Phase 3 Evaluation of Pembrolizumab and Olaparib with Chemoradiation in Unresectable Stage III Non-Small Cell Lung Cancer
- Trial ID
- 2023-503591-25-00
- Protocol
- MK-7339-012
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3 study is to compare the efficacy of **pembrolizumab** with concurrent chemoradiation therapy followed by pembrolizumab plus **olaparib** to concurrent chemoradiation therapy followed by **durvalumab** in terms of progression-free survival (PFS) as assessed by RECIST 1.1 criteria through blinded independent central review (BICR). Additionally, the study aims to compare the same treatment regimens with respect to overall survival (OS). These objectives are clinically relevant as they aim to determine the potential benefits of adding olaparib to pembrolizumab in improving survival outcomes in patients with unresectable, locally advanced, Stage III non-small cell lung cancer (NSCLC).
Secondary objectives include: - Evaluating the safety and tolerability of pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab plus olaparib compared to concurrent chemoradiation therapy followed by durvalumab. - Evaluating the safety and tolerability of pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab compared to concurrent chemoradiation therapy followed by durvalumab. - Comparing the treatment regimens with respect to objective response rate (ORR) and duration of response (DOR) per RECIST 1.1 as assessed by BICR. - Evaluating changes from baseline and time to deterioration (TTD) in global health status/quality of life (QoL), cough, chest pain, dyspnea, physical functioning, and role functioning following treatment with pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab plus olaparib compared to concurrent chemoradiation therapy followed by durvalumab.
Participants
The clinical trial involves a total of **596 participants** diagnosed with **non-small cell lung cancer** (NSCLC). The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on specific inclusion criteria, such as having a pathologically confirmed diagnosis of NSCLC, adequate organ and pulmonary function, and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. The trial population is characterized by individuals who are unable to undergo surgery with curative intent for Stage III NSCLC and have no evidence of metastatic disease. Lifestyle considerations include the requirement for contraception use among participants to prevent pregnancy during the study period. The trial also includes a vulnerable population, ensuring comprehensive representation of the affected demographic. Participants have not received prior treatment for Stage III NSCLC, and those with a history of neoadjuvant or adjuvant therapy for early-stage disease are excluded. The study aims to evaluate the efficacy of pembrolizumab in combination with chemoradiation therapy, with a focus on progression-free survival and overall survival outcomes.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **pembrolizumab** in combination with concurrent chemoradiation therapy, followed by pembrolizumab with or without **olaparib**, compared to concurrent chemoradiation therapy followed by **durvalumab** in participants with unresectable, locally advanced, Stage III non-small cell lung cancer (NSCLC). This is a Phase III, randomized, double-blind, controlled trial. The trial is expected to last until July 2026, with participant recruitment having commenced in May 2020.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as a confirmed diagnosis of NSCLC, adequate organ function, and no prior treatment for Stage III NSCLC. Following the screening, participants will be randomized to receive either the investigational treatment or the control. The trial includes multiple follow-up visits to monitor the participants' health, assess the progression-free survival (PFS) and overall survival (OS), and evaluate any adverse events. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any ongoing health concerns are addressed.
The expected length of participant involvement varies depending on the treatment arm, with a maximum treatment period of up to 61 weeks for those receiving pembrolizumab. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, disease progression, or withdrawal of consent by the participant. The primary endpoints of the trial are PFS and OS, assessed by blinded independent central review (BICR) according to RECIST 1.1 criteria. Secondary endpoints include the incidence of adverse events, objective response rate, and changes in quality of life measures.
Treatment
The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. **PEMETREXED** is provided as a solution for infusion, with a maximum daily dose of 500 mg/m² and a total dose of 1500 mg/m² over a treatment period of 9 weeks. It is administered via intravenous infusion. **CISPLATIN** is also administered as a solution for infusion, with a maximum daily dose of 75 mg/m² and a total dose of 300 mg/m² over 9 weeks, delivered intravenously. **ETOPOSIDE** is given in a similar form and route, with a maximum daily dose of 50 mg/m² and a total dose of 750 mg/m² over 9 weeks. **PACLITAXEL** is administered as a solution for infusion, with a maximum daily dose of 200 mg/m² and a total dose of 470 mg/m² over 9 weeks, also via intravenous infusion. **CARBOPLATIN** is provided as a solution for infusion, with a maximum daily dose of 900 mg and a total dose of 2700 mg over 9 weeks, administered intravenously.
**OLAPARIB** is administered in the form of film-coated tablets, with a maximum daily dose of 600 mg and a total dose of 219,000 mg over a treatment period of 52 weeks. The route of administration is oral. **DURVALUMAB** is provided as a solution for infusion, with a maximum daily dose of 10 mg/kg and a total dose of 260 mg/kg over 52 weeks, administered via intravenous infusion. **PEMBROLIZUMAB**, marketed as KEYTRUDA, is administered as a concentrate for solution for infusion, with a maximum daily dose of 200 mg and a total dose of 4000 mg over 61 weeks, delivered intravenously. **IMFINZI**, containing DURVALUMAB, is also administered as a concentrate for solution for infusion, with the same dosing schedule as DURVALUMAB, via intravenous infusion.
