| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-small Cell Lung Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029521 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIB |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
-To compare PFS as assessed by BICR using RECIST v1.1 of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy in the overall population.
-To compare OS of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy in the overall population. |
|
| E.2.2 | Secondary objectives of the trial |
•To compare PFSasassessedby(BICR)using(RECISTv1.1)ofniraparibplus
pembrolizumab versus placebo plus pembrolizumabasmaintenance
therapy in the non-squamous (NSQ) population •To compare PFS as
assessed by(BICR) using (RECIST v1.1) of niraparib plspembrolizumab
versus placebo plus pembrolizumab as maintenance therapy in best
response to standard of care induction chemotherapy with(CR/PR)
population
•To compare OS of niraparib plus pembrolizumab versus placebo plus
pembrolizumab as maintenance therapy in the NSQ population
•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
-To evaluate and compare the TTP in the CNS as assessed by BICR using RANO-BM criteria
-To evaluate CNS PFS as assessed by BICR using RANO-BM.
-To evaluate PFS as assessed by the Investigator using RECIST v1.1
For more details please refer 15page of Protocolv04 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants will be eligible for study entry if all of the following criteria are met:
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 not amenable to definitive chemoradiotherapy or Stage IIIC) 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).
Note: To support the transition from first-line (1L) induction to first-line maintenance therapy, a transition period that is 6 weeks, in duration, starting from the last dose of 1L induction therapy should occur (up to 7 weeks may be permitted with Sponsor approval). This transition period allows for recovery from chemotherapy-related hematological toxicity before initiating treatment with niraparib/placebo. During this transition period, pembrolizumab administration in the absence of chemotherapy should occur in the cycle immediately following the last cycle of 1L induction therapy (ie, 21 [±3] days after the last cycle of induction). If a transition period with administration of pembrolizumab only is not in accordance with standard prescribing directions and/or a pembrolizumab dose delay is needed that is greater than 3 weeks then the delay must be discussed with the Sponsor and reasons for the delay should be documented in the eCRF.
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
Note: Baseline imaging may be done as part of standard of care first-line induction period so long as imaging is within 28 days of randomization. If baseline imaging falls outside of this 28 day window, then new imaging will be needed (CT [preferred] or MRI scan [if clinically indicated] of the chest and abdomen, and MRI [preferred; CT if MRI not possible] of the brain).
Note: For participants with only non-measurable/non-target disease at the onset of platinum-based induction therapy, a RECIST v1.1 response of non-complete response (CR)/non-progressive disease (PD) is onsistent with SD as an overall response.
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
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 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.
Please see study protocol section 5.1 Inclusion Criteria pp 49-51 for a complete list of Inclusion Criteria. |
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| E.4 | Principal exclusion criteria |
Participants will be excluded from study entry if any of the following criteria are met:
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.
Please see study protocol section 5.2 Exclusion Criteria pp 51-53 for a complete list of Exclusion Criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Compare progression-free survival (PFS) as assessed by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors Version 1.1 of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy. Compare overall survival (OS) of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy. 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.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim analysis (IA) is planned when approximately 404 OS events in
the overall population and approximately 503 PFS events in the overall
population are observed (44 months from FSFD) . This is the primary
analysis for and the interim analysis for OS. The final OS analysis is
planned when approximately 505 OS events are observed in the overall
population (59 months from FSFD). |
|
| E.5.2 | Secondary end point(s) |
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 NSQ population
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
To compare OS of niraparib plus pembrolizumab versus placebo plus
pembrolizumab as maintenance therapy in the NSQ population
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
To evaluate PFS as assessed by the Investigator using RECIST v1.1. v1.1. To
evaluate CNS PFS as assessed by BICR using RANO-BM. Evaluate PFS as assessed by BICR using RECIST v1.1 and OS by programmed cell death ligand (PD-L1) status (PD-L1 tumor cells [TCs] <1% versus ≥1%). 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). 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. To evaluate safety and tolerability in participants treated with niraparib plus pembrolizumab compared to placebo plus pembrolizumab. To evaluate population pharmacokinetics (PK) of niraparib when given in combination with pembrolizumab.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Biomarker analyses of plasma will be done to evaluate ctDNA burden. Plasma & tumor tissue analysis will identify biomarkers to predict sensitivity to niraparib+pembro, to identify other factors that are important for study therapy including not limited to,immunophenotype and HRD, & explore potential mechanisms of action & de novo or treatment emergent resistance. Blood samples (including plasma) & tumor tissue may undergo genetic/genomic, proteomic, metabolomic, & transcriptional analyses.
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|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 99 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Chile |
| Colombia |
| Peru |
| Switzerland |
| Australia |
| Brazil |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Turkey |
| United Kingdom |
| United States |
| Belgium |
| Bulgaria |
| France |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Romania |
| Spain |
| Sweden |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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