Ensayos clínicos

Inclusion Criteria:

Part A only

• No previous systemic therapy for inoperable, locally advanced or metastatic G/GEJ adenocarcinoma:
  • 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 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.
  • 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;
  • Prior trastuzumab (or biosimilar) treatment is acceptable for patients with history of HER2-positive G/GEJ adenocarcinoma;
  • Prior therapy with an anti-programmed cell death protein 1 (PD-1), anti-PD-L1 in any treatment setting (including adjuvant/neoadjuvant) is acceptable.
• 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

• Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments.
• Age ≥ 18 years in North America or ≥ 19 years in the Republic of Korea on the day of signing the informed consent form.
• Histologically proven gastric adenocarcinoma or Siewert I-III GEJ adenocarcinoma.
• At least one measurable lesion on radiographic imaging as defined by RECIST v1.1:
  • 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;
  • 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.
• Tumor tissue for mandatory pre-treatment evaluation (fresh biopsy [preferred] or archived specimen).
• ECOG performance status ≤ 1 within 7 days of first dose of study drug.
• Acceptable liver function:
  • Total bilirubin ≤ 2.0 times upper limit of normal (ULN). Total bilirubin must be < 3 × ULN for patients with Gilbert’s syndrome;
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN (if liver metastases are present, then ≤ 5 × ULN is allowed).
• Acceptable renal function:
  • Serum creatinine ≤ 1.5 × ULN or estimated Glomerular Filtration Rate ≥ 30 mL/min/1.73 m^2 by Chronic Kidney Disease Epidemiology Collaboration equation.
• 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):
  • Absolute neutrophil count (ANC) ≥ 1.5 × 10^9 /L;
  • Platelets:
    • Part A only:  ≥ 100 × 10^9 /L;
    • Part B only:  ≥ 75 × 10^9 /L;
  • Hemoglobin ≥ 9 g/dL.
• Acceptable coagulation status:
  • 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 below);
  • INR ≤ 1.5 (unless receiving anticoagulation therapy):
    • 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).
• 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.
• 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 sterile male is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility;
  • 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 only

• Diagnosis of HER2-positive G/GEJ adenocarcinoma.
• 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
• 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

• Squamous cell or undifferentiated or other histological type of gastric cancer.
• 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).
• Active autoimmune diseases or history of autoimmune diseases that may relapse.
  • Note: Patients with the following diseases are not excluded and may proceed to further screening:
    • Controlled Type I diabetes;
    • Hypothyroidism (provided it is managed with hormone replacement therapy only);
    • Controlled celiac disease;
    • Skin diseases not requiring systemic treatment (e.g., vitiligo, psoriasis, alopecia);
    • Any other disease that is not expected to recur in the absence of external triggering factors.
• 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.
  • Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded:
    • Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent);
    • Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption;
    • Short course (≤ 7 days) of corticosteroid prescribed prophylactically (e.g., for contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type hypersensitivity reaction caused by contact allergen).
• 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.
• 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).
• 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.
• 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).
• Clinically significant anorexia (CTCAE ≥ Grade 2) within 7 days prior to first dose of study drug.
• History of interstitial lung disease, non-infectious pneumonitis, pulmonary fibrosis, acute lung disease or uncontrolled systemic diseases.
  • 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.
• Severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infection within 14 days of first dose of study drug.
• Prior allogeneic stem cell transplantation or organ transplantation.
• History of severe hypersensitivity reactions to other monoclonal antibodies or any components of study treatment.
• Known dihydropyrimidine dehydrogenase deficiency.
• Any of the following cardiovascular risk factors:
  • Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, within 28 days before first dose of study drug;
  • Pulmonary embolism within 28 days before first dose of study drug;
  • Any history of acute myocardial infarction within 6 months before first dose of study drug;
  • Any history of heart failure meeting New York Heart Association (NYHA) Classification III or IV within 6 months before first dose of study drug;
  • Any event of ventricular arrhythmia ≥ Grade 2 in severity within 6 months before first dose of study drug;
  • Any history of cerebrovascular accident within 6 months before first dose of study drug;
  • Uncontrolled hypertension that cannot be managed by standard anti-hypertension medications within 28 days before first dose of study drug;
  • Any episode of syncope or seizure within 28 days before first dose of study drug.
• 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.
• Known to be human immunodeficiency virus (HIV)-positive, have hepatitis B surface antigen, or hepatitis C antibodies unless hepatitis C virus RNA is undetected/negative.
• Serious nonmalignant disease that could compromise protocol objectives in the opinion of the investigator and/or the sponsor.
• 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 asymptomatic patients is not required.
• Known osteoblastic bony metastasis. Screening of asymptomatic patients without a history of metastatic bony lesions is not required.
• 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).
• Major surgery within 4 weeks of first dose of study drug.
• Serious psychiatric or medical conditions that could interfere with treatment.
• 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).
• Aministration of a live vaccine within 28 days before first dose of study drug.
  • Note: Seasonal vaccines for influenza or COVID vaccines are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.
• 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.
• Women who are pregnant or are breastfeeding.
• Concurrent participation in another therapeutic clinical study.
  • 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.
• Treatment with radiation therapy within 14 days prior to first dose of study drug.

Eligibility last updated 10/27/21. Questions regarding updates should be directed to the study team contact.