Placebo-controlled Study Comparing Niraparib Plus Pembrolizumab Versus Placebo Plus Pembrolizumab as Maintenance Therapy in Participants with Advanced/Metastatic Non-Small Cell Lung Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Glaxosmithkline Research & Development Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

18 Dec 2020 → 24 Mar 2026

Decision date (initial)

2024-02-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-508443-40-00

EudraCT number

2020-002202-20

ClinicalTrials.gov

NCT04475939

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Dual Primary Objectives:
• To compare progression-free survival (PFS) as assessed by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy in the overall population
• To compare overall survival (OS) of niraparib plus pe
mbrolizumab versus placebo plus pembrolizumab as maintenance therapy in the overall population

Secondary objectives 12

1. To compare PFS as assessed by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy in the non-squamous (NSQ) population
2. To compare PFS as assessed by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy in best response to standard of care induction chemotherapy with complete and partial response (CR/PR) population
3. To compare OS of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy in the NSQ population
4. To compare OS of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy in the best response to standard of care induction chemotherapy with CR/PR population
5. To evaluate and compare the time to progression (TTP) in the central nervous system (CNS) as assessed by BICR using Response Assessment in Neuro-Oncology Brain Metastases (RANO BM) criteria
6. To evaluate PFS as assessed by the Investigator using RECIST v1.1
7. To evaluate CNS PFS as assessed by BICR using RANO-BM.
8. To evaluate PFS as assessed by BICR using RECIST v1.1 and OS by programmed cell death-ligand 1 (PD-L1) status (PD-L1 tumor cells [TCs] <1% versus ≥1%)
9. To evaluate and compare time to deterioration in lung symptoms (TTD), defined as time from randomization to meaningful deterioration on a composite endpoint of dyspnea, chest pain, and cough, from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 13 item lung cancer-specific module (EORTC QLQ LC13)
10. To evaluate changes from baseline in health-related quality of life (HRQoL) and symptoms as assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item Core module (EORTC QLQ-C30) and the EORTC QLQ LC13 total and domain scores
11. To evaluate safety and tolerability in participants treated with niraparib plus pembrolizumab compared to placebo plus pembrolizumab
12. To describe the exposure of niraparib when given in combination with pembrolizumab

Conditions and MedDRA coding

Lung Cancer, Non-Small Cell

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Participants must be ≥18 years of age. Note: Participants in Korea are eligible if they are ≥19 years of age at the time informed consent is obtained.
2. Participants must have a histologically or cytologically confirmed diagnosis of NSCLC without known targetable driver alteration (either non-squamous or squamous histology; mixed histology is allowed) for which an approved targeted therapy is available in the 1L induction/maintenance therapy setting.
3. Participants must have advanced (Stage IIIB or Stage IIIC, not amenable to definitive chemoradiotherapy [CRT]) or metastatic (Stage IV) NSCLC as defined by the AJCC 8th Edition Staging Manual.
4. Participants must have completed at least 4 but no more than 6 cycles of standard of care first line platinum-based induction chemotherapy with pembrolizumab (according to standard of care defined by NCCN and/or ESMO Clinical Practice Guidelines for NSCLC).
5. Participants must have SD, PR, or CR of their NSCLC per Investigator’s assessment after completion of 4 to 6 cycles of standard of care first-line platinum-based induction chemotherapy with pembrolizumab.
6. Participants must have an ECOG performance status of 0 or 1.
7. Participants must have a life expectancy of at least 12 weeks.
8. Participants must have adequate organ and bone marrow function defined as: Absolute neutrophil count: ≥1,500/μL Platelets: ≥100,000/μL Hemoglobin: ≥9 g/dL or 5.6 mmol/L CLCr: >30 mL/min as estimated by the Cockcroft Gault equation (Appendix 11) Total bilirubin: ≤1.5×ULN (except in participants with Gilbert’s syndrome. Participants with Gilbert’s syndrome: isolated bilirubin >1.5×ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%) AST and ALT: ≤2.5×ULN (unless liver metastases are present, in which case they must be ≤5×ULN) Note: CBC test should be obtained without transfusion or receipt of colony stimulating factors within 4 weeks prior to obtaining sample. Participants with current active liver or biliary disease are excluded (with the exception of Gilbert’s syndrome or asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease per Investigator assessment).
9. Participants must submit FFPE tumor specimens preferably collected after being diagnosed with metastatic disease and prior to initiating standard of care induction therapy (chemotherapy or radiation) (ie, collected at time of diagnosis of advanced [Stage IIIB/IIIC] or metastatic [Stage 4] NSCLC), from location(s) not irradiated prior to biopsy. If available, a FFPE tissue block should be provided; if not available, freshly cut, unstained slides (<30 days from the date of sectioning) are acceptable.
10. Participants with toxicity from standard of care (SoC) 1L induction therapy must have recovered to a level of organ and bone marrow function as defined by Inclusion Criterion #8 and there is no ongoing toxicity of CTCAE Grade >=3.
11. Participants must be able to swallow and retain orally administered study treatment.
12. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: • Is not a WOCBP. OR • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, as described in Appendix 3, during the intervention period and for at least 180 days after the last dose of study treatment and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The Investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment. • A WOCBP must have a negative pregnancy test (either a highly sensitive urine or a serum pregnancy test as required by local regulations) within 72 hours before the first dose of study treatment. • If a highly sensitive urine test cannot be confirmed as negative (eg, 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. • Additional requirements for pregnancy testing during and after study treatment are described in Section 6.6.2. • The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. See Appendix 3 for a list of acceptable birth control methods. Information must be captured appropriately within the site’s source documents.
13. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of study treatment: • Refrain from donating sperm plus, either: • Be abstinent from sexual activity as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent or • Must agree to use a male condom (and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak; See Appendix 3)
14. Participants must be able to understand the study procedures and agree to participate in the study by providing written informed consent. Participants must be informed that their participation is voluntary. Participants will be required to sign a statement of informed consent to participate in the study.

Exclusion criteria 22

1. Participants have mixed small cell lung cancer or sarcomatoid variant NSCLC.
2. Participants have received prior PARP inhibitor(s) in prior lines of treatment.
3. Participants have systolic BP >140 mmHg or diastolic BP >90 mmHg
4. Participants have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.
5. Participants have leptomeningeal disease, carcinomatous meningitis, symptomatic BM, or radiographic signs of CNS hemorrhage. Note: Participants with asymptomatic BM (ie, off corticosteroids and anticonvulsants for at least 7 days) are permitted.
6. Participants have received colony-stimulating factors (eg, granulocyte macrophage colony-stimulating factor or recombinant erythropoietin) within 4 weeks prior to the first dose of study treatment.
7. Participants have active or previously documented autoimmune or inflammatory disorder, including: a. Active infection b. Known diagnosis of immunodeficiency (including known history of human immunodeficiency, HIV, or infection) or is receiving chronic systemic steroid therapy (eg, >30 days) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment c. Active autoimmune disease that has required systemic treatment in the 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. d. History of organ transplant
8. Participants are receiving chronic systemic steroids (prednisone >20 mg per day). Participants with asthma who require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study.
9. Participants have previously or are currently participating in a treatment study of an investigational agent within 4 weeks of the first dose of standard of care first-line induction therapy preceding the study.
10. Participants have received prior systemic cytotoxic chemotherapy (IV or intraperitoneal), biological therapy (including checkpoint inhibitor), or hormonal therapy for cancer, or received thoracic radiation therapy of >30 Gy within 6 months of the first dose of the start of standard of care first-line induction therapy.
11. Participants have received live vaccine within 30 days of planned start of study randomization.
12. Participants have known hypersensitivity to the components of niraparib, placebo, or pembrolizumab or their formulation excipients.
13. Participants have undergone major surgery within 4 weeks of starting the first dose of study treatment or have not recovered from any effects of any major surgery.
14. Participants have other active concomitant malignancy that warrants systemic, biologic, or hormonal therapy.
15. Participants have any clinically significant concomitant disease or condition (such as transfusion-dependent anemia or thrombocytopenia) that could interfere with, or for which the treatment might interfere with, the conduct of the study or that would, in the opinion of the Investigator, pose an unacceptable risk to the participants in this study.
16. Participants have any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study requirements and/or follow up procedures. Those conditions should be discussed with the participants before study entry.
17. Participants have high medical risk due to a serious, uncontrolled medical disorder; non malignant systemic disease; or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, active uncontrolled coagulopathy, bleeding disorder, or any psychiatric disorder that prohibits obtaining informed consent.
18. Participant is pregnant, breastfeeding, or expecting to conceive children while receiving study treatment and/or for up to 180 days after the last dose of study treatment.
19. Participants have presence of hepatitis B surface antigen or a positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. For potent immunosuppressive agents, participants with presence of hepatitis B core antibody should also be excluded.
20. Participants have a known history of MDS or AML
21. Participants have a known history of active tuberculosis [Lewinsohn, 2017].
22. Participants have current active pneumonitis within 90 days of planned start of the study or a known history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis requiring steroid treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. This study has dual primary efficacy endpoints: PFS and OS in overall population. The study will have met its primary objective if niraparib plus pembrolizumab is superior to placebo plus pembrolizumab for either PFS or OS at the interim or final analyses in overall population. Progression will be assessed by BICR using the RECIST v.1.1 criteria. Participants who are alive will be censored at the date of last contact.

Secondary endpoints 11

1. Key secondary efficacy endpoints: PFS in NSQ population defined as per primary PFS endpoint
2. PFS in CR/PR population defined as per primary PFS endpoint
3. OS in NSQ population defined as per primary OS endpoint
4. OS in the CR/PR population
5. TTP in the CNS, which is defined as the time from the date of randomization until the earliest date of documented PD in the CNS, based on BICR assessment using RANO-BM criteria
6. The following secondary efficacy endpoints will be evaluated: PFS as assessed by the Investigator using RECIST v1.1
7. PFS, per RECIST v1.1 based on BICR, and OS by PD-L1 status (PD L1 TC <1% and NE versus ≥1%)
8. TTD, defined as the time from randomization to meaningful deterioration on a composite endpoint of dyspnea, chest pain, and cough, on the EORTC QLQ LC13
9. Change from baseline in the EORTC QLQ C30 and EORTC QLQ LC13 domains
10. Safety Analysis Safety will be evaluated based on the incidence of AEs, SAEs, and AESIs, treatment discontinuations, dose interruptions, and dose reductions due to AEs, SAEs, or AESIs, changes in ECOG performance status, changes in clinical laboratory results, vital sign measurements, observations during physical examination, and use of concomitant medications. AEs will be coded using the current version of the MedDRA and severity of AEs will be graded by NCI‑CTCAE v5.0
11. PK Analysis (Secondary Endpoint) To evaluate niraparib exposure, blood samples for niraparib pharmacokinetics (PK) will be collected at the time points specified in Table 3 for all study participants with sparse PK sampling. In addition, analysis of the exposure-response relationship for niraparib may be conducted if the PK data are deemed appropriate.

Investigational products

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

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Glaxosmithkline Research & Development Limited

Sponsor organisation

Glaxosmithkline Research & Development Limited

Address

G S K House, 980 Great West Road 980 Great West Road

City

Brentford

Postcode

TW8 9GS

Country

United Kingdom

Scientific contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Public contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Third parties 23

Locations

14 EU/EEA countries · 103 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 173 files

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

Application history

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