The study also includes a **placebo** for OLAPARIB, referred to as MK-7339, Olaparib Placebo, which is used as a comparator in the trial. The placebo is not associated with any active substance and is used to assess the efficacy of OLAPARIB in the study. Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols.
Efficacy
The efficacy of the clinical trial will be assessed using the primary endpoints of **Progression-Free Survival (PFS)** and **Overall Survival (OS)**. PFS will be evaluated according to the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR). OS will be measured to determine the duration of survival of participants from the start of the trial until death from any cause.
Secondary endpoints include the incidence of adverse events, the discontinuation rate of study intervention due to adverse events, and the Objective Response Rate (ORR) per RECIST 1.1 as assessed by BICR. Additionally, the Duration of Response (DOR) will be evaluated. Patient-reported outcomes will be measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) and the Lung Cancer Module 13 (QLQ-LC13). These will assess changes from baseline in global health status, quality of life, cough, chest pain, dyspnea, physical functioning, and role functioning. Time to deterioration in health-related quality of life and specific symptoms will also be evaluated using these tools.
The schedule for measuring these efficacy parameters will include various timepoints throughout the trial, with assessments conducted at baseline and at regular intervals as specified in the trial protocol. The data collected will be analyzed to compare the efficacy of pembrolizumab in combination with concurrent chemoradiation therapy followed by pembrolizumab with or without olaparib, against concurrent chemoradiation therapy followed by durvalumab in participants with unresectable, locally advanced, Stage III Non-Small Cell Lung Cancer (NSCLC).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Has pathologically (histologically or cytologically) confirmed diagnosis of non-small cell lung cancer (NSCLC)
- Has Stage IIIA, IIIB, or IIIC NSCLC by American Joint Committee on Cancer Version 8
- Is unable to undergo surgery with curative intent for Stage III NSCLC
- Has no evidence of metastatic disease indicating Stage IV NSCLC
- Has measurable disease as defined by RECIST 1.1
- Has not received prior treatment (chemotherapy, targeted therapy or radiotherapy) for Stage III NSCLC; participants who have received neoadjuvant and/or adjuvant therapy for early stage disease are not eligible
- Has provided a tumor tissue sample (tissue biopsy [core, incisional, or excisional])
- Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 assessed within 7 days prior to the first administration of study intervention
- Has a life expectancy of at least 6 months
- A male participant must agree to use contraception and refrain from donating sperm during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention unless confirmed to be azoospermic (vasectomized or secondary to medical cause). The length of time required to continue contraception for each study intervention is as follows: Olaparib, platinum doublet, and radiotherapy: 90 days
- A female participant is eligible to participate if she is not pregnant, not breastfeeding, and agrees to use contraception and refrain from donating eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during the treatment period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees to abstain from breastfeeding during the study intervention period and for at least 120 days after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows: Pembrolizumab: 120 days; Olaparib, platinum doublet, and radiotherapy: 180 days
- Has a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within 24 hours for urine or within 72 hours for serum before the first dose of study intervention. If a urine test cannot be confirmed as negative (e.g., 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
- Has had her medical history, menstrual history, and recent sexual activity reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy
- Has adequate pulmonary function tests
- Has adequate organ function
- Has provided written informed consent
Exclusion Criteria
- Has small cell lung cancer or a mixed tumor with presence of small cell elements
- Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or has features suggestive of MDS/AML
- Has had documented weight loss >10% (from baseline) in the preceding 3 months
- Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus, mediastinum, or for breast cancer
- Has received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), or anti- programmed cell death ligand 2 (anti-PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor
- Has received prior therapy with olaparib or with any other polyadenosine 5'diphosphoribose (polyADP ribose) polymerization (PARP) inhibitor
- Has had major surgery <4 weeks prior to the first dose of study treatment (except for placement of vascular access)
- Is expected to require any other form of antineoplastic therapy, while on study
- Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention; administration of killed vaccines is allowed
- Has received colony-stimulating factors (e.g., granulocyte colony-stimulating factor [GCSF], granulocyte-macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 28 days prior to the first dose of study treatment
- Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (e.g. bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study
- Is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study
- Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 grams per day, for at least 2 days before, during, and for at least 2 days after administration of pemetrexed
- Is unable/unwilling to take folic acid, vitamin B12, and dexamethasone during administration of pemetrexed
- Has received an investigational agent or has used an investigational device within 4 weeks prior to study treatment
- The presence of uncontrolled, potentially reversible cardiac conditions, as judged by the investigator or has congenital long QT syndrome
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention
- Has a known additional malignancy that is progressing or has required active treatment within the past 5 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ (excluding carcinoma-in situ-of the bladder) that have undergone potentially curative therapy
- Has severe hypersensitivity (≥Grade 3) to study intervention and/or any of its excipients
- Has an active autoimmune disease that has required systemic treatment in past 2 years
- Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
- Has an active infection requiring systemic therapy
- Has a known history of human immunodeficiency virus (HIV) infection
- Has a known history of Hepatitis B or known active Hepatitis C virus infection
- Has active tuberculosis (TB; Mycobacterium tuberculosis) and is receiving treatment
- Has a history or current evidence of any condition, therapy, laboratory abnormality or other circumstance that might confound the results of the study, or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator
- Is considered a poor medical risk due to a serious, uncontrolled medical disