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SNCTP000004412 | EUCTR2020-002202-20 | BASEC2021-00599

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).

Data source: BASEC (Imported from 21.06.2021), WHO (Imported from 18.04.2021)
Changed: 03.06.2021
Disease category: Lung Cancer

Brief description of trial (Data source: BASEC)

Bei dieser Erkrankung, in dem oben beschriebenen Krankheitsstadium soll untersucht werden, ob das neue Krebsmedikament Niraparib (GSK3985771) (auch als sogenannter PARP-Hemmer bezeichnet) in Kombination mit Pembroli-zumab, ein bei dieser Erkrankung bereits eingesetztes Krebsmedikament, besser wirkt als Pembrolizumab allein und ob die Kombination dazu beitragen kann, das Leben von Patienten mit einem nicht-kleinzelligen Lungenkarzinom (NSCLC) zu verlängern.
Niraparib gehört zu einer Gruppe von Arzneimitteln, die zur Behandlung von Krebs verwendet werden, den so genannten PARP-Hemmern. PARP-Hemmer blockieren ein Enzym namens Poly-(Adenosin-Diphosphat-Ribose-)Polymerase (PARP). PARP ist in den Körperzellen notwendig um geschädigte DNA (Erbinformation der Zellen) zu reparieren. Wenn dieses Enzym blockiert wird, kann die DNA von Krebszellen nicht repariert werden. Das lässt die Tumorzellen absterben und kahilft so, die Krebserkrankung zu kontrollieren. Das Medikament Niraparib (Zejula®) wird zur Behandlung von Eierstock-, Eileiter- oder primärem Peritonealkrebs (Bauchfells) bei erwachsenen Frauen eingesetzt. Es wird angewendet, wenn der Krebs auf eine vorherige Behandlung mit einer Chemotherapie auf Platin-Basis angesprochen hat.

Pembrolizumab KEYTRUDA®, das andere, bei dieser Studie verwendete Medikament (von Merck, Sharp & Dohme, MSD), ist ein immuntherapeutischer Antikörper, der jedoch bereits von den Regulierungsbehörden in den USA, anderen Ländern und auch in der Schweiz zur Behandlung von Plattenepithelkarzinomen in der Lunge und von anderen Krebsarten
zugelassen ist. Wenn das Protein PD-L1 auf den Krebszellen, das
Angriffsziel des Antikörpers, vorhanden ist, wirkt Pembrolizumab besonders gut. Pembrolizumab gehört zu den neusten Medikamenten, das bei diesen Tumoren zur Behandlung eingesetzt werden kann. Beide Behandlungsgruppen erhalten diese Behandlung.

Health conditions investigated (Data source: BASEC)

Fortgeschrittener oder bereits Ableger bildender (metastasierend) sogenannten nicht-kleinzelligen Lungenkarzinom (NSCLC) / Lungenkrebs. Die Erkrankung ist nach einer Behandlung mit einer sogenannten Chemotherapie und Pembrolizumab stabil oder hat sich gebessert.

Health conditions (Data source: WHO)

Non-small Cell Lung Cancer
MedDRA version: 21.1Level: PTClassification code 10029521Term: Non-small cell lung cancer stage IIIBSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.1Level: PTClassification code 10029522Term: Non-small cell lung cancer stage IVSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps);Therapeutic area: Diseases [C] - Cancer [C04]

Rare disease (Data source: BASEC)

No

Intervention investigated (e.g. drug, therapy or campaign) (Data source: BASEC)

Alle Teilnehmer werden mithilfe eines Computers durch Zufallsauswahl einer Behandlungsgruppe zugeteilt. Weder die Patientin/der Patient noch der Studienarzt oder die Studienmitarbeiter haben hierbei Einfluss auf die Zuteilung in die beiden Gruppen. Diese Zuteilung nennt man Randomisierung und eine Zuteilung in eine der folgenden Behandlungsgruppen ist möglich:

o Niraparib (Tablette 100mg, tägliche Einnahme von 2-3 Tabl. ) und Pembrolizumab 200mg als Infusion alle 3 Wochen
o Placebo (Tabletten, tägliche Einnahme von 2-3 Tabl.) und Pembrolizumab 200mg als Infusion alle 3 Wochen

Die Wahrscheinlichkeit, dass Sie der Gruppe mit der Medikamentenkombination (Gruppe mit Niraparib plus Pembrolizumab) zugeteilt werden, beträgt 50 zu 50.

Das Medikament Pemprolizumab (Keytruda) haben die Patienten bereits erhalten, wenn sie an dieser Studie teilnehmen können, und dieses wird als intravenöse (i.v.) Infusion alle 3 Wochen weiter verabreicht. Das heisst, Pembrolizumab wird mit einer Kanüle oder über einen Schlauch direkt in eine Vene gegeben. Der Begriff „in-travenös“ bedeutet genau gesagt „in eine Vene“. Bei der intravenösen Verabreichung wird ein dünner Plastikschlauch, ein so genannter intravenöser Katheter, in eine Vene eingelegt.

Interventions (Data source: WHO)


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/l milligram(s)/litre
Concentration type: equal
Concentration number: 25-

Criteria for participation in trial (Data source: BASEC)

Es können alle Personen teilnehmen, die an einem fortgeschrittenen oder bereits Ableger bildenden (metastasierend) sogenannten nicht-kleinzelligen Lungenkarzinom (NSCLC) leiden, welches die folgenden Eigenschaften aufweist:
- Es wurde ein fortgeschrittenes NSCLC diagnostiziert und die Erkrankung ist nach einer Behandlung mit einer Chemotherapie und Pembrolizumab stabil oder hat sich gebessert.
- Die Patienten müssen 18 Jahre oder älter sein und ansonsten noch bei ordentlicher sonstiger Gesundheit.
- Die Patienten müssen der Teilnahme an der Studie zustimmen.

Exclusion criteria (Data source: BASEC)

Nicht teilnehmen hingegen dürfen Personen,
- die bereits mit einem PARP-Hemmer behandelt wurden,
- einen zu hohen Blutdruck aufweisen oder
- eine Magen-Darm-Erkrankung haben, die die Aufnahme von Nahrungsmittel und Medikamenten beeinflussen.
- Ebenfalls können Personen nicht teil-nehmen, die eine frühere Krebsbehandlung infolge sehr schweren, toxischen unerwünschten Wirkungen abgebrochen werden musste und/oder diese nur schwerlich behandelt werden konnte oder an einer anderen schweren Erkrankung (eingeschlossen gewisse Tumorerkrankungen, HIV, Lebererkrankungen) leiden oder litten.

Inclusion/Exclusion Criteria (Data source: WHO)

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.
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 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: Participants may be randomized directly after completing the standard of care 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 standard of care 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 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).
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
>1.5xULN 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
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 (minimum of 5 slides; <30 days from the date of sectioning) a
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

Further information on the trial in WHO primary registry

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-002202-20

Further information on the trial from WHO database (ICTRP)

http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2020-002202-20-NL

Further information on trial

Date trial registered

08.10.2020

Incorporation of the first participant

18.12.2020

Recruitment status

Authorised-recruitment may be ongoing or finished

Academic title (Data source: WHO)

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 forStage IIIB/IIIC or IV Non-Small Cell Lung Cancer (ZEAL 1L)

Type of trial (Data source: WHO)

Interventional clinical trial of medicinal product

Design of the trial (Data source: WHO)

Controlled: yes
Randomised: yes
Open: no
Single blind: no
Double blind: yes
Parallel group: no
Cross over: no
Other: no
If controlled, specify comparator, Other Medicinial Product: no
Placebo: yes
Other: no
Number of treatment arms in the trial: 2

Phase (Data source: WHO)

Human pharmacology (Phase I): noTherapeutic exploratory (Phase II): noTherapeutic confirmatory - (Phase III): yesTherapeutic use (Phase IV): no

Primary end point (Data source: WHO)

Main Objective: -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;Secondary Objective: -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 describe the exposure of niraparib when given in combination with pembrolizumab;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.
;Timepoint(s) of evaluation of this end point: Three interim analysis are planned. First being when approximately 241 OS events have occurred (22 months from FPFD) Second IA to occur when 321 events have occurred (29 months from FSFD), final analysis when 401 events have occurred (39 months from FSFD)

Secundary end point (Data source: WHO)

Timepoint(s) of evaluation of this end point: Ongoing throughout trial;Secondary end point(s): To evaluate PFS as assessed by the Investigator using RECIST v1.1. 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.

Contact information (Data source: WHO)

GlaxoSmithkline R&D

Trial results (Data source: WHO)

Results summary

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 forStage IIIB/IIIC or IV Non-Small Cell Lung Cancer (ZEAL 1L)

Link to the results in the primary register

no information available yet

Information on the availability of individual participant data

no information available yet

Trial sites

Trial sites in Switzerland (Data source: BASEC)

Bern, Lausanne

Countries (Data source: WHO)

Argentina, Australia, Belgium, Brazil, Bulgaria, Chile, China, Colombia, Denmark, France, Germany, Greece, Hungary, Italy, Japan, Mexico, Netherlands, Norway, Peru, Romania, Russian Federation, Spain, Sweden, Switzerland, United Kingdom, United States

Contact for further information on the trial

Details of contact in Switzerland (Data source: BASEC)

Prof. Dr. Solange Peters, MD, PhD
+41 21 314 44 62
solange.peters@chuv.ch

Contact for general information (Data source: WHO)

Clinical Trials Help Desk
980 Great West Road
GlaxoSmithKline Research & development Ltd
+44 208 990 4466
GSKClinicalSupportHD@gsk.com

Contact for scientific information (Data source: WHO)

Clinical Trials Help Desk
980 Great West Road
GlaxoSmithKline Research & development Ltd
+44 208 990 4466
GSKClinicalSupportHD@gsk.com

Principal Sponsor/Investigator

Principal sponsor (Data source: WHO)

GlaxoSmithKline Research & Development Ltd.

Authorisation by the ethics committee (Data source: BASEC)

Name of the authorising ethics committee (for multicentre studies only the lead committee)

Commission cantonale d’Éthique de la Recherche sur l’être humain Vaud (CER-VD)

Date of authorisation by the ethics committee

11.05.2021

Further trial identification numbers

Trial identification number of the ethics committee (BASEC-ID) (Data source: BASEC)

2021-00599

Secondary ID (Data source: WHO)

213400
2020-002202-20-GB