Study of Chemoradiotherapy With or Without Pembrolizumab for the Treatment of High-risk, Locally Advanced Cervical Cancer

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

6 Apr 2020 → 26 Jan 2026

Decision date (initial)

2024-07-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2022-501972-25-00

EudraCT number

2019-003152-37

WHO UTN

U1111-1282-6395

ClinicalTrials.gov

NCT04221945

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacogenetic, Therapy

1. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to progression-free survival per RECIST 1.1 as assessed by investigator or by histopathologic confirmation of suspected disease progression (in the absence of radiographic disease progression per RECIST 1.1) as assessed by investigator
2. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to overall survival.

Secondary objectives 14

1. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to progression-free survival per RECIST 1.1 as assessed by blinded independent central review (BICR).
2. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to progression-free survival at 2 years per RECIST 1.1 as assessed by investigator or by histopathologic confirmation of suspected disease progression (in the absence of radiographic disease progression per RECIST 1.1.
3. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to progression-free survival at 2 years per RECIST 1.1 as assessed by blinded independent central review.
4. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to overall survival at 3 years.
5. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to complete response rate at 12 weeks after completion of concurrent chemoradiotherapy per RECIST 1.1 as assessed by investigator in all randomly assigned participants with measurable disease at study entry.
6. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to objective response rate per RECIST 1.1 as assessed by investigator in all randomly assigned participants with measurable disease at study entry.
7. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to complete response rate at 12 weeks after completion of concurrent chemoradiotherapy per RECIST 1.1 as assessed by blinded independent central review in all randomly assigned participants with measurable disease at study entry.
8. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to objective response rate per RECIST 1.1 as assessed by blinded independent central review in all randomly assigned participants with measurable disease at study entry.
9. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to overall survival and progression-free survival per RECIST 1.1 as assessed by investigator or by histopathologic confirmation of suspected disease progression (in the absence of radiographic disease progression per RECIST 1.1), by PD-L1 status (by combined positivity score.
10. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to overall survival and progression-free survival per RECIST 1.1 as assessed by blinded independent central review, by PD-L1 status (by combined positivity score).
11. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to progression-free survival after next-line treatment (progression-free survival 2) following discontinuation of study treatment administration as determined by the investigator according to the local standard of clinical practice.
12. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to change from baseline score in global quality of life and physical function using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) global health status/Quality of Life scale and Physical Function subscale.
13. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to change from baseline score in symptom experience using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (Symptom Score for Cervical Cancer) the EORTC CX24 symptom specific scale (11 items).
14. To evaluate the safety and tolerability of pembrolizumab in combination with concurrent chemoradiotherapy.

Conditions and MedDRA coding

Locally Advanced Cervical Cancer

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 9

1. Has high-risk locally advanced cervical cancer (LACC): The International Federation of Gynecology and Obstetrics (FIGO) 2014 Stage IB2-IIB (with node-positive disease) or FIGO 2014 Stages III-IVA
2. Has histologically-confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix
3. Has not previously received any definitive surgical, radiation, or systemic therapy for cervical cancer, including investigational agents, and is immunotherapy-naïve
4. Female participants must not be pregnant or breastfeeding and agree to use highly effective contraception during the treatment period and for at least 120 days after the last dose of pembrolizumab or placebo and 180 days following the end of chemoradiotherapy and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period
5. Female participants must abstain from breastfeeding during the study intervention period and for at least 120 days after the last dose of pembrolizumab or placebo and 180 days following the end of chemoradiotherapy
6. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days prior to the first dose of study treatment
7. Has provided a tissue sample from a core incisional or excisional biopsy of a tumor lesion
8. Has radiographically evaluable disease, either measurable or non-measurable per RECIST 1.1, as assessed by the local site investigator/radiology
9. Has adequate organ function within 7 days prior to the start of study treatment

Exclusion criteria 23

1. Has excluded subtypes of LACC
2. Has FIGO 2014 Stage IVB disease
3. Has undergone a previous hysterectomy defined as removal of the entire uterus or will have a hysterectomy as part of their initial cervical cancer therapy
4. Has bilateral hydronephrosis, unless at least one side has been stented or resolved by positioning of nephrostomy or considered mild and not clinically significant in the opinion of the investigator
5. Has anatomy or tumor geometry or any other reason or contraindication that cannot be treated with intracavitary brachytherapy or a combination of intracavitary and interstitial brachytherapy
6. Has received a live vaccine within 30 days prior to the first dose of study treatment
7. Has received treatment with systemic immunostimulatory agents, colony stimulating factors, interferons, interleukins and vaccine combinations within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1
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 (e.g, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX-40, CD137)
9. Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization
10. 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
11. Has any contraindication to the use of cisplatin
12. 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 the first dose of study treatment
13. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
14. Has severe hypersensitivity to pembrolizumab and/or any of its excipients
15. Has an active autoimmune disease that has required systemic treatment in past 2 years
16. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
17. Has an active infection requiring systemic therapy
18. Has a known history of Human Immunodeficiency Virus (HIV) infection
19. Has a known history of Hepatitis B or known active Hepatitis C virus infection
20. Has a history or current evidence of any condition, therapy, lab abnormality, or other circumstance that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results, and in the judgment of the investigator or Sponsor, would make the participant inappropriate for entry into this study
21. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
22. Has had an allogenic tissue/solid organ transplant
23. Has evidence of metastatic disease per RECIST 1.1 including lymph nodes above the first lumbar vertebra (L1) cephalad body, in the inguinal region

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by the Investigator
2. Overall Survival (OS)

Secondary endpoints 18

1. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
2. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) at Month 24 as Assessed by the Investigator
3. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) at Month 24 as Assessed by Blinded Independent Central Review (BICR)
4. Overall Survival (OS) at Month 36
5. Complete Response (CR) Rate Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) at Week 12 as Assessed by the Investigator
6. Complete Response (CR) Rate Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) at Week 12 as Assessed by Blinded Independent Central Review (BICR)
7. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by the Investigator
8. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
9. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants as Assessed by the Investigator
10. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants as Assessed by Blinded Independent Central Review (BICR)
11. Overall Survival (OS) in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants as Assessed by the Investigator
12. Overall Survival (OS) in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants as Assessed by Blinded Independent Central Review (BICR)
13. Progression-Free Survival (PFS) After Next-Line Treatment (PFS 2) Following Discontinuation of Study Treatment
14. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status Score
15. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Physical Function Score
16. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Symptom Specific Scale for Cervical Cancer (EORTC QLQ-CX24) Score
17. Number of Participants Who Experience One or More Adverse Events (AEs)
18. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)

Investigational products

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

Test 1

Placebo 1

Auxiliary 1

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

Martina Puglisi, MD, Clinical Director

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Martina Puglisi, MD, Clinical Director

Third parties 9

Locations

12 EU/EEA countries · 45 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 139 files

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

Application history

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