Etude : ZEAL-1L / 213400

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Acronyme / Nom
Situation thérapeutique
Cadre réglementaire
Présentation de l'étude
Acronyme / Nom : ZEAL-1L / 213400

Situation thérapeutique : Métastatique ou localement avancé

Traitement : Immunothérapie / Thérapie ciblée

Cadre réglementaire : RIPH1

Dernière MÀJ : 30/11/2021
CIM10 - Localisation(s)
Informations principales
Titre : 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

Spécialité : Organes respiratoires et intrathoraciques
Localisation : C34 - Tumeur maligne des bronches et du poumon
Informations complémentaires
This is a multicenter, randomized, double-blind, placebo-controlled study of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy in participants with Stage IIIB or IV non-small cell lung cancer (NSCLC) (both squamous and non-squamous histology) who have achieved Stable disease (SD), Partial response (PR), or complete response (CR) following completion of platinum-based first-line induction chemotherapy with pembrolizumab. Eligible participants will be randomized to receive niraparib plus pembrolizumab or placebo plus pembrolizumab as maintenance therapy. The study's primary hypotheses are that 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).

- 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).

-To compare PFS as assessed by BICR using RECIST v1.1 of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy
-To compare OS of niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance therapy

-To evaluate and compare the TTP in the CNS as assessed by BICR using RANO-BM criteria
-To evaluate PFS as assessed by the Investigator using RECIST v1.1
-To evaluate PFS as assessed by BICR using RECIST v1.1 and OS by PD-L1 status (PDL1 TCs <1% versus >1%)
-To evaluate and compare TTD, defined as time from randomization to meaningful deterioration on a composite endpoint of
dyspnea, chest pain, and cough, from the EORTC QLQ-LC13
-To evaluate changes from baseline in HRQoL and symptoms as assessed by the 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 PK of niraparib when given in combination with pembrolizumab

Phase : III

Stade : Localement avancé à Métastatique

Informations libres de droit
Critères d'inclusion
Critères de non-inclusion
Informations libres de droit
Critères d'inclusion et de non-inclusion
Critères d'inclusion : 1. Participants must be ≥ 18 years of age.
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).
3. Participants must have advanced (Stage IIIB not amenable to definitive chemoradiotherapy) 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 platinum-based first-line induction chemotherapy with pembrolizumab (according to standard of care defined by NCCN and/or ESMO Clinical Practice Guidelines for NSCLC).
Note: Participants may be randomized directly after completing the induction period or, under the Investigator’s discretion, they may be randomized within 6 weeks of the last dose of chemotherapy. If the 6-week recovery period is used, pembrolizumab, in the absence of chemotherapy, must continue in the cycle immediately following the last cycle of induction and in accordance with standard prescribing directions. Up to 7 weeks recovery from last dose of chemotherapy may be granted upon Sponsor approval.
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.
Note: Baseline imaging may be done as part of 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 CNS).
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
Serum creatinine: <2 × ULN
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 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
9. Participants must submit FFPE tumor specimens preferably collected after being diagnosed with metastatic disease and prior to initiating induction therapy (chemotherapy or radiation) (ie, collected at time of diagnosis of advanced [Stage IIIB] or metastatic [Stage 4] NSCLC), from location(s) not irradiated prior to biopsy. Either tissue block or freshly cut slides (minimum of 5 slides; <30 days from the date of sectioning) are acceptable.
10. Participants with toxicity from induction therapy must have recovered to Grade 1. (A participant with Grade 2 neuropathy or Grade 2 alopecia is an exception to this criterion and may qualify for this study.)
11. Participants must be able to swallow and retain orally administered study treatment.

---Please see study protocol section 5.1 Inclusion Criteria pp 42-44 for a complete list of Inclusion Criteria.---

Critères de non-inclusion : 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 radiologic 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 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 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 44-46 for a complete list of Exclusion Criteria.---
Informations relatives au promoteur
Promoteur :
GlaxoSmithKline GSK
Type de sponsor : Industriel

Coordonnateur :
Centre investigateur
Informations relatives aux investigateurs
Centre investigateur :
Centre Hospitalier Universitaire de Lille - 2 Avenue Oscar Lambret - 59000 LILLE

Investigateur :
Professeur Alexis Cortot

Eric Wasielewski

Statut de l'essai : OUVERT

MAJ : 24/02/2021