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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Leap Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

13 Oct 2023 → 21 Apr 2025

Decision date (initial)

2023-07-31

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2023-504940-32-00

ClinicalTrials.gov

NCT04363801

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacogenomic, Pharmacokinetic, Therapy, Safety

Part A and Part B
• To characterize the safety and tolerability of DKN-01 in combination with tislelizumab ± CAPOX (capecitabine + oxaliplatin) in patients with inoperable, locally advanced or metastatic G/GEJ adenocarcinoma

Part C
• 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 patients with advanced DKK1-high G/GEJ adenocarcinoma compared to tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) as a first-line therapy

Secondary objectives 8

1. Part A: To estimate the objective response rate (ORR) of patients with inoperable, locally advanced or metastatic G/GEJ adenocarcinoma treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
2. Part A: To estimate duration of response (DoR), duration of complete response (DoCR), progression-free survival (PFS), overall survival (OS), duration of clinical benefit (DoCB), durable clinical benefit (DCB), disease control rate (DCR) and time to response (TTR) in patients with inoperable, locally advanced or metastatic G/GEJ adenocarcinoma treated with DKN 01 in combination with tislelizumab + CAPOX as a first-line therapy.
3. Part B: To estimate the ORR of patients with inoperable, locally advanced or metastatic DKK1-high G/GEJ adenocarcinoma treated with DKN-01 in combination with tislelizumab as a second-line therapy using RECIST v1.1.
4. Part B: To estimate DoR, DoCR, PFS, OS, DoCB, DCB, DCR and TTR in patients with inoperable, locally advanced or metastatic DKK1-high G/GEJ adenocarcinoma treated with DKN-01 in combination with tislelizumab as a second-line therapy.
5. Part C: To determine whether the addition of DKN-01 to the combination of tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) improves PFS according to RECIST v1.1 as assessed by the investigator in all patients with advanced G/GEJ adenocarcinoma compared to tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) as a first-line therapy.
6. Part C: 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.
7. Part C: 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.
8. Part C: To characterize the frequency of toxicity ≥Grade 3 treatment-related adverse events (TRAE) associated with each of the treatment arms.

Conditions and MedDRA coding

Gastric cancer

Study design 3 periods

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Part A and C only: No previous systemic therapy for inoperable, locally advanced or metastatic G/GEJ adenocarcinoma. a. Patients may have received prior neoadjuvant or adjuvant therapy as long as it was completed without disease recurrence for at least 6 months since last treatment.
2. Part C only: 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.
3. General: Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments.
4. General: Age ≥18 years on the day of signing the informed consent (exception: ≥19 years in the Republic of Korea)
5. General: Histologically proven gastric adenocarcinoma or Siewert I-III GEJ adenocarcinoma
6. General: Acceptable coagulation status: a. Prothrombin time/activated partial thromboplastin time ≤1.2 × ULN (unless receiving anticoagulation therapy; if receiving anticoagulation therapy, eligibility will be based upon international normalized ratio [INR]) see (b)(i) below b. INR ≤1.5 (unless receiving anticoagulation therapy) i. If receiving anticoagulant: INR ≤3.0 and no active bleeding (i.e., no clinically significant bleeding within 14 days prior to first dose of study drugs).
7. General: Females of childbearing potential 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, and have a negative urine or serum pregnancy test within 7 days before first dose of study drugs.
8. General: At least one measurable lesion on radiographic imaging as defined by RECIST v1.1. a. A lesion in an area subjected to prior loco-regional therapy, including previous radiotherapy, is not considered measurable unless there has been demonstrated progression in the lesion since the therapy as defined by RECIST v1.1. b. Previously irradiated lesions can only be considered as measurable disease if disease progression has been unequivocally documented at that site since radiation and the previously irradiated lesion is not the only site of disease.
9. General: Tumor tissue for mandatory pre-treatment evaluation (fresh biopsy [preferred] or archived specimen).
10. General: Acceptable renal function: a. Serum creatinine ≤1.5 × ULN or estimated glomerular filtration rate ≥30 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration equation
11. General: Acceptable hematologic status (in the Republic of Korea patients must not have required blood transfusion or growth factor support within 14 days before sample collection at Screening for the following): a. Absolute neutrophil count (ANC) ≥1.5 × 109/L. b. Platelets: i. Part A and C only: ≥100 × 109/L ii. Part B only: ≥75 × 109/L c. Hemoglobin ≥9 g/dL
12. General: ECOG performance status ≤1 within 7 days of first dose of study drug.
13. General: Acceptable liver function: a. Parts A and B only: i. Total bilirubin ≤2.0 times upper limit of normal (ULN). Total bilirubin must be <3 × ULN for patients with Gilbert’s syndrome. ii. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 times ULN (if liver metastases are present, then ≤5 × ULN is allowed). b. Part C only: i. Total bilirubin ≤2.0 times upper limit of normal (ULN). ii. AST and ALT ≤2.5 times ULN. 1. If liver metastases are present, then ≤5 × ULN is allowed (excluding Republic of Korea).
14. Part B only: Documented objective radiographic or symptomatic disease progression following first-line therapy with any platinum and/or fluoropyrimidine-based regimen for unresectable or metastatic disease. a. Patients may have received prior neoadjuvant or adjuvant therapy. If progression has occurred within 6 months from last dose of neoadjuvant or adjuvant treatment, this regimen will be considered as 1 line of therapy for advanced disease. b. Prior trastuzumab (or biosimilar) treatment is acceptable for patients with history of HER2-positive G/GEJ adenocarcinoma. c. Prior therapy with an anti-programmed cell death protein 1 (PD-1), anti-PD-L1 in any treatment setting (including adjuvant/neoadjuvant) is acceptable.
15. Part B only: Documentation of elevated DKK1 mRNA expression in tumor cells from a fresh tumor biopsy (preferred) or archived tumor biopsy specimen. High DKK1 is defined as an H-score ≥35 in mRNA by ISH conducted in a Sponsor designated central laboratory
16. General: 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 a. A sterile male is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility. b. Males with known “low sperm counts” (consistent with “sub-fertility”) are not to be considered sterile for purposes of this study.

