Endometrial Cancer
Conditions
Keywords
Endometrial Cancer, Uterine Cancer, Endometrial Carcinoma, Human epidermal growth factor receptor 2 (HER2), pMMR, Trastuzumab deruxtecan, T-DXd, DS-8201a, Anti-HER2-Antibody Drug Conjugate(ADC), DESTINY-Endometrial01, Programmed Cell Death-1 (PD1, PD-1), Immune checkpoint inhibitor, TIGIT, Pembrolizumab, Carboplatin, Paclitaxel, Rilvegostomig
Brief summary
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.
Interventions
DRUGTrastuzumab deruxtecan
Experimental therapy by intravenous infusion
DRUGRilvegostomig
Experimental therapy by intravenous infusion
DRUGPembrolizumab
Immunotherapy by intravenous infusion
DRUGCarboplatin
Standard of Care (SoC) chemotherapy by intravenous infusion
DRUGPaclitaxel
Standard of Care (SoC) chemotherapy by intravenous infusion
DRUGDocetaxel
Standard of Care (SoC) chemotherapy by intravenous infusion
Sponsors
AstraZeneca
Daiichi Sankyo Co., Ltd.
GOG Foundation
European Network of Gynaecological Oncological Trial Groups (ENGOT)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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.
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).
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key 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. Key
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS), as assessed by BICR | Until progression or death due to any cause (assessed up to approximately 45 months). | Defined as time from randomization until progression per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR), or death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Until the date of death due to any cause (assessed up to approximately 70 months). | Defined as the time from randomization until the date of death due to any cause. |
| Progression Free Survival (PFS) as assessed by the investigator | Until progression or death due to any cause (assessed up to approximately 70 months). | PFS by investigator has the same attributes as estimand of PFS by BICR except tumor assessment is by the investigator. |
| Time from randomization to second progression or death (PFS2) | Until the earliest of the progression event (following the initial investigator-assessed progression), after first subsequent therapy, or death (assessed up to approximately 70 months). | PFS2 will be defined as the time from randomization to the earliest of the progression event (following the initial investigator-assessed progression), after first subsequent therapy, or death. |
| Objective response rate (ORR), as assessed by BICR and investigator | Until progression or the starting of subsequent anticancer therapy (assessed up to approximately 45 months). | ORR as assessed and confirmed by BICR is defined as the proportion of participants who have a complete response (CR) or partial response (PR), as determined and confirmed by BICR. ORR as assessed and confirmed by the investigator has the same attributes as estimand of ORR by BICR except tumor assessment per the investigator. |
| Duration of response (DoR), as assessed by BICR and investigator | Until progression or death due to any cause (assessed up to approximately 45 months). | DoR as assessed by BICR will be defined as the time from the date of first documented response of confirmed responders until date of documented progression per RECIST 1.1, or death due to any cause. DoR as assessed by the investigator has the same attributes as estimand of DoR by BICR except tumor assessment per the investigator. |
| Safety and tolerability | Safety is assessed until the 90 days (+7) after the last dose (assessed up to approximately 70 months). | Safety and tolerability will be evaluated in terms of AEs/serious AEs (SAEs), AESI, vital signs, clinical safety laboratory assessments, ECG and ECHO/MUGA scan results. |
| Pharmacokinetics of T-DXd, total anti-HER2 antibody, DXd and rilvegostomig | Up to safety follow-up period (assessed up to approximately 45 months). | Serum concentration of T-DXd, total anti-HER2 antibody, DXd and rilvegostomig. |
| Immunogenicity of T- DXd and rilvegostomig | Up to safety follow-up period (assessed up to approximately 45 months). | Presence of ADAs for T-DXd or rilvegostomig. |
| Patient-reported tolerability | Until progression as assessed by BICR (assessed up to approximately 45 months). | Patient-reported tolerability will be described among participants, as treated, using the following outcomes: * Symptomatic AEs: Descriptive summary of the proportion of participants reporting symptomatic AEs while on treatment, as assessed by items from the EORTC Item Library and the FACT/GOG-NTX-4 * Overall side-effect bother: Descriptive summary of the proportion of participants reporting overall side-effect bother on the PGI-TT while on treatment |
| Progression-free survival (PFS) according to MMR status to determine the clinical utility of a MMR diagnostic test | Through completion of study, assessed up to approximately 70 months. | PFS is defined as time from randomization until progression per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) as assessed by BICR, or death due to any cause. |
| Overall survival (OS) according to MMR status to determine the clinical utility of a MMR diagnostic test | Through completion of study, assessed up to approximately 70 months. | OS defined as the time from randomization until the date of death due to any cause. |
| Progression-free survival (PFS) according to HER2 expression to determine the clinical utility of a HER2 diagnostic test | Through completion of study, assessed up to approximately 70 months. | PFS is defined as time from randomization until progression per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) as assessed by BICR, or death due to any cause. |
| Overall survival (OS) according to HER2 expression to determine the clinical utility of a HER2 diagnostic test | Through completion of study, assessed up to approximately 70 months. | OS is defined as the time from randomization until the date of death due to any cause. |
Countries
Australia, Austria, Belgium, Brazil, Canada, China, Denmark, Finland, France, Germany, Hungary, Italy, Japan, Netherlands, Norway, Poland, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
Outcome results
None listed