Phase 3 study of pembrolizumab plus lenvatinib in endometrial carcinoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

20 Sep 2019 → 5 Feb 2025

Decision date (initial)

2023-10-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC · Eisai Limited, UK

External identifiers

EU CT number

2023-505614-17-00

EudraCT number

2018-003009-24

WHO UTN

U1111-1292-1245

ClinicalTrials.gov

NCT03884101

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Pharmacogenetic, Pharmacogenomic, Safety, Efficacy, Therapy, Pharmacoeconomic

1. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by blinded independent central review (BICR), modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ for the combination of pembrolizumab (MK-3475) plus lenvatinib (MK-7902) versus chemotherapy
2. To compare Overall Survival (OS) for the combination of pembrolizumab plus lenvatinib versus chemotherapy

Secondary objectives 3

1. To compare objective response rate (ORR) per RECIST 1.1 by BICR in mismatch repair proficient (pMMR) participants and in all-comer participants who have measurable disease at study entry
2. To evaluate the impact of treatment on Health-Related Quality-of-Life (HRQoL) as assessed by using the global score of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ C30) in pMMR and in all-comer participants
3. To compare the safety and tolerability of pembrolizumab plus lenvatinib versus chemotherapy in all-comer participants

Conditions and MedDRA coding

Participants with advanced or recurrent endometrial carcinoma

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Has Stage III, Stage IV, or recurrent, histologically-confirmed endometrial carcinoma with disease that is either measurable or nonmeasurable but radiographically apparent, per RECIST 1.1 as assessed by BICR (note: may have received prior chemotherapy only if administered concurrently with radiation; may have received prior radiation without concurrent chemotherapy; may have received prior hormonal therapy for treatment of endometrial carcinoma, provided that it was discontinued ≥1 week prior to randomization; and may have received 1 prior line of systemic platinum-based adjuvant and/or neoadjuvant chemotherapy)
2. Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion that was not previously irradiated, for determination of mismatch repair (MMR) status
3. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 7 days prior to the first dose of study intervention
4. Is not pregnant or breastfeeding, and is either not a woman of childbearing potential (WOCBP) or is a WOCBP who agrees to use contraception during the study and for ≥120 days after pembrolizumab, ≥30 days after lenvatinib, or ≥180 days after (chemotherapy) [if a WOCBP, a pregnancy test will be required within 24 hours of first dose of study drug]
5. Has adequately controlled blood pressure within 7 days prior to randomization
6. Has adequate organ function based on assessment within 7 days prior to the first dose of study intervention

Exclusion criteria 25

1. Has carcinosarcoma (malignant mixed Műllerian tumor), endometrial leiomyosarcoma or other high grade sarcomas, or endometrial stromal sarcomas
2. Has a central nervous system (CNS) metastasis, unless local therapy (e.g., whole brain radiation therapy, surgery, or radiosurgery) has been completed and have discontinued use of corticosteroids for this indication for ≥4 weeks prior to starting study medication (major surgery within 3 weeks of the first dose of study drug will be exclusionary)
3. Has a known additional malignancy (other than endometrial carcinoma) that is progressing or has required active treatment in the last 3 years
4. Has gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib
5. Has a pre-existing Grade ≥3 gastrointestinal or nongastrointestinal fistula
6. Has radiographic evidence of major blood vessel invasion/infiltration
7. Has active hemoptysis (bright red blood at ≥0.5 teaspoon) within 3 weeks prior to the first dose of study intervention or tumor bleeding within 2 weeks prior to randomization
8. Has clinically significant cardiovascular disease within 12 months from first dose of study intervention including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction or cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability
9. Has any infection requiring systemic treatment
10. Has not recovered adequately from any toxicity and/or complications from major surgery prior to randomization
11. Has a known history of human immunodeficiency virus (HIV) infection (HIV test is required at screening)
12. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (HCV) [defined as HCV ribonucleic acid (RNA) is detected] (hepatitis B and C testing is required at screening only when mandated by local health authority)
13. Has a history of (noninfectious) pneumonitis that required treatment with steroids, or has current pneumonitis
14. 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
15. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
16. 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 randomization
17. Has an active autoimmune disease (with the exception of psoriasis) that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
18. Has received prior systemic chemotherapy in any setting for the treatment of endometrial carcinoma (note: prior chemotherapy administered concurrently with radiation is permitted)
19. Has received prior radiotherapy within 4 weeks prior to randomization (participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis - a 2-week washout is permitted for palliative radiation to non-CNS disease and vaginal brachytherapy)
20. Has received prior hormonal therapy for the treatment of endometrial carcinoma within 1 week of randomization
21. Has received prior therapy with any treatment targeting vascular endothelial growth factor (VEGF)-directed angiogenesis, an anti-programmed cell death (PD)-1, anti-PD ligand (L)1, or anti-PD L2 agent, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137)
22. Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention
23. Has known intolerance to study intervention (or any of the excipients)
24. Has had an allogenic tissue/solid organ transplant
25. 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 randomization

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Progression-free survival (PFS) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR), modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ
2. Overall Survival

Secondary endpoints 6

1. Objective response rate (ORR; either confirmed complete response [CR] or partial response [PR]) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent review (BICR) in mismatch repair proficient (pMMR) participants and in all-comer participants who have measurable disease at study entry
2. Change from baseline in Health-Related Quality-of-Life (HRQoL) global score of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ C30) in pMMR and in all-comer participants
3. Percentage of participants experiencing an adverse event (AE)
4. Percentage of participants experiencing a serious AE (SAE)
5. Percentage of participants experiencing an immune-related AE (irAE)
6. Percentage of participants discontinuing from study treatment due to an AE(s)

Investigational products

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

Test 3

Comparator 2

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

Katrin Katrin Moeschlin

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Katrin Katrin Moeschlin

Third parties 6

Locations

7 EU/EEA countries · 29 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 45 files

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

Application history

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