Phase 3, Randomized, Double-Blind Study of Pembrolizumab versus Placebo in Combination With Adjuvant Chemotherapy With or Without Radiotherapy for the Treatment of Newly Diagnosed High-Risk Endometrial Cancer After Surgery With Curative Intent

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

30 Jan 2020 → ongoing

Decision date (initial)

2023-08-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2022-501973-37-00

EudraCT number

2020-003424-17

WHO UTN

U1111-1282-6430

ClinicalTrials.gov

NCT04634877

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

1.To compare pembrolizumab with placebo, both in combination with adjuvant chemotherapy +/- XRT, with respect to disease-free survival (DFS) assessed radiographically by the investigator or by histopathologic confirmation of suspected disease recurrence.
2.To compare pembrolizumab with placebo, both in combination with adjuvant chemotherapy +/- XRT, with respect to overall survival (OS).

Secondary objectives 4

1. To compare pembrolizumab with placebo, both in combination with adjuvant chemotherapy +/- XRT, with respect to DFS assessed radiographically by blinded independent central review or by histopathologic confirmation of disease recurrence.
2. To compare pembrolizumab with placebo, both in combination with adjuvant chemotherapy +/- XRT, with respect to OS and DFS assessed radiographically by the investigator or by histopathologic confirmation of disease recurrence by PD-L1 status, and by tumor mutation burden (TMB) status.
3. To evaluate the safety and tolerability of pembrolizumab in combination with adjuvant chemotherapy +/- XRT.
4. To compare pembrolizumab with placebo, both in combination with adjuvant chemotherapy +/- XRT, with respect to change from baseline score in the EORTC Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status/Quality of Life (QoL) scale and Physical Function subscale, and the EORTC endometrial cancer-specific QoL module (EORTC QLQ-EN24).

Conditions and MedDRA coding

Endometrial cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Is female and has a histologically confirmed new diagnosis of Endometrial Carcinoma or Carcinosarcoma (Mixed Mullerian Tumor) and a) has undergone curative intent surgery that included hysterectomy and bilateral salpingo-oophorectomy; and * Is at high risk for recurrence following treatment with curative intent surgery, ie: Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) 2009 surgical stage I/II with myometrial invasion of non-endometrioid histology; FIGO 2009 surgical stage I/II with myometrial invasion of any histology with known aberrant p53 expression or p53 mutation; or FIGO (2009) surgical stage III or IVA of any histology.
2. Is disease-free with no evidence of loco-regional disease or distant metastasis post operatively and on imaging.
3. Has not received any radiation or systemic therapy, including immunotherapy, hormonal therapy, or hyperthermic intraperitoneal chemotherapy (HIPEC), in any setting including the neoadjuvant setting for endometrial cancer (EC)
4. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days before randomization.
5. Submission of a tumor tissue sample from current diagnosis of Endometrial Carcinoma or Carcinosarcoma for prospective determination of histology and mismatch repair (MMR) status by central vendor is required for all participants.
6. Has adequate organ function within 7 days of randomization.

Exclusion criteria 23

1. Has recurrent endometrial carcinoma or carcinosarcoma.
2. Has uterine mesenchymal tumor such as an endometrial stromal sarcoma, leiomyosarcoma, or other types of pure sarcomas. Adenosarcomas and neuroendocrine tumors are also not allowed.
3. Has FIGO (2009) Surgical Stage I/II EC of endometrioid histology without a known aberrant p53 expression
4. Is known to have a deoxyribonucleic acid (DNA) polymerase epsilon catalytic subunit A (POLE) mutation.
5. Has FIGO Stage IVB disease of any histology even if there is no evidence of disease after surgery.
6. Has residual tumor whether measurable or non-measurable after surgery.
7. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 3 years. * Note: The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in situ cancers. Note: Adjuvant hormonal therapy that is ongoing for prior definitively treated breast cancer is permitted.
8. Has received prior therapy with an anti-programmed cell death receptor 1 (PD-1), anti-programmed cell death receptor ligand 1 (PD-L1), or anti-programmed cell death receptor ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX-40, CD137).
9. Has received a live vaccine within 30 days before the first dose of study intervention. * Note: killed vaccines are allowed.
10. Has a known intolerance to study intervention (or any of the excipients).
11. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention. * Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
12. Has any contraindication to the use of carboplatin or paclitaxel.
13. 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 the first dose of study intervention.
14. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
15. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
16. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
17. Has an active infection requiring systemic therapy.
18. Has a known history of HIV infection.
19. Has a known history of Hepatitis B or known active Hepatitis C virus infection.
20. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
21. Has had an allogenic tissue/solid organ transplant.
22. Has not recovered adequately from surgery and/or any complications from the surgery.
23. Is breastfeeding.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Disease-Free Survival (DFS) as Assessed Radiographically by Investigator or by Histopathologic Confirmation of Suspected Disease Recurrence
2. Overall Survival (OS)

Secondary endpoints 10

1. Disease-Free Survival (DFS) as Assessed Radiographically by Blinded Independent Central Review (BICR) or by Histopathologic Confirmation of Suspected Disease Recurrence
2. Disease-Free Survival (DFS) as Assessed Radiographically by Investigator or by Histopathologic Confirmation of Suspected Disease Recurrence by Combined Positivity Score (CPS)-Determined Programmed Cell Death 1 Ligand 1 (PD-L1) Status
3. Overall Survival (OS) as Assessed Radiographically by Investigator or by Histopathologic Confirmation of Suspected Disease Recurrence by Combined Positivity Score (CPS)-Determined Programmed Cell Death 1 Ligand 1 (PD-L1) Status
4. Disease-Free Survival (DFS) as Assessed Radiographically by Investigator or by Histopathologic Confirmation of Suspected Disease Recurrence by Tumor Mutation Burden (TMB) Status
5. Overall Survival (OS) as Assessed Radiographically by Investigator or by Histopathologic Confirmation of Suspected Disease Recurrence by Tumor Mutation Burden (TMB) Status
6. Number of Participants Who Experience One or More Adverse Events (AEs)
7. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
8. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status/Quality of Life (QoL) Score
9. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Physical Function Score
10. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Symptom Specific Scale for Endometrial Cancer (EORTC QLQ-EN24) Score

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Sonja Schaefer

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Sonja Schaefer

Third parties 10

Locations

13 EU/EEA countries · 69 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 76 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

19 submissions — initial application plus substantial / non-substantial modifications