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

Study Overview
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Brief Summary
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This is a multicenter, randomized, double-blind, placebo-controlled study of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy in participants with advanced or metastatic non-small cell lung cancer (NSCLC) who have achieved stable disease (SD), partial response (PR), or complete response (CR) following completion of standard of care first-line platinum-based induction chemotherapy with pembrolizumab. The primary hypotheses are: participants with confirmed diagnosis of NSCLC could benefit from niraparib plus pembrolizumab versus placebo plus pembrolizumab with respect to Progression-free survival (PFS) and Overall survival (OS).

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Comparing Niraparib Plus Pembrolizumab Versus Placebo Plus Pembrolizumab as Maintenance Therapy in Participants Whose Disease Has Remained Stable or Responded to First-Line Platinum Based Chemotherapy With Pembrolizumab for Stage IIIB/IIIC or IV Non-Small Cell Lung Cancer (ZEAL-1L)

Conditions
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Lung Cancer, Non-Small Cell

Intervention / Treatment
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* Drug: Niraparib
* Drug: Pembrolizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Participant must be >=18 years of age. Has 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). Has advanced (Stage IIIB or Stage IIIC, not amenable to definitive chemoradiotherapy) or metastatic (Stage IV) or metastatic (Stage IV) NSCLC. Has completed at least 4 but no more than 6 cycles of standard of care first-line platinum-based induction chemotherapy with pembrolizumab. Has SD, PR, or CR of the NSCLC per Investigator's assessment after completion of 4 to 6 cycles of standard of care first-line platinum-based induction chemotherapy with pembrolizumab. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Has a life expectancy of at least 12 weeks. Has adequate organ and bone marrow function. Must submit tumor specimens. Must be able to swallow and retain orally administered study treatment. A female is eligible to participate if she is not pregnant or breastfeeding, and must follow contraceptive guidance during the treatment period and 180 days afterwards. A male is eligible to participate if he agrees to contraceptive guidance and refrains from sperm donation during the intervention period and for at least 90 days after the last dose of study treatment. Is able to understand the study procedures and agrees 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: Has mixed small cell lung cancer or sarcomatoid variant NSCLC. Has received prior Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor(s) in prior lines of treatment. Has systolic blood pressure (BP) >140 millimeters of mercury (mmHg) or diastolic BP >90 mmHg. Has any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels. Has leptomeningeal disease, carcinomatous meningitis, symptomatic brain metastases, or radiographic signs of CNS hemorrhage. Has received colony-stimulating factors (granulocyte macrophage colony-stimulating factor or recombinant erythropoietin) within 4 weeks prior to the first dose of study treatment. Has an active or previously documented autoimmune or inflammatory disorder. Is receiving chronic systemic steroids (prednisone >20 mg per day) other than intermittent use of bronchodilators, inhaled steroids, or local steroid. Has other active concomitant malignancy that warrants systemic, biologic, or hormonal therapy. 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. Has a known history of Myelodysplastic syndrome (MDS) or Acute myeloid leukemia (AML). Has a known history of active tuberculosis. Has 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter, randomized, double-blind, placebo-controlled study.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants receiving niraparib plus pembrolizumab<br>Eligible participants will receive niraparib along with pembrolizumab. | Drug: Niraparib<br>* Niraparib will be administered<br>Drug: Pembrolizumab<br>* Pembrolizumab will be administered<br>|
| Placebo Comparator: Participants receiving placebo plus pembrolizumab<br>Eligible participants will receive matching placebo along with pembrolizumab. | Drug: Pembrolizumab<br>* Pembrolizumab will be administered<br>Drug: Placebo<br>* Matching placebo will be administered<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 in overall population | PFS is defined as the time from the date of randomization to the date of first radiographic progression as determined by BICR or death from any cause in the absence of progression, whichever occurs first. | Up to approximately 3 years | 
| Overall survival (OS) in overall population | OS is defined as the time from randomization to the date of death due to any cause. | Up to approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS assessed by BICR using RECIST v 1.1 in non-squamous histology (NSQ) population | PFS is defined as the time from the date of randomization to the date of first radiographic progression as determined by BICR or death from any cause in the absence of progression, whichever occurs first | Up to approximately 3 years | 
| PFS assessed by BICR using RECIST v 1.1 in complete and partial response (CR/PR) population | PFS is defined as the time from the date of randomization to the date of first radiographic progression as determined by BICR or death from any cause in the absence of progression, whichever occurs first | Up to approximately 3 years | 
| OS in NSQ population | OS is defined as the time from randomization to the date of death due to any cause. | Up to approximately 5 years | 
| OS in CR/PR population | OS is defined as the time from randomization to the date of death due to any cause | Up to approximately 5 years | 
| Time to progression (TTP) | TTP in the Central nervous system (CNS) 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 response assessment in neuro-oncology brain metastases (RANO-BM) criteria. | Up to approximately 3 years | 
| PFS by investigator assessment using RECIST v1.1 | PFS is defined as the time from the date of randomization to the date of first radiographic progression as determined by the Investigator using RECIST v1.1 or death from any cause in the absence of progression, whichever occurs first. | Up to approximately 3 years | 
| CNS PFS as assessed by BICR using RANO-BM | PFS is defined as the time from the date of randomization to the date of first radiographic progression as determined by BICR using RANO-BM criteria. | Up to approximately 3 years | 
| PFS as assessed by BICR using RECIST v1.1 by programmed cell death-ligand 1 (PD-L1) status | PFS is defined as the time from the date of randomization to the date of first radiographic progression as determined by BICR using RECIST v1.1 or death from any cause in the absence of progression, whichever occurs first. PFS will be assessed by PD-L1 status (PD-L1 tumor cells [TCs] less than [<]1% and not evaluable (NE) versus more than or equal to [>=]1%). | Up to approximately 3 years | 
| OS by PD-L1 status | OS is defined as the time from randomization to the date of death due to any cause. OS will be assessed by PD-L1 status (PD-L1-TCs <1% and NE versus >=1%). | Up to approximately 5 years | 
| Time to Deterioration (TTD) in Lung Symptoms | TTD is defined as the time from randomization to meaningful deterioration as measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 13-item lung cancer-specific module (EORTC QLQ-LC13) questionnaire. | Up to approximately 3 years | 
| Change from Baseline in Health-related quality of life (HRQoL) and symptoms by EORTC QLQ-C30-item Core module (EORTC QLQ-C30) (Scores on a scale) | EORTC QLQ-C30 is a validated questionnaire to assess overall health-related quality of life in participants with cancer. | Baseline, Day 1 in Cycles 1, 2, 3, 4, 5 (Each cycle is of 21 Days); thereafter every 2 cycles until 90 days after last treatment dose (up to approximately 3 years) | 
| Change from Baseline in HRQoL and symptoms by EORTC QLQ-LC13 (Scores on a scale) | The EORTC QLQ-LC13 is a clinically valid and useful tool for assessing disease- and treatment-specific symptoms in lung cancer participants. | Baseline, Day 1 in Cycles 1, 2, 3, 4, 5 (Each cycle is of 21 Days); thereafter every 2 cycles until 90 days after last treatment dose (up to approximately 3 years) | 
| Number of participants with adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs) | AEs, SAEs and AESIs will be collected. | Up to approximately 3 years | 
| Plasma concentrations of niraparib | Blood samples will be collected to assess the plasma concentrations of niraparib. | Up to approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Niraparib, Pembrolizumab, Maintenance therapy, Chemotherapy, Platinum-based