Exclusion criteria 33

1. Part A and C only: Diagnosis of HER2-positive G/GEJ adenocarcinoma.
2. General: Prior allogeneic stem cell transplantation or organ transplantation
3. General: Active leptomeningeal disease or uncontrolled brain metastases. Patients with equivocal findings or with confirmed brain metastases are eligible for the study provided that they are asymptomatic and radiologically stable without the need for corticosteroid treatment or seizure prophylaxis for ≥4 weeks before first dose of study drug
4. General: 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
5. General: Fridericia-corrected QT interval >470 msec (female) or >450 (male), or history of congenital long QT syndrome. Any ECG abnormality that in the opinion of the Investigator would preclude safe participation in the study; patients with pacemakers where QTc is not a reliable measure will require an evaluation by a cardiologist to exclude co-existing cardiac conditions which would prohibit safe participation in the study
6. General: Known to be human immunodeficiency virus (HIV) positive unless HIV ribonucleic acid (RNA) is undetected; known to have active hepatitis B (acute or chronic infection requiring antiviral treatment; hepatitis B surface antigen-positive) or have hepatitis C antibodies unless hepatitis C virus RNA is undetected/negative
7. General: Serious nonmalignant disease or other circumstance that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor
8. General: History of osteonecrosis of the hip or have evidence of structural bone abnormalities in the proximal femur on magnetic resonance imaging (MRI) scan that are symptomatic and clinically significant. Degenerative changes of the hip joint are not exclusionary. Screening of patients is not required
9. General: Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage within 7 days prior to first dose of study drug (the cytological confirmation of any effusion is permitted)
10. General: Clinically significant anorexia (CTCAE ≥Grade 2) within 7 days prior to first dose of study drug.
11. General: Any active malignancy ≤2 years before first dose of study drug, with the exception of the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast).
12. General: Known dihydropyrimidine dehydrogenase deficiency
13. Part A and C only: Unable to swallow capsules or disease significantly affecting 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).
14. Part A and C only: Prior therapy with an anti-programmed cell death protein 1 (PD-1) or anti-PD-L1 antibody
15. Part B only: Systemic anti-cancer therapy (e.g., chemotherapy or immunotherapy) within 21 days prior to first dose of study drug.
16. General: Prior allogeneic stem cell transplantation or organ transplantation
17. General: Known osteoblastic bony metastasis. Screening of patients without a history of metastatic bony lesions is not required
18. General: History of gastrointestinal perforation and/or fistulae within 6 months prior to first dose of study drug, clinically significant bleeding from the gastrointestinal tract within 1 month prior to first dose of study drug, or clinically significant bowel obstruction (CTCAE ≥Grade 2).
19. General: Major surgery within 4 weeks of first dose of study drug
20. General: Serious psychiatric or medical conditions that could interfere with treatment.
21. General: Any of the following cardiovascular risk factors: a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, within 28 days before first dose of study drug b. Pulmonary embolism within 28 days before first dose of study drug c. Any history of acute myocardial infarction within 6 months before first dose of study drug d. Any history of heart failure meeting New York Heart Association (NYHA) Classification III or IV within 6 months before first dose of study drug e. Any event of ventricular arrhythmia ≥Grade 2 in severity within 6 months before first dose of study drug f. Any history of cerebrovascular accident within 6 months before first dose of study drug g. Uncontrolled hypertension that cannot be managed by standard anti-hypertension medications within 28 days before first dose of study drug h. Any episode of syncope or seizure within 28 days before first dose of study drug.
22. General: Squamous cell or undifferentiated or other histological type of gastric cancer.
23. General: 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 (Part B exception, see entry criterion 2c)
24. General: Active autoimmune diseases or history of autoimmune diseases that may relapse. a. Note: Patients with the following diseases are not excluded and may proceed to further Screening: i. Controlled Type I diabetes ii. Hypothyroidism (provided it is managed with hormone replacement therapy only) iii. Controlled celiac disease iv. Skin diseases not requiring systemic treatment (e.g., vitiligo, psoriasis, alopecia) v. Any other disease that is not expected to recur in the absence of external triggering factors.
25. General: Any condition that required treatment with corticosteroids (≥10 mg per day prednisone or equivalent) or other immune suppressive drugs within the 14 days prior to first dose of study drug. a. Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded: i. Adrenal replacement steroid (dose ≤10 mg daily of prednisone or equivalent) ii. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption iii. Short course (≤7 days) of corticosteroid prescribed prophylactically (e.g., for contrast dye allergy) or for the treatment of a non-autoimmune condition (e.g., delayed-type hypersensitivity reaction caused by contact allergen).
26. General: History of interstitial lung disease, non-infectious pneumonitis, pulmonary fibrosis, acute lung disease, or uncontrolled systemic diseases. a. Patients with radiation pneumonitis may be eligible for the study if the radiation pneumonitis has been confirmed as stable (beyond acute phase) without any concerns about recurrence. Patients with severe but stable radiation-induced pneumonitis may be required to undergo routine pulmonary function studies.
27. General: Severe chronic or active infections requiring systemic antibacterial, antifungal, or antiviral therapy, including tuberculosis infection within 14 days of first dose of study drug
28. General: 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. General: Administration of a live vaccine within 28 days before first dose of study drug. a. Note: Seasonal vaccines for influenza or COVID vaccines are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.
30. General: Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that will be unfavorable for the administration of study drug, or affect the explanation of drug toxicity or AEs, or result in insufficient or impaired compliance with study conduct.
31. General: Women who are pregnant or are breastfeeding
32. General: Concurrent participation in another therapeutic clinical study. a. Note: Concurrent participation in observational or non-interventional studies is allowed. In addition, patients who have completed active treatment in a clinical study and are in the follow-up period can be enrolled in this study.
33. General: Treatment with radiation therapy within 14 days prior to first dose of study drug.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Part A & B: Incidence of TEAEs, Grade ≥3 TEAEs, treatment-related TEAEs, treatment-emergent serious adverse events (TESAEs), treatment-related TESAEs, and TEAEs leading to study drug discontinuation.
2. Part C: Progression-free survival (PFS), as determined by the Investigator per RECIST v1.1, of DKN-01 plus tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) versus tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) in DKK1-high patients.

Secondary endpoints 14

1. Part A and Part B: ORR (the proportion of patients with best overall response of CR + PR), as assessed by the Investigator, using RECIST v1.1.
2. Part A and Part B: DoR, defined as the time from initial response (CR or PR) until radiographically documented progressive disease or death due to any cause; progressive disease is defined using RECIST v1.1.
3. Part A and Part B: DoCR, defined as the time from initial CR until radiographically documented progressive disease or death due to any cause; progressive disease is defined using RECIST v1.1.
4. Part A & B: PFS, defined as the time from first study drug dose (i.e., C1D1) to first radiographically documented progressive disease, as determined using RECIST v1.1, or death due to any cause.
5. Part A & B: OS, defined as the time from first study drug dose (i.e., C1D1) to death due to any cause.
6. Part A & B: DoCB, defined as the time from the first study drug dose (i.e., C1D1) to the time of progressive disease, as determined using RECIST v1.1, or death due to any cause in patients who had a best overall response of CR, PR, or SD of ≥6 weeks.
7. Part A & B: DCB, defined as DoCB ≥180 days. Patients who have best overall response of PD or those having clinical benefit but DoCB lasting <180 days will be considered as “non-DCB”.
8. Part A & B: DCR (i.e., CR+PR+ SD at ≥6 weeks), as assessed by the Investigator, using RECIST v1.1.
9. Part A & B: TTR, defined as the time from the first dose of study treatment to the assessment date of the BOR of either CR or PR.
10. Part C: PFS, as determined by the Investigator per RECIST v1.1, of DKN-01 plus tislelizumab + chemotherapy reg (CAPOX or mFOLFOX6) versus tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) in all patients.
11. ORR, as determined by the Investigator per RECIST v1.1, of DKN-01 plus tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) versus tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) in DKK1-high and all patients.
12. DoR, as determined by the Investigator per RECIST v1.1, of DKN-01 plus tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) versus tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) in DKK1-high and all patients.
13. OS with DKN-01 plus tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) versus tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) in DKK1-high and in all patients
14. Incidence of =Grade 3 treatment-related adverse events (TRAEs).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Leap Therapeutics Inc.

Sponsor organisation

Leap Therapeutics Inc.

Address

47 Thorndike Street Suite B1-1

City

Cambridge

Postcode

02141-1799

Country

United States

Scientific contact point

Organisation

Leap Therapeutics Inc.

Contact name

Christine Granfield

Public contact point

Organisation

Leap Therapeutics Inc.

Contact name

Christine Granfield

Third parties 14

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 23 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications