Randomisierte, doppelblinde, placebokontrollierte, multizentrische Phase-III-Studie zu Niraparib plus Pembrolizumab im Vergleich zu Placebo plus Pembrolizumab als Erhaltungstherapie bei Patienten, deren Erkrankung unter einer platinbasierten Erstlinien-Chemotherapie zur Behandlung des fortgeschrittenen/metastasierenden nicht-kleinzelligen Lungenkarzinoms (NSCLC) Stadium IIIB/IIIC oder IV stabil geblieben ist oder auf die Therapie angesprochen hat (ZEAL-1L).

Product Name: Niraparib
Product Code: GSK3985771
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: NIRAPARIB
CAS Number: 1038915-60-4
Current Sponsor code: GSK3985771
Other descriptive name: niraparib tosylate monohydrate
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: KEYTRUDA
Product Name: Pembrolizumab
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Pembrolizumab
CAS Number: 1374853-91-4
Current Sponsor code: MK-3475
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-

Gender:
Female: yes
Male: yes

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 pembrolizumab plus platinum-based first-line 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 consistent 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/?L
Platelets: =100,000/?L
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
>1.5xULN is acceptable if bilirubin is fractionated and direct
bilirubin <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
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 and/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 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