DKN-01 in Combination with Pembrolizumab for the Treatment of Women with Advanced or Recurrent Endometrial Cancer

Inclusion Criteria

• Written informed consent and any locally-required authorization (e.g., Health Insurance Portability and Accountability Act [HIPAA] in the United States of America [USA]) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
• Female participants age >= 18 years at the time of signing informed consent
• Must have histologically confirmed diagnosis of advanced or recurrent endometrioid endometrial cancer that is deemed non-curable with either surgery or radiation therapy. Mixed endometrioid patient will be allowed if the endometrioid component is greater than 50% of the tumor and does not include serous or carcinosarcoma. Non-endometrioid endometrial cancer must have a confirmed Wnt-activating mutation (CTNNB1, RNF-43, APC, AXIN1/2, RSPO2/3, and ZNRF3)
• Patients may have received up to 2 prior systemic therapies for recurrent disease * Note: Chemotherapy given in conjunction with radiation or as part of primary therapy does not count as prior systemic therapy for recurrence. Hormonal therapy does not count toward prior therapy
• Must consent to allow for a pre-treatment tumor biopsy. Tumor material from biopsies done before the screening period are acceptable if: * The biopsy was performed within 3 months prior to the planned treatment start and no other systemic cancer therapy was administered in the interim * A biopsy is performed as part of the study and the specimen is considered non-diagnostic or does not have enough tissue (occurs less than 10% of the time), archival tissue can be used to determine the study cohort and the patient can still participate in the trial
• Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Measurable disease is defined as at least one “target lesion” that can be accurately measured in at least one dimension (>= 10 mm longest dimension to be recorded; Lymph nodes must be >= 15 mm per short axis)
• Patients must be off all other anti-tumor therapies (including immunologic agents) for at least four weeks prior to start of treatment. Patients on hormonal agents require a washout for 10 days
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention
• Women of childbearing potential (WoCBP) must be permanently or surgically sterilized (undergone a total hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are postmenopausal for greater than 12 months. (If uncertain of amenorrhea for 12 months, a pregnancy test will be done to confirm pregnancy status.) If ovaries are present and were not previously menopausal at the time of hysterectomy, should have a serum estradiol < 10 pm/mL to confirm ovarian senescence
• Absolute neutrophil count (ANC) >= 1500/uL
• Platelets >= 100 000/uL
• Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L
• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR calculated creatinine clearance (Cockcroft-Gault formula) >= 30 mL/min OR 24-hour urine creatinine clearance >= 30 mL/min
• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN unless liver metastases are present, in which case it must be =< 5 x ULN
• Adequate coagulation function laboratory values of international normalized ratio (INR) OR prothrombin time (PT) activated partial thromboplastin time (aPTT) of =< 1.5 x ULN receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
• Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
• Creatinine clearance (CrCl) should be calculated per institutional standard. Laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies

Exclusion Criteria

• Have uterine sarcomas, carcinosarcomas, serous tumors (any component) or pure clear cell carcinomas without documentation of a Wnt-activating mutation
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137) administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies
• Previously treated with an anti-DKK1 therapy
• Has deficient mismatch repair (dMMR) or microsatellite instability (MSI-H) are excluded
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to enrollment
• Patient has not recovered from all toxicities related to prior anticancer therapies to National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v) 5.0 grade =< 1 (Exception to this criterion: any grade of alopecia is eligible for the study)
• Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease
• Major surgical procedures, open biopsy or significant traumatic injury within 4 weeks prior to treatment start (minor procedures within 1 week)
• Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. (Note: administration of killed vaccines is allowed)
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are eligible
• Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging. Note: repeat imaging should be performed during study screening. Participants must be clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention
• Has severe hypersensitivity (>= Grade 3) to pembrolizumab and/or any of its excipients
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Note: Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• Has an active infection requiring systemic therapy
• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) anti-viral therapy for at least 4 weeks, and have undetectable HBV viral load prior to randomization. * Note: Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention. Hepatitis B screening tests are not required unless: * Known history of HBV infection * As mandated by local health authority
• Participants with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening * Note: Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization Hepatitis C screening tests are not required unless: * Known history of HCV infection * As mandated by local health authority
• HIV-infected participants must have well-controlled HIV on antiretroviral therapy (ART), defined as: * Participants on ART must have a CD4+ T-cell count >= 350 cells/mm^3 at the time of screening * Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV ribonucleic acid (RNA) level below 50 or the lower limit of quantitation (LLOQ) (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening * It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months. * Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (day 1) and agree to continue ART throughout the study * The combination ART regimen must not contain any antiretroviral medications that interact with CYP3A4 inhibitors/inducers/substrates (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers)
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Has had an allogenic tissue/solid organ transplant
• Has New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, or unstable arrhythmia
• Have Fridericia-corrected QT interval (QTcF) > 470 msec, 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
• History of osteonecrosis of the hip or 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
• Clinically-significant gastrointestinal disorders, such as perforation, gastrointestinal bleeding, or diverticulitis
• Women of childbearing potential (WoCBP) or who are pregnant or breastfeeding are excluded from this study