Phase 3 Randomized Study of Niraparib and Pembrolizumab Versus Placebo in Maintenance Therapy for Advanced Non-Small Cell Lung Cancer
- Trial ID
- 2023-508443-40-00
- Protocol
- 213400
Trial statistics
Objectives
The primary objectives of this study are to compare **progression-free survival** (PFS) and **overall survival** (OS) of **niraparib** plus **pembrolizumab** versus placebo plus pembrolizumab as maintenance therapy in the overall population of patients with advanced or metastatic non-small cell lung cancer (NSCLC). These objectives are clinically relevant as they aim to determine the efficacy of the combination therapy in prolonging survival and delaying disease progression, which are critical outcomes in the management of NSCLC.
Secondary objectives include:
- Comparing PFS as assessed by Blinded Independent Central Review (BICR) using RECIST v1.1 in specific subpopulations, such as the non-squamous (NSQ) population and those with complete or partial response to standard induction chemotherapy.
- Comparing OS in the NSQ population and in those with the best response to induction chemotherapy.
- Evaluating and comparing time to progression (TTP) in the central nervous system (CNS) using RANO BM criteria.
- Assessing PFS as evaluated by the Investigator using RECIST v1.1.
- Evaluating CNS PFS using RANO-BM criteria.
- Evaluating PFS and OS by programmed cell death-ligand 1 (PD-L1) status.
- Evaluating and comparing time to deterioration in lung symptoms using the EORTC QLQ LC13.
- Evaluating changes in health-related quality of life (HRQoL) and symptoms using the EORTC QLQ-C30 and LC13.
- Assessing safety and tolerability of the treatment regimens.
- Describing the exposure of niraparib when combined with pembrolizumab.
Participants
The clinical trial involves a total of **281 participants** diagnosed with **Non-Small Cell Lung Cancer (NSCLC)**. The study population includes both male and female subjects, aged 18 years and older, with no specific upper age limit. Participants were selected based on their confirmed diagnosis of advanced or metastatic NSCLC, specifically those who have completed 4 to 6 cycles of first-line platinum-based induction chemotherapy with pembrolizumab. The trial does not include a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The general health status of participants must include adequate organ and bone marrow function, and they must have a life expectancy of at least 12 weeks. Lifestyle considerations such as diet and physical activity are not specified in the trial data. The selection criteria ensure that participants are capable of understanding the study procedures and providing informed consent, and they must not have any ongoing severe toxicity from prior treatments. The trial does not focus on any specific lifestyle habits or dietary restrictions.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy of **niraparib** plus **pembrolizumab** versus placebo plus pembrolizumab as maintenance therapy in participants with **non-small cell lung cancer** (NSCLC) who have shown stability or response to first-line platinum-based chemotherapy with pembrolizumab. The trial aims to assess progression-free survival (PFS) and overall survival (OS) as primary endpoints, with progression evaluated by Blinded Independent Central Review (BICR) using RECIST v1.1 criteria. The study is expected to conclude by October 2025, with recruitment having commenced in January 2021.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, ability to swallow oral medication, and adequate organ function. Following randomization, participants will receive either the investigational treatment or placebo, with regular follow-up visits scheduled to monitor safety, efficacy, and adherence to the treatment protocol. The end-of-study visit will occur after the final dose of study medication, where comprehensive assessments will be conducted to evaluate the overall outcomes of the trial.
The expected duration of participant involvement is up to 36 months, contingent upon individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or disease progression as determined by the investigator. Participants are required to adhere to the study protocol, including the use of effective contraception for the duration of the study and a specified period thereafter, to minimize the risk of pregnancy during the trial.
Treatment
The clinical trial involves the administration of **Niraparib Tosilate Monohydrate**, an experimental medication, in the form of tablets. The pharmaceutical form is a tablet, and the active substance is of chemical origin. The maximum daily dose is 300 mg, with a total maximum dose of 324,000 mg over a treatment period of 36 months. The route of administration is oral, and the medication is provided by GlaxoSmithKline. Participant compliance with the dosing schedule will be monitored throughout the trial.
In addition to the experimental medication, the trial includes the use of **Pembrolizumab**, marketed as KEYTRUDA, which is a concentrate for solution for infusion. This biological product is administered via infusion, with a maximum daily dose of 200 mg and a total maximum dose of 10,400 mg over a 36-month treatment period. The product is supplied by Merck Sharp & Dohme B.V. The commercial secondary packaging will be replaced with a plain carton, and a clinical trial label will be applied to both the drug product vial and the secondary package.
The trial also utilizes **Niraparib Placebo Tablets** as a comparator treatment. These tablets are used to maintain the double-blind nature of the study. The placebo is administered orally, mirroring the administration route of the active Niraparib tablets. The placebo is designed to match the experimental medication in appearance and administration schedule to ensure blinding is maintained.
Efficacy
The efficacy of the clinical trial will be assessed through dual primary endpoints: **Progression-Free Survival (PFS)** and **Overall Survival (OS)** in the overall population. The trial aims to determine if niraparib plus pembrolizumab is superior to placebo plus pembrolizumab for either PFS or OS. Progression will be evaluated by Blinded Independent Central Review (BICR) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Participants who are alive will be censored at the date of last contact.
Secondary efficacy endpoints include PFS and OS in specific subpopulations, such as the non-squamous (NSQ) and complete/partial response (CR/PR) populations, as well as Time to Progression (TTP) in the central nervous system (CNS) based on BICR assessment using RANO-BM criteria. Additional secondary endpoints involve PFS and OS by PD-L1 status, Time to Deterioration (TTD) on a composite endpoint of dyspnea, chest pain, and cough, and changes from baseline in the EORTC QLQ C30 and EORTC QLQ LC13 domains.
Safety will be evaluated through the incidence of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs), along with treatment discontinuations, dose interruptions, and dose reductions due to AEs, SAEs, or AESIs. Changes in ECOG performance status, clinical laboratory results, vital sign measurements, and observations during physical examination will also be monitored. AEs will be coded using the current version of the MedDRA, and their severity will be graded by NCI-CTCAE v5.0.
Pharmacokinetic (PK) analysis will be conducted to evaluate niraparib exposure. Blood samples for niraparib PK will be collected at specified time points for all study participants with sparse PK sampling. An analysis of the exposure-response relationship for niraparib may be conducted if the PK data are deemed appropriate.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- 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.
- Participants must have advanced (Stage IIIB or Stage IIIC, not amenable to definitive chemoradiotherapy [CRT]) or metastatic (Stage IV) NSCLC as defined by the AJCC 8th Edition Staging Manual.
- 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).
- 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.
- Participants must have an ECOG performance status of 0 or 1.
- Participants must have a life expectancy of at least 12 weeks.
- 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 (Appendix 11) 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).
- 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.
- Participants with toxicity from standard of care (SoC) 1L 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.
- Participants must be able to swallow and retain orally administered study treatment.
- A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: • Is not a WOCBP. OR • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, as described in Appendix 3, during the intervention period and for at least 180 days after the last dose of study treatment and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The Investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment. • A WOCBP must have a negative pregnancy test (either a highly sensitive urine or a serum pregnancy test as required by local regulations) within 72 hours before the first dose of study treatment. • If a highly sensitive urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. • Additional requirements for pregnancy testing during and after study treatment are described in Section 6.6.2. • The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. See Appendix 3 for a list of acceptable birth control methods. Information must be captured appropriately within the site’s source documents.
- Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of study treatment: • Refrain from donating sperm plus, either: • Be abstinent from sexual activity as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent or • Must agree to use a male condom (and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak; See Appendix 3)
- Participants must be able to understand the study procedures and agree to participate in the study by providing written informed consent. Participants must be informed that their participation is voluntary. Participants will be required to sign a statement of informed consent to participate in the study.
Exclusion Criteria
- Participants have mixed small cell lung cancer or sarcomatoid variant NSCLC.
- Participants have received prior PARP inhibitor(s) in prior lines of treatment.
- Participants have systolic BP >140 mmHg or diastolic BP >90 mmHg
- Participants have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.
- 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.
- 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.
- 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
- 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.
- 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.
- 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.
- Participants have received live vaccine within 30 days of planned start of study randomization.
- Participants have known hypersensitivity to the components of niraparib, placebo, or pembrolizumab or their formulation excipients.
- 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.
- Participants have other active concomitant malignancy that warrants systemic, biologic, or hormonal therapy.
- 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.
- 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.
- 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.
- 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.
- 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.
- Participants have a known history of MDS or AML
- Participants have a known history of active tuberculosis [Lewinsohn, 2017].
- Participants have 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 29 Jan 2021 | 6 |
 Bulgaria | Not Recruiting | 29 Jan 2021 | 15 |
 France | Not Recruiting | 29 Jan 2021 | 45 |
 Germany | Not Recruiting | 29 Jan 2021 | 50 |
 Greece | Not Recruiting | 29 Jan 2021 | 88 |
 Hungary | Not Recruiting | 29 Jan 2021 | 17 |
 Ireland | Not Recruiting | 29 Jan 2021 | 5 |
 Italy | Not Recruiting | 29 Jan 2021 | 45 |
 The Netherlands | Not Recruiting | 29 Jan 2021 | — |
 Norway | Not Recruiting | 29 Jan 2021 | 9 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Niraparib Placebo Tablets | Placebo | N/A | — | — | — | N/A |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 200 | 36 | PRD4323105 |