Patients with active autoimmune diseases or history of autoimmune diseases that may relapse.
  4. Any condition that required treatment with steroids or any other immune suppressive drugs within 14 days prior to first dose of study drug.
  5. Active leptomeningeal disease or uncontrolled brain metastases.
  6. Any active cancer ≤ 2 years before first dose of study drug with the exception of cancer for this study.
  7. New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, or unstable arrhythmia.
  8. Fridericia-corrected QT interval (QTcF) > 470 msec (female) or history of congenital long QT syndrome.
  9. Active, uncontrolled bacterial, viral, or fungal infections, within 14 days of study entry requiring systemic therapy.
  10. Serious nonmalignant disease
  11. Pregnant or nursing.
  12. 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.
  13. Known osteoblastic bony metastasis.
  14. Major surgery 28 days prior to study entry.
  15. Prior radiation therapy within 14 days prior to study entry.
  16. Previously treated with an anti-DKK1 therapy, PD-1, anti-PD-L1, anti-PD-L-2
  17. Significant allergy to a pharmaceutical therapy that, in the opinion of the Investigator, poses an increased risk to the patient.
  18. Active substance abuse.
  19. Known dihydropyrimidine dehydrogenase deficiency.
  20. Administration of a live vaccine within 28 days before first dose of study drug.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04363801


Contacts
Layout table for location contacts
Contact: Cynthia Sirard, MD 617-714-0357 CSirard@leaptx.com
Contact: Elizabeth Parker Eparker@leaptx.com

Locations
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Sponsors and Collaborators
Leap Therapeutics, Inc.
BeiGene
Investigators
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Study Director: Cynthia Sirard, MD Chief Medical Officer
More Information
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Responsible Party: Leap Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT04363801    
Other Study ID Numbers: DEK-DKK1-P205
First Posted: April 27, 2020    Key Record Dates
Last Update Posted: April 25, 2022
Last Verified: April 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Leap Therapeutics, Inc.:
Gastric cancer
Gastroesophageal junction
cancer
adenocarcinoma
 DKK1
Tislelizumab
DKN-01
Additional relevant MeSH terms:
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Adenocarcinoma
Stomach Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
 Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Capecitabine
Oxaliplatin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents