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

  • ≥ 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). - Participant must have primary advanced disease (Stage III/IV) or recurrent endometrial cancer and meet at least one of the following criteria: 1. Primary Stage III (per FIGO 2023) disease with measurable disease at baseline per RECIST 1.1 based on the investigator's assessment. 2. Primary Stage IV (per FIGO 2023) disease regardless of presence of measurable disease at baseline. 3. Recurrent disease regardless of presence of measurable disease at baseline. - Endometrial cancer with HER2 IHC expression of 3+ or 2+ by prospective central testing. - Endometrial cancer that is determined pMMR by prospective central testing. - Provision of an adequate FFPE tumor tissue sample for central HER2, MMR, and PD-L1 IHC testing. - Prior therapy: 1. No prior chemotherapy for the treatment of EC, except for one prior line of adjuvant/ neoadjuvant chemotherapy with curative intent (chemotherapy or chemoradiation) if completed ≥ 6 months prior to signature of the main ICF. Prior trastuzumab in the adjuvant/neoadjuvant setting is allowed. 2. No prior exposure to antibody-drug conjugates or immune checkpoint inhibitors 3. Participants may have received prior radiation therapy for the treatment of endometrial cancer. Adequate treatment washout period is required 4. Participants may have received prior hormonal therapy for the treatment of endometrial cancer. Adequate treatment washout period is required - ECOG 0-1. - Left ventricular ejection fraction ≥ 50% within 28 days before randomization. - Adequate organ and bone marrow function within 14 days before randomization. - The participant is not considered a candidate for curative therapy in the judgment of the investigator.

Exclusion Criteria

  • Any severe or uncontrolled systemic diseases which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or would jeopardize compliance with the protocol. - Active or ongoing serious chronic gastrointestinal conditions associated with diarrhea, primary immunodeficiency, or non-infectious skin disease requiring systemic treatment. - Active or prior documented autoimmune or inflammatory disorders requiring chronic systemic treatment with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs. - 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: 1. 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, etc.). 2. Any autoimmune, connective tissue or inflammatory disorders where there is documented, or a suspicion of pulmonary involvement at the time of screening. 3. Prior pneumonectomy (complete). - History of myocardial infarction or unstable angina within 6 months before randomization, or symptomatic congestive heart failure (NYHA Class II to IV), clinically significant arrhythmia, uncontrolled hypertension, cardiomyopathy of any etiology or history of myocarditis. - History of organ transplant or allogeneic stem cell transplant. - Spinal cord compression or clinically active central nervous system metastases. Participants with clinically inactive brain metastases may be included in the study. - Evidence of any of the following infections: 1. Active tuberculosis 2. HIV infection that is not well controlled. 3. Active hepatitis B or C infection.

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 for 6 cycles, followed by maintenance with pembrolizumab IV Q6W for 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
Little Rock, Arkansas 72205

Research Site
Duarte, California 91010

Research Site
Irvine, California 92618

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
Ann Arbor, Michigan 48109

Research Site
Minneapolis, Minnesota 55455

Research Site
Rochester, Minnesota 55905

Research Site
Jackson, Mississippi 39216

Research Site
Springfield, Missouri 65804

Research Site
St Louis, Missouri 63141

Research Site
Lebanon, New Hampshire 03756

Research Site
Hackensack, New Jersey 07601

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
Columbus, Ohio 43210

Research Site
Eugene, Oregon 97401

Research Site
Philadelphia, Pennsylvania 19111

Research Site
Pittsburgh, Pennsylvania 15224

Research Site
Providence, Rhode Island 02905

Research Site
Charleston, South Carolina 29425

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
Charlottesville, Virginia 22908

Research Site
Madison, Wisconsin 53792

More Details

NCT ID
NCT06989112
Status
Recruiting
Sponsor
AstraZeneca

Study Contact

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