Placebo-controlled Study Comparing Niraparib Plus Pembrolizumab Versus Placebo Plus Pembrolizumab as Maintenance Therapy in Participants With Advanced/Metastatic Non-small Cell Lung Cancer (ZEAL-1L)

• ClinicalTrials.gov Identifier: NCT04475939
• Recruitment Status: Active, not recruiting
• First Posted: July 17, 2020
• Last Update Posted: February 5, 2024
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Tracking Information

• First Submitted Date: July 14, 2020
• First Posted Date: July 17, 2020
• Last Update Posted Date: February 5, 2024
• Actual Study Start Date: October 26, 2020
• Estimated Primary Completion Date: December 20, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 8, 2023)

• 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 [ Time Frame: Up to approximately 3 years ]
  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.
• Overall survival (OS) in overall population [ Time Frame: Up to approximately 5 years ]
  OS is defined as the time from randomization to the date of death due to any cause.

Original Primary Outcome Measures (submitted: July 14, 2020)

• Progression-free survival (PFS) by BICR using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 [ Time Frame: Up to approximately 3 years ]
  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
• Overall survival (OS) [ Time Frame: Up to approximately 5 years ]
  OS is defined as the time from randomization to the date of death due to any cause.

Current Secondary Outcome Measures (submitted: March 8, 2023)

• PFS assessed by BICR using RECIST v 1.1 in non-squamous histology (NSQ) population [ Time Frame: Up to approximately 3 years ]
  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
• PFS assessed by BICR using RECIST v 1.1 in complete and partial response (CR/PR) population [ Time Frame: Up to approximately 3 years ]
  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
• OS in NSQ population [ Time Frame: Up to approximately 5 years ]
  OS is defined as the time from randomization to the date of death due to any cause.
• OS in CR/PR population [ Time Frame: Up to approximately 5 years ]
  OS is defined as the time from randomization to the date of death due to any cause
• Time to progression (TTP) [ Time Frame: Up to approximately 3 years ]
  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.
• PFS by investigator assessment using RECIST v1.1 [ Time Frame: Up to approximately 3 years ]
  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.
• CNS PFS as assessed by BICR using RANO-BM [ Time Frame: Up to approximately 3 years ]
  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.
• PFS as assessed by BICR using RECIST v1.1 by programmed cell death-ligand 1 (PD-L1) status [ Time Frame: Up to approximately 3 years ]
  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%).
• OS by PD-L1 status [ Time Frame: Up to approximately 5 years ]
  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%).
• Time to Deterioration (TTD) in Lung Symptoms [ Time Frame: Up to approximately 3 years ]
  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.
• 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) [ Time Frame: 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) ]
  EORTC QLQ-C30 is a validated questionnaire to assess overall health-related quality of life in participants with cancer.
• Change from Baseline in HRQoL and symptoms by EORTC QLQ-LC13 (Scores on a scale) [ Time Frame: 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) ]
  The EORTC QLQ-LC13 is a clinically valid and useful tool for assessing disease- and treatment-specific symptoms in lung cancer participants.
• Number of participants with adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs) [ Time Frame: Up to approximately 3 years ]
  AEs, SAEs and AESIs will be collected.
• Plasma concentrations of niraparib [ Time Frame: Up to approximately 3 years ]
  Blood samples will be collected to assess the plasma concentrations of niraparib.

Original Secondary Outcome Measures (submitted: July 14, 2020)

