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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 or IV Non-Small Cell Lung Cancer - GSK 213400

Studio Clinico

Patologia: Neoplasie del polmone

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: 

Fase di studio: III

Richiesta mandatoria di tessuto: 

Linee di trattamento: Mantenimento

Criteri di inclusione: 

- 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).
- Has advanced (Stage IIIB not amenable to definitive chemoradiotherapy) or metastatic (Stage IV) NSCLC.
- Has completed at least 4 but no more than 6 cycles of platinum-based first-line induction chemotherapy with pembrolizumab.
- Has SD, PR, or CR of the NSCLC after completion of 4 to 6 cycles of pembrolizumab plus platinum-based first line induction chemotherapy.
- 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 180 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.

Criteri di esclusione: 

- 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) and/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 BM, or radiologic 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.

Schema di trattamento: 

Experimental: Participants receiving niraparib plus pembrolizumab
Participants will be administered pembrolizumab at a dose of 200 milligrams (mg) via an intravenous infusion over 30 minutes on Day 1 of each treatment cycle (each cycle of 21 days). Niraparib will be administered orally once a day, continuously throughout the 21-day cycle starting on Cycle 1 (Day 1).

Placebo Comparator: Participants receiving placebo plus pembrolizumab
Participants will be administered pembrolizumab at a dose of 200 mg via an intravenous infusion over 30 minutes on Day 1 of each treatment cycle (each cycle of 21 days). Placebo will be administered orally once a day, continuously throughout the 21-day cycle starting on Cycle 1 (Day 1).

Trattamento sperimentale: 

GSK3985771 (Niraparib)
Pembrolizumab

Trattamento di controllo: 

Pembrolizumab
Placebo

Obiettivi primari dello studio: 

1. 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

2. 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.

Obiettivi secondari dello studio: 

1. 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.

2. 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.

3. 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%).

4. 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%).

5. 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).

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

Note generali: 

Lo studio prevede di attivare altri dodici centri

Data di inizio dell'arruolamento: 01.10.2020

Data di fine dell'arruolamento: 01.02.2022

Centri partecipanti

Nord Italia

IRCCS Ca' Granda Ospedale Maggiore Policlinico
Via Francesco Sforza 35 - 20122 Milano - MI

Riferimento: Dr. Francesco Grossi
Telefono: 0255032556
Email: francesco.grossi@policlinico.mi.it

 

IRCCS Istituto Nazionale dei Tumori
Via Venezian 1 - 20133 Milano - MI

Riferimento: Dr.ssa Marina Garassino
Telefono: 0223903813
Email: marina.garassino@istitutotumori.mi.it

 

A.U.L.S.S. 9 Legnago
Via Gianella 1 - 37045 Legnago - VR
Ospedale Mater Salutis

Riferimento: Dr. Andrea Bonetti
Telefono: 0442622801
Email: usc@aulss9.veneto.it

 

Sud Italia e isole

A.O.S.G. Moscati
Contrada Amoretta - 83100 Avellino - AV

Riferimento: Dr. Cesare Gridelli
Telefono: 0825203573
Email: oncologia-avellino@libero.it

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2020-002202-20

Data di inserimento: 09.03.2021

Promotore

GlaxoSmithKline

CRO

NA

Principal Investigator ITALIA

Fondazione IRCCS - Istituto nazionale dei Tumori, Milano

Riferimento: Dr.ssa Marina Garassino

Telefono: 0223903813

Email: marina.garassino@istitutotumori.mi.it

Localita: Milano

 

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