DESTINY-Endometrial01: A Phase III Study of Trastuzumab Deruxtecan Plus Rilvegostomig or Pembrolizumab as First-Line Treatment of HER2-Expressing (IHC 3+/2+), Mismatch Repair Proficient (pMMR) Endometrial Cancer

Purpose

DESTINY-Endometrial01 will investigate the efficacy of first-line T-DXd + rilvegostomig (Arm A) and/or T-DXd+ pembrolizumab (Arm B) when compared to chemotherapy (carboplatin + paclitaxel) + pembrolizumab (Arm C), by assessment of progression free survival (PFS), as assessed by BICR, in participants with HER2-expressing (IHC 3+/2+), pMMR, primary advanced (Stage III/IV) or recurrent EC.

Condition

  • Endometrial Cancer

Eligibility

Eligible Ages
Over 18 Years
Eligible Sex
Female
Accepts Healthy Volunteers
No

Inclusion Criteria

  • Participants must be ≥ 18 years of age at the time of screening. Other age restrictions may apply as per local regulations. - Histologically confirmed diagnosis of epithelial endometrial carcinoma. All histologies are allowed except for sarcomas (carcinosarcomas are allowed). - Following surgery or diagnostic biopsy, participant must have primary advanced disease (Stage III/IV) or first recurrent endometrial cancer and meet at least one of the following criteria: - Primary Stage III (per FIGO 2023) disease with measurable disease at baseline per RECIST 1.1 based on the investigator's assessment. - Primary Stage IV disease (per FIGO 2023) regardless of presence of measurable disease at baseline. - First recurrent disease regardless of presence of measurable disease at baseline. - Endometrial cancer with HER2 IHC expression of 3+ or 2+ as assessed by prospective central testing. - Endometrial cancer that is determined pMMR by prospective central IHC testing. - Provision of adequate FFPE tumor tissue sample of a tumor lesion that was not previously irradiated for central HER2, MMR, and PD-L1 IHC testing and valid central test results for randomization/ stratification. - Prior therapy: - Naïve to first-line systemic anticancer therapy. Participants may have received one prior line of adjuvant/neoadjuvant chemotherapy with curative intent (chemotherapy or chemoradiation) if disease recurrence or progression occurred ≥ 6 months after last dose of chemotherapy. Prior trastuzumab in the adjuvant/neoadjuvant setting is allowed. - No prior exposure to ADCs or immune checkpoint inhibitors including (but not limited to) anti-PD-1/PD-L1/PD-L2 and anti-CTLA-4 antibodies and therapeutic anticancer vaccines. - Participants may have received prior radiation therapy for the treatment of endometrial cancer. Prior radiation therapy may have included pelvic radiation therapy, extended field pelvic/para-aortic radiation therapy, and/or intravaginal brachytherapy. Adequate treatment washout period is required. - Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1. - Left ventricular ejection fraction (LVEF) ≥ 50% within 28 days before randomization. - Adequate organ and bone marrow function within 14 days before randomization. -

Exclusion Criteria

  • History of organ transplant - Uncontrolled intercurrent illness, including, but not limited to ongoing or active known infection, serious chronic gastrointestinal conditions associated with diarrhea and active non-infectious skin disease requiring systemic treatment. - Spinal cord compression or clinically active central nervous system metastases - Participants with a medical history of myocardial infarction (MI) within 6 months before randomization, or symptomatic congestive heart failure (CHF) (NYHA Class II to IV), clinically significant arrhythmia, or cardiomyopathy of any etiology. Participants with troponin levels above ULN at screening (as defined by the manufacturer), should have a cardiologic consultation before enrollment to rule out MI - History of (non-infectious) ILD/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. - Lung criteria: - Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within 3 months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, pleural effusion etc.). - Any autoimmune, connective tissue or inflammatory disorders where there is documented, or a suspicion of pulmonary involvement at the time of screening. - Prior pneumonectomy (complete). - Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment. - Active primary immunodeficiency/ active infectious disease(s) including: - Tuberculosis (TB) - HIV infection that is not well controlled. - Chronic or active hepatitis B, chronic or active hepatitis C; however, participants who have chronic hepatitis B and are receiving suppressive antiviral therapy are allowed to be enrolled if alanine aminotransferase (ALT) is normal and viral load is controlled. - Any concurrent anticancer treatment without an adequate washout period prior to the first dose of study intervention. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., HRT) is allowed.

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
Participants with HER2-expressing (IHC 3+/2+), pMMR, primary advanced (Stage III/IV) or recurrent EC will be randomly assigned to treatment with trastuzumab deruxtecan (T-DXd) plus rilvegostomig (Arm A), T-DXd plus pembrolizumab (Arm B), or chemotherapy (carboplatin plus paclitaxel) plus pembrolizumab (Arm C).
Primary Purpose
Treatment
Masking
None (Open Label)
Masking Description
This is an open-label, Sponsor-blinded study. To maintain the integrity of the study, Sponsor personnel directly involved in study conduct will not undertake or have access to efficacy data aggregated by treatment arm prior to final data readout for the primary endpoint.

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Arm A: T-DXd + Rilvegostomig 		T-DXd IV Q3W plus rilvegostomig IV Q3W. Treatment will continue until objective disease progression according to RECIST v1.1 as assessed by the Investigator and confirmed by BICR or until other discontinuation criteria is met, whichever occurs first.
  • Drug: Trastuzumab deruxtecan
    Experimental therapy by intravenous infusion
    Other names:
    • DS-8201a, T-DXd
  • Drug: Rilvegostomig
    Experimental therapy by intravenous infusion
Experimental
Arm B: T-DXd + Pembrolizumab 		T-DXd IV Q3W plus pembrolizumab IV Q3W. Treatment will continue until objective disease progression according to RECIST v1.1 as assessed by the Investigator and confirmed by BICR or until other discontinuation criteria is met, whichever occurs first.
  • Drug: Trastuzumab deruxtecan
    Experimental therapy by intravenous infusion
    Other names:
    • DS-8201a, T-DXd
  • Drug: Pembrolizumab
    Immunotherapy by intravenous infusion
    Other names:
    • Keytruda
Active Comparator
Arm C: Carboplatin + Paclitaxel + Pembrolizumab 		Carboplatin, paclitaxel and pembrolizumab administered Q3W during 6 cycles, followed by maintenance with pembrolizumab IV Q6W during 14 cycles. Treatment with pembrolizumab will continue for up to 20 total cycles (approximately 24 months, accounting for combination and maintenance phases) or until other discontinuation criteria is met, whichever occurs first. At the discretion of the investigator, participants may continue to receive carboplatin, paclitaxel and pembrolizumab Q3W for up to 10 cycles. Docetaxel can be used as an alternative to paclitaxel for participants who had a hypersensitivity reaction to paclitaxel with a failed rechallenge (or not amenable to rechallenge), according to the investigator's clinical judgment.
  • Drug: Pembrolizumab
    Immunotherapy by intravenous infusion
    Other names:
    • Keytruda
  • Drug: Carboplatin
    Standard of Care (SoC) chemotherapy by intravenous infusion
    Other names:
    • Carbomedac, Carbosin, Paraplatin
  • Drug: Paclitaxel
    Standard of Care (SoC) chemotherapy by intravenous infusion
    Other names:
    • Anzatax, Ebetaxel, Oncotaxel, Paclitax, Paclitaxin, Paxene, Taxol
  • Drug: Docetaxel
    Standard of Care (SoC) chemotherapy by intravenous infusion
    Other names:
    • Docirena, Taxceus, Taxotere

Recruiting Locations

Research Site
La Jolla, California 92037

Research Site
Fort Myers, Florida 33901

Research Site
Miami Beach, Florida 33140

Research Site
St. Petersburg, Florida 33705

Research Site
Tampa, Florida 33612

Research Site
West Palm Beach, Florida 33401

Research Site
Augusta, Georgia 30912

Research Site
Arlington Heights, Illinois 60005

Research Site
Evanston, Illinois 60201

Research Site
Shreveport, Louisiana 71103

Research Site
Baltimore, Maryland 21201

Research Site
Boston, Massachusetts 02111

Research Site
Minneapolis, Minnesota 55455

Research Site
Jackson, Mississippi 39216

Research Site
St Louis, Missouri 63141

Research Site
New York, New York 10065

Research Site
Charlotte, North Carolina 28204

Research Site
Winston-Salem, North Carolina 27103

Research Site
Cincinnati, Ohio 45220

Research Site
Eugene, Oregon 97401

Research Site
Pittsburgh, Pennsylvania 15224

Research Site
Providence, Rhode Island 02905

Research Site
Sioux Falls, South Dakota 57105

Research Site
Austin, Texas 78758

Research Site
Fort Worth, Texas 76104

Research Site
Houston, Texas 77030

Research Site
San Antonio, Texas 78240

Research Site
Saint Johnsbury, Vermont 05819

Research Site
Charlottesville, Virginia 22908

More Details

NCT ID
NCT06989112
Status
Recruiting
Sponsor
AstraZeneca

Study Contact

AstraZeneca Clinical Study Information Center
1-877-240-9479
information.center@astrazeneca.com