Phase 2 Study of DKN-01 and Tislelizumab ± Chemotherapy in Inoperable Advanced Gastric or Gastroesophageal Junction Adenocarcinoma
- Trial ID
- 2023-504940-32-00
- Protocol
- DEK-DKK1-P205
- Sponsor
- Leap Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to characterize the **safety** and tolerability of DKN-01 in combination with tislelizumab ± CAPOX (capecitabine + oxaliplatin) in patients with inoperable, locally advanced, or metastatic gastric or gastroesophageal junction adenocarcinoma. This is clinically relevant as it aims to determine the safety profile of this combination therapy, which could potentially offer a new treatment option for patients with advanced stages of these cancers.
Secondary objectives include:
- Part A: Estimating the objective response rate (ORR) using RECIST v1.1, and evaluating 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 treated with DKN-01 in combination with tislelizumab + CAPOX as a first-line therapy.
- Part B: Estimating the ORR and evaluating DoR, DoCR, PFS, OS, DoCB, DCB, DCR, and TTR in patients with DKK1-high gastric or gastroesophageal junction adenocarcinoma treated with DKN-01 in combination with tislelizumab as a second-line therapy.
- Part C: Determining 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, and characterizing the frequency of toxicity ≥Grade 3 treatment-related adverse events (TRAE) associated with each treatment arm.
Participants
The clinical trial involves a total of **217 participants** diagnosed with **gastric cancer**, **gastric adenocarcinoma**, or **gastroesophageal cancer**. The study population includes both male and female subjects, aged **18 years and older**, with a focus on those with inoperable, locally advanced, or metastatic conditions. Participants were selected based on specific inclusion criteria, such as having histologically proven gastric adenocarcinoma or Siewert I-III GEJ adenocarcinoma, and demonstrating acceptable renal, hepatic, and hematologic function. The trial also considers lifestyle factors, requiring non-sterile males and females of childbearing potential to use highly effective birth control methods during the study and for a specified period afterward. The population includes vulnerable groups, ensuring comprehensive representation. Participants must have at least one measurable lesion on radiographic imaging and be able to provide informed consent. The trial does not specify any particular dietary or physical activity requirements for participants.
Plans and Procedures
The clinical trial is designed as a **Phase II**, multicenter, open-label study to evaluate the safety and efficacy of DKN-01 in combination with **tislelizumab** with or without chemotherapy in patients with inoperable, locally advanced, or metastatic gastric or gastroesophageal junction adenocarcinoma. The trial is structured into three parts: Part A, Part B, and Part C, each with specific objectives and endpoints. The study is expected to commence recruitment on September 30, 2023, and conclude by October 31, 2025, with an estimated duration of 24 months for each participant.
Participants will undergo a series of study visits, beginning with a screening visit to assess eligibility based on inclusion criteria such as acceptable renal and liver function, hematologic status, and performance status. The screening will also involve obtaining informed consent and conducting necessary baseline assessments. Following the screening, eligible participants will be enrolled and receive the study treatment according to their assigned part of the trial. Regular follow-up visits will be scheduled to monitor safety, tolerability, and treatment efficacy, with assessments including imaging studies to evaluate disease progression according to RECIST v1.1 criteria.
The end-of-study visit will occur after the completion of the treatment period or upon early termination. Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The primary endpoints include the incidence of treatment-emergent adverse events and progression-free survival, while secondary endpoints focus on overall response rate, duration of response, and overall survival. The trial aims to provide comprehensive data on the therapeutic potential of the investigational regimen in this patient population.
Treatment
The clinical trial involves the administration of several experimental and non-experimental treatments for patients with inoperable, locally advanced, or metastatic gastric or gastroesophageal junction adenocarcinoma. The experimental medication **Tislelizumab** is a concentrate for solution for infusion, administered intravenously. It is a protein-based substance, specifically a monoclonal antibody, with a maximum daily dose of 400 mg. The treatment period extends up to 24 weeks.
**DKN-01**, also known as Sirexatamab, is another experimental treatment used in this trial. It is an injection form, administered intravenously, with a maximum daily dose of 600 mg. DKN-01 is a humanized IgG4-kappa monoclonal antibody targeting DKK1, and the treatment duration is up to 24 weeks.
**Folinic Acid**, marketed as Folinato Cálcico Normon, is used as an auxiliary treatment. It is provided as a solution for injection and administered intravenously. The maximum daily dose is 400 mg/m², with a treatment period of up to 24 weeks.
**Capecitabine**, marketed as Capecitabine Dr. Reddy’s 500 mg Film-Coated Tablets, is an oral chemotherapy agent used as a comparator treatment. The maximum daily dose is 2000 mg/m², and the treatment period is up to 24 weeks.
