Study of Pembrolizumab With Concurrent Chemoradiation Therapy Followed by Pembrolizumab With or Without Olaparib in Stage III Non-Small Cell Lung Cancer (NSCLC) (MK-7339-012/KEYLYNK-012)

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

9 Jun 2020 → ongoing

Decision date (initial)

2023-11-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2023-503591-25-00

EudraCT number

2019-003237-41

WHO UTN

U1111-1287-5477

ClinicalTrials.gov

NCT04380636

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

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

1. To compare pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab plus olaparib to concurrent chemoradiation therapy followed by durvalumab with respect to PFS per RECIST 1.1 as assessed by BICR.
2. To compare pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab to concurrent chemoradiation therapy followed by durvalumab with respect to PFS per RECIST 1.1 as assessed by BICR.
3. To compare pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab plus olaparib to concurrent chemoradiation therapy followed by durvalumab with respect to OS.
4. To compare pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab to concurrent chemoradiation therapy followed by durvalumab with respect to OS.

Secondary objectives 6

1. To evaluate the safety and tolerability of pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab plus Olaparib compared to concurrent chemoradiation therapy followed by durvalumab
2. To evaluate the safety and tolerability of pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab compared to concurrent chemoradiation therapy followed by durvalumab.
3. To compare pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab plus Olaparib to concurrent chemoradiation therapy followed by durvalumab with respect to ORR and DOR per RECIST 1.1 as assessed by BICR.
4. To compare pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab to concurrent chemoradiation therapy followed by durvalumab with respect to ORR and DOR per RECIST 1.1 as assessed by BICR.
5. To evaluate the change from baseline (at Cycle 1) and the TTD in global health status/QoL, cough, chest pain, dyspnea, physical functioning, and role functioning following treatment with pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab plus olaparib compared to concurrent chemoradiation therapy followed by durvalumab.
6. To evaluate the change from baseline (at Cycle 1) and the TTD in global health status/QoL, cough, chest pain, dyspnea, physical functioning and role functioning following treatment with pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab compared to concurrent chemoradiation therapy followed by durvalumab.

Conditions and MedDRA coding

Non-small cell lung cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Has pathologically (histologically or cytologically) confirmed diagnosis of non-small cell lung cancer (NSCLC)
2. Has Stage IIIA, IIIB, or IIIC NSCLC by American Joint Committee on Cancer Version 8
3. Is unable to undergo surgery with curative intent for Stage III NSCLC
4. Has no evidence of metastatic disease indicating Stage IV NSCLC
5. Has measurable disease as defined by RECIST 1.1
6. Has not received prior treatment (chemotherapy, targeted therapy or radiotherapy) for Stage III NSCLC; participants who have received neoadjuvant and/or adjuvant therapy for early stage disease are not eligible
7. Has provided a tumor tissue sample (tissue biopsy [core, incisional, or excisional])
8. Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 assessed within 7 days prior to the first administration of study intervention
9. Has a life expectancy of at least 6 months
10. A male participant must agree to use contraception and refrain from donating sperm during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention unless confirmed to be azoospermic (vasectomized or secondary to medical cause). The length of time required to continue contraception for each study intervention is as follows: Olaparib, platinum doublet, and radiotherapy: 90 days
11. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and agrees to use contraception and refrain from donating eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during the treatment period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees to abstain from breastfeeding during the study intervention period and for at least 120 days after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows: Pembrolizumab: 120 days; Olaparib, platinum doublet, and radiotherapy: 180 days
12. Has a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within 24 hours for urine or within 72 hours for serum before the first dose of study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
13. Has had her medical history, menstrual history, and recent sexual activity reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy
14. Has adequate pulmonary function tests
15. Has adequate organ function
16. Has provided written informed consent

Exclusion criteria 30

1. Has small cell lung cancer or a mixed tumor with presence of small cell elements
2. Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or has features suggestive of MDS/AML
3. Has had documented weight loss >10% (from baseline) in the preceding 3 months
4. Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus, mediastinum, or for breast cancer
5. Has received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), or anti- programmed cell death ligand 2 (anti-PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor
6. Has received prior therapy with olaparib or with any other polyadenosine 5'diphosphoribose (polyADP ribose) polymerization (PARP) inhibitor
7. Has had major surgery <4 weeks prior to the first dose of study treatment (except for placement of vascular access)
8. Is expected to require any other form of antineoplastic therapy, while on study
9. Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention; administration of killed vaccines is allowed
10. Has received colony-stimulating factors (e.g., granulocyte colony-stimulating factor [GCSF], granulocyte-macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 28 days prior to the first dose of study treatment
11. Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (e.g. bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study
12. Is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study
13. Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 grams per day, for at least 2 days before, during, and for at least 2 days after administration of pemetrexed
14. Is unable/unwilling to take folic acid, vitamin B12, and dexamethasone during administration of pemetrexed
15. Has received an investigational agent or has used an investigational device within 4 weeks prior to study treatment
16. The presence of uncontrolled, potentially reversible cardiac conditions, as judged by the investigator or has congenital long QT syndrome
17. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention
18. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ (excluding carcinoma-in situ-of the bladder) that have undergone potentially curative therapy
19. Has severe hypersensitivity (≥Grade 3) to study intervention and/or any of its excipients
20. Has an active autoimmune disease that has required systemic treatment in past 2 years
21. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
22. Has an active infection requiring systemic therapy
23. Has a known history of human immunodeficiency virus (HIV) infection
24. Has a known history of Hepatitis B or known active Hepatitis C virus infection
25. Has active tuberculosis (TB; Mycobacterium tuberculosis) and is receiving treatment
26. Has a history or current evidence of any condition, therapy, laboratory abnormality or other circumstance that might confound the results of the study, or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator
27. Is considered a poor medical risk due to a serious, uncontrolled medical disorder or nonmalignant systemic disease in the opinion of the treating investigator
28. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
29. Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption
30. Has had an allogenic tissue/solid organ transplant

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
2. Overall Survival (OS)

Secondary endpoints 16

1. Incidence of Adverse Events (AE)
2. Discontinuation Rate of Study Intervention Due to an AE
3. Objective Response Rate (ORR) Per RECIST 1.1 as assessed by BICR
4. Duration of Response (DOR) Per RECIST 1.1 as assessed by BICR
5. Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Scale Score
6. Change From Baseline in Cough Using the EORTC Quality of Life Questionnaire Lung Cancer Module 13 (QLQ-LC13) Item 1 Score
7. Change From Baseline in Chest Pain Using the EORTC QLQ-LC13 Item 10 Score
8. Change From Baseline in Dyspnea Using the EORTC QLQ-C30 Item 8 Score
9. Change From Baseline in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score
10. Change From Baseline in Role Functioning Using the EORTC QLQ-C30 Items 6-7 Score
11. Time to Deterioration (TTD) in health-related quality of life (HRQoL) Using the EORTC QLQ-C30 Items 29 and 30 Score
12. TTD in Cough Using the EORTC QLQ-LC13 Item 1 Score
13. TTD in Chest Pain Using the EORTC QLQ-LC13 Item 10 Score
14. TTD in Dyspnea Using the EORTC QLQ-C30 Item 8 Score
15. TTD in Physical Functioning Using the EORTC QLQ-C30 Items 1- 5 Score
16. TTD in Role Functioning Using the EORTC QLQ-C30 Items 6-7 Score

Investigational products

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

Test 3

Comparator 2

Placebo 1

Auxiliary 5

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

Andrew Song

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Andrew Song

Third parties 10

Locations

12 EU/EEA countries · 56 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 112 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