• Time to progression (TTP) [ Time Frame: Up to approximately 3 years ]
  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.
• PFS by investigator assessment [ Time Frame: Up to approximately 3 years ]
  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.
• PFS by programmed cell death-ligand 1 (PD-L1) status [ Time Frame: Up to approximately 3 years ]
  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% versus more than or equal to [>=]1%).
• OS by PD-L1 status [ Time Frame: Up to approximately 5 years ]
  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% versus >=1%).
• Time to Deterioration (TTD) in Lung Symptoms [ Time Frame: Up to approximately 3 years ]
  TTD is defined as the time from randomization to meaningful deterioration on a composite endpoint of dyspnea, chest pain, and cough on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 13-item lung cancer-specific module (EORTC QLQ-LC13).
• Change from Baseline in Health-related quality of life (HRQoL) and symptoms by EORTC 30-item Core module (EORTC QLQ-C30) (Scores on a scale) [ Time Frame: 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) ]
  EORTC QLQ-C30 is a validated questionnaire to assess overall health-related quality of life in participants with cancer and contains 30 questions including multi-item scales and single item measures. These include five functional scales (physical, role, emotional, cognitive and social), three symptom scales (fatigue, nausea/vomiting, and pain), a global health status/quality of life scale (GHS/QOL), and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). The QLQ-C30 employs a week recall period for all items and a 4-point scale for the functional and symptom scales/items with response categories "Not at all", "A little", "Quite a bit" and "Very much". The two items assessing GHS/QOL utilize a 7-point scale ranging from 1 ("Very Poor") to 7 ("Excellent"). Scores are averaged, and transformed to a 0-100 scale. A higher score on functional scales represents better function, and on symptom scales represents more severe symptoms.
• Change from Baseline in HRQoL and symptoms by EORTC QLQ-LC13 (Scores on a scale) [ Time Frame: 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) ]
  The EORTC QLQ-LC13 is a clinically valid and useful tool for assessing disease- and treatment-specific symptoms in lung cancer participants. It is a lung cancer-specific questionnaire module designed to supplement the EORTC QLQ-C30. The measures in the lung cancer questionnaire module assess both lung cancer-associated symptoms, such as coughing, shortness of breath (dyspnea), hemoptysis, and pain, as well as side effects from conventional chemo- and radiotherapy, such as hair loss, neuropathy, sore mouth, and dysphagia.
• Number of participants with adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs) [ Time Frame: Up to approximately 3 years ]
  An AE is any untoward medical occurrence in a clinical study participant temporally associated with the use of study treatment whether or not related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose; results in death or is life-threatening or requires inpatient hospitalization or prolongation of existing hospitalization or results in persistent or significant disability or incapacity or is a congenital anomaly or birth defect or any other situation that require medical or scientific judgment. Selected non-serious AEs and SAEs are also known as AESI. Non-serious AEs, SAEs and AESIs will be assessed.
• Number of participants discontinuing study treatment due to AEs [ Time Frame: Up to approximately 3 years ]
  Number of participants discontinuing the treatment due to AEs will be assessed.
• Number of participants with niraparib/placebo and pembrolizumab dose interruptions due to AEs [ Time Frame: Up to approximately 3 years ]
  Number of participants with dose interruptions due to AEs will be assessed.
• Number of participants with dose reductions due to AEs [ Time Frame: Up to approximately 3 years ]
  Number of participants with dose reductions due to AEs will be assessed.
• Number of participants with clinically significant changes in hematology parameters [ Time Frame: Baseline and until 90 days after last treatment dose (up to approximately 3 years) ]
  Blood samples will be collected for the assessment of hematology parameters.
• Number of participants with clinically significant changes in clinical chemistry parameters [ Time Frame: Baseline and until 90 days after last treatment dose (up to approximately 3 years) ]
  Blood samples will be collected for the assessment of chemistry parameters.
• Number of participants with abnormal urine parameters [ Time Frame: At Baseline ]
  Urine samples will be collected at indicated time points for the assessment of specific gravity, occult blood, glucose, ketones, protein, nitrite, leukocyte esterase, bilirubin, urobilinogen in urine.
• Number of participants with change from baseline in Thyroid Function Parameters [ Time Frame: Baseline and until 90 days after last treatment dose (up to approximately 3 years) ]
  Blood samples will be collected for the assessment of thyroid parameters.
• Apparent total oral clearance of niraparib in plasma after oral administration (CL/F) [ Time Frame: Up to approximately 3 years ]
  Blood samples will be collected at indicated time points for pharmacokinetic (PK) analysis of niraparib when given in combination with pembrolizumab.
• Apparent central (Vc/F) and peripheral (Vp/F) volume of niraparib in plasma after oral administration [ Time Frame: Up to approximately 3 years ]
  Blood samples will be collected at indicated time points for PK analysis of niraparib when given in combination with pembrolizumab.
• Area under the plasma concentration-time curve (AUC) of niraparib [ Time Frame: Up to approximately 3 years ]
  Blood samples will be collected at indicated time points for PK analysis of niraparib when given in combination with pembrolizumab.
• Maximum concentration (Cmax) and Minimum concentration (Cmin) of niraparib at steady state [ Time Frame: Up to approximately 3 years ]
  Blood samples will be collected at indicated time points for PK analysis of niraparib when given in combination with pembrolizumab.
• Dose normalized Cmax and Cmin of niraparib [ Time Frame: Up to approximately 3 years ]
  Blood samples will be collected at indicated time points for PK analysis of niraparib when given in combination with pembrolizumab.
• Average Concentration (Cave) and Dose-normalized Concentration (Cave) of niraparib at steady state [ Time Frame: Up to approximately 3 years ]
  Blood samples will be collected at indicated time points for PK analysis of niraparib when given in combination with pembrolizumab.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Placebo-controlled Study Comparing Niraparib Plus Pembrolizumab Versus Placebo Plus Pembrolizumab as Maintenance Therapy in Participants With Advanced/Metastatic Non-small Cell Lung Cancer
• Official Title: 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)
• Brief Summary: 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Multicenter, randomized, double-blind, placebo-controlled study.

Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:

The participant, Investigator, study staff, and the Sponsor study team will be blinded.

Primary Purpose: Treatment

• Condition: Lung Cancer, Non-Small Cell

Intervention

• Drug: Niraparib
  Niraparib will be administered
• Drug: Pembrolizumab
  Pembrolizumab will be administered
• Drug: Placebo
  Matching placebo will be administered

Study Arms

• Experimental: Participants receiving niraparib plus pembrolizumab
  Eligible participants will receive niraparib along with pembrolizumab.
  Interventions:

  • Drug: Niraparib
  • Drug: Pembrolizumab
• Placebo Comparator: Participants receiving placebo plus pembrolizumab
  Eligible participants will receive matching placebo along with pembrolizumab.
  Interventions:

  • Drug: Pembrolizumab
  • Drug: Placebo

• Publications *: Ramalingam SS, Thara E, Awad MM, Dowlati A, Haque B, Stinchcombe TE, Dy GK, Spigel DR, Lu S, Iyer Singh N, Tang Y, Teslenko I, Iannotti N. JASPER: Phase 2 trial of first-line niraparib plus pembrolizumab in patients with advanced non-small cell lung cancer. Cancer. 2022 Jan 1;128(1):65-74. doi: 10.1002/cncr.33885. Epub 2021 Sep 3. Erratum In: Cancer. 2023 Dec 15;129(24):3987.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 19, 2023): 666
• Original Estimated Enrollment (submitted: July 14, 2020): 650
• Estimated Study Completion Date: February 19, 2025
• Estimated Primary Completion Date: December 20, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Bulgaria, Chile, Colombia, France, Germany, Greece, Hungary, Ireland, Italy, Korea, Republic of, Mexico, Netherlands, Norway, Peru, Poland, Romania, Russian Federation, Spain, Sweden, Switzerland, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT04475939
• Other Study ID Numbers: 213400
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal. Details on GSK's data sharing criteria can be found at: https://www.gsk.com/en-gb/innovation/trials/data-transparency/
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or terminated asset(s) across all indications.
• Access Criteria: Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension may be granted, when justified, for up to 6 months.
• URL: https://www.gsk.com/en-gb/innovation/trials/data-transparency/

• Current Responsible Party: GlaxoSmithKline
• Original Responsible Party: Same as current
• Current Study Sponsor: GlaxoSmithKline
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

• PRS Account: GlaxoSmithKline
• Verification Date: February 2024