**Fluorouracil**, marketed as 5-FU medac, is a solution for injection administered intravenously. It is used as a standard-of-care therapy with a maximum daily dose of 1600 mg/m², and the treatment duration is up to 24 weeks.
**Oxaliplatin**, marketed as Oxaliplatin 5mg/ml concentrate for solution for infusion, is administered intravenously. It is used as a standard-of-care therapy with a maximum daily dose of 130 mg/m², and the treatment period is up to 24 weeks.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to evaluate the safety, tolerability, and efficacy of these treatments in combination or as standalone therapies.
Efficacy
The efficacy of the clinical trial will be assessed using a variety of endpoints and parameters. The primary endpoint for Part C of the trial is **Progression-Free Survival (PFS)**, as determined by the investigator using RECIST v1.1 criteria. This will compare the efficacy of DKN-01 plus tislelizumab combined with a chemotherapy regimen (CAPOX or mFOLFOX6) against tislelizumab with the same chemotherapy regimen in patients with DKK1-high gastric or gastroesophageal junction adenocarcinoma. Secondary endpoints for Parts A and B include the Overall Response Rate (ORR), Duration of Response (DoR), Duration of Complete Response (DoCR), and PFS, all assessed using RECIST v1.1. Additionally, Overall Survival (OS) and Duration of Clinical Benefit (DoCB) will be evaluated.
The trial will utilize validated scales and criteria, such as RECIST v1.1, to measure and analyze these efficacy parameters. The schedule for measuring these endpoints includes assessments at various timepoints throughout the study, with specific attention to the time from the first dose of the study drug to the occurrence of events such as disease progression or death. The efficacy assessments will be conducted by investigators who will document and analyze the data according to the predefined criteria and methodologies outlined in the trial protocol.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- 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.
- 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.
- General: Age ≥18 years on the day of signing the informed consent (exception: ≥19 years in the Republic of Korea)
- General: Histologically proven gastric adenocarcinoma or Siewert I-III GEJ adenocarcinoma
- 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).
- 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.
- 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.
- General: Tumor tissue for mandatory pre-treatment evaluation (fresh biopsy [preferred] or archived specimen).
- 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
- 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
- General: ECOG performance status ≤1 within 7 days of first dose of study drug.
- 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).
- 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.
- 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
- 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
- Part A and C only: Diagnosis of HER2-positive G/GEJ adenocarcinoma.
- General: Prior allogeneic stem cell transplantation or organ transplantation
- 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
- 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
- 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
- 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
- General: Serious nonmalignant disease or other circumstance that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor
- 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
- 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)
- General: Clinically significant anorexia (CTCAE ≥Grade 2) within 7 days prior to first dose of study drug.
- 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).
- General: Known dihydropyrimidine dehydrogenase deficiency
- 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).
- Part A and C only: Prior therapy with an anti-programmed cell death protein 1 (PD-1) or anti-PD-L1 antibody
- Part B only: Systemic anti-cancer therapy (e.g., chemotherapy or immunotherapy) within 21 days prior to first dose of study drug.
- General: Prior allogeneic stem cell transplantation or organ transplantation
- General: Known osteoblastic bony metastasis. Screening of patients without a history of metastatic bony lesions is not required
- 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).
- General: Major surgery within 4 weeks of first dose of study drug
- General: Serious psychiatric or medical conditions that could interfere with treatment.
- 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.
- General: Squamous cell or undifferentiated or other histological type of gastric cancer.
- 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)
- 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.
- 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).
- 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.
- 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
- 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).
- 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.
- 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.
- General: Women who are pregnant or are breastfeeding
- 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.
- General: Treatment with radiation therapy within 14 days prior to first dose of study drug.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 30 Sept 2023 | 15 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
FOLINATO CÁLCICO NORMON 350 mg Polvo para solución inyectable EFG. | Other | POLVO PARA SOLUCIÓN INYECTABLE | INTRAVENOUS USE | 400 | 24 | PRD403742 |
Tislelizumab | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 400 | 24 | PRD10156087 |
DKN-01 | Test | INJECTION | INTRAVENOUS ADMINISTRATION | 600 | 24 | PRD9964637 |
Capecitabine Dr. Reddy’s 500 mg Film-Coated Tablets | Other | FILM-COATED TABLETS | ORAL USE | 2000 | 24 | PRD968813 |
5-FU medac 50 mg/ml, Injektionslösung | Other | INJEKTIONSLÖSUNG | INTRAVENOUS | 1600 | 24 | PRD536079 |
Oxaliplatin 5mg/ml concentrate for solution for infusion | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 130 | 24 | PRD8279123 |