ACTIVE_NOT_RECRUITING

Phase 2 Study Evaluating the Efficacy of the Combination of DKN-01 (DKK1 Inhibitor, Leap Therapeutics) and Pembrolizumab in the Treatment of Advanced or Recurrent Endometrial Cancer

Conditions

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

To learn if the combination of DKN-01 and pembrolizumab can help to control advanced or recurrent endometrial cancer.

Official Title

Phase 2 Study Evaluating the Efficacy of the Combination of DKN-01 (DKK1 Inhibitor, Leap Therapeutics) and Pembrolizumab in the Treatment of Advanced or Recurrent Endometrial Cancer

Quick Facts

Study Start:2023-08-29

Study Completion:2029-01-31

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:ACTIVE_NOT_RECRUITING

Study ID

NCT05761951

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
1. Written informed consent and any locally-required authorization (e.g., HIPAA in the USA) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations. 2. Female participants age ≥ 18 years at the time of signing informed consent. 3. 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). 4. 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. 5. 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. If 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. 6. Must not have received/progressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. 7. 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 8. Patients must be off all other anti-tumor therapies (including immunologic agents) for at least four weeks prior to study registration. Patients on hormonal agents require a washout for 10 days 9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention. 10. Women of childbearing potential (WoCBP) must be permanently or surgically sterilized (undergone a total hysterectomy, bilateral lubal tigation, 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. 11. Adequate hematological organ function laboratory values are defined below: * Absolute neutrophil count (ANC) ≥1500/µL * Platelets ≥100 000/µL * Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La 12. Adequate renal organ function laboratory values are defined below: 13. Adequate hepatic organ function laboratory values are defined below: * Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels \>1.5 × ULN * AST (SGOT) and ALT (SGPT) ≤2.5 × ULN unless liver metastasis are present, in which case it must be ≤5 × ULN 14. Adequate coagulation function laboratory values of international normalized ratio (INR) OR prothrombin time (PT) activated partial thromboplastin time (aPTT) of ≤1.5 × ULN receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants. 15. Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks. 16. 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.	1. Have uterine sarcomas, carcinosarcomas, serous tumors (any component) or pure clear cell carcinomas without documentation of a Wnt-activating mutation (see Figure 2 for definition) 2. 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). 3. Previously treated with an anti-DKK1 therapy. 4. Has deficient mismatch repair (dMMR) or microsatellite instability (MSI-H) are excluded. 5. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to enrollment. 6. Patient has not recovered from all toxicities related to prior anticancer therapies to NCI-CTCAEv5.0 Grade \<1 (Exception to this criterion: any grade of alopecia is eligible for the study). 7. 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-CNS disease. 8. Major surgical procedures, open biopsy or significant traumatic injury within 4 weeks prior to treatment start (minor procedures within 1 week) 9. 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.) 10. 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. 11. 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. 12. 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. 13. 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. 14. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 15. 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. 16. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. 17. Has an active infection requiring systemic therapy. 18. Has known history of human immunodeficiency virus (HIV) unless patient meets the following criteria: 1. HIV RNA is undetected 2. Have hepatitis B surface antigen 3. Have hepatitis C antibodies unless hepatitis C virus ribonucleic acid (RNA) is undetected/negative). 19. 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. 20. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 21. Has had an allogenic tissue/solid organ transplant. 22. Has New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, or unstable arrhythmia. 23. 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. 24. 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. 25. Clinically-significant gastrointestinal disorders, such as perforation, gastrointestinal bleeding, or diverticulitis. 26. Women of childbearing potential (WoCBP) or who are pregnant or breastfeeding are excluded from this study.

Inclusion Criteria

Exclusion Criteria

1. Written informed consent and any locally-required authorization (e.g., HIPAA in the USA) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
2. Female participants age ≥ 18 years at the time of signing informed consent.
3. 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).
4. 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.
5. 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. If 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.
6. Must not have received/progressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies.
7. 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
8. Patients must be off all other anti-tumor therapies (including immunologic agents) for at least four weeks prior to study registration. Patients on hormonal agents require a washout for 10 days
9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.
10. Women of childbearing potential (WoCBP) must be permanently or surgically sterilized (undergone a total hysterectomy, bilateral lubal tigation, 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.
11. Adequate hematological organ function laboratory values are defined below:
* Absolute neutrophil count (ANC) ≥1500/µL
* Platelets ≥100 000/µL
* Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La
12. Adequate renal organ function laboratory values are defined below:
13. Adequate hepatic organ function laboratory values are defined below:
* Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels \>1.5 × ULN
* AST (SGOT) and ALT (SGPT) ≤2.5 × ULN unless liver metastasis are present, in which case it must be ≤5 × ULN
14. Adequate coagulation function laboratory values of international normalized ratio (INR) OR prothrombin time (PT) activated partial thromboplastin time (aPTT) of ≤1.5 × ULN receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants.
15. Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.
16. 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.

1. Have uterine sarcomas, carcinosarcomas, serous tumors (any component) or pure clear cell carcinomas without documentation of a Wnt-activating mutation (see Figure 2 for definition)
2. 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).
3. Previously treated with an anti-DKK1 therapy.
4. Has deficient mismatch repair (dMMR) or microsatellite instability (MSI-H) are excluded.
5. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to enrollment.
6. Patient has not recovered from all toxicities related to prior anticancer therapies to NCI-CTCAEv5.0 Grade \<1 (Exception to this criterion: any grade of alopecia is eligible for the study).
7. 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-CNS disease.
8. Major surgical procedures, open biopsy or significant traumatic injury within 4 weeks prior to treatment start (minor procedures within 1 week)
9. 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.)
10. 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.
11. 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.
12. 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.
13. 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.
14. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
15. 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.
16. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
17. Has an active infection requiring systemic therapy.
18. Has known history of human immunodeficiency virus (HIV) unless patient meets the following criteria:
1. HIV RNA is undetected
2. Have hepatitis B surface antigen
3. Have hepatitis C antibodies unless hepatitis C virus ribonucleic acid (RNA) is undetected/negative).
19. 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.
20. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
21. Has had an allogenic tissue/solid organ transplant.
22. Has New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, or unstable arrhythmia.
23. 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.
24. 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.
25. Clinically-significant gastrointestinal disorders, such as perforation, gastrointestinal bleeding, or diverticulitis.
26. Women of childbearing potential (WoCBP) or who are pregnant or breastfeeding are excluded from this study.

Contacts and Locations

Principal Investigator

Pamela Soliman, MD

PRINCIPAL_INVESTIGATOR

M.D. Anderson Cancer Center

Study Locations (Sites)

M D Anderson Cancer Center

Houston, Texas, 77030

United States

Collaborators and Investigators

Sponsor: M.D. Anderson Cancer Center

Pamela Soliman, MD, PRINCIPAL_INVESTIGATOR, M.D. Anderson Cancer Center

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2023-08-29

Study Completion Date2029-01-31

Study Record Updates

Study Start Date2023-08-29

Study Completion Date2029-01-31

Terms related to this study

Additional Relevant MeSH Terms

Endometrial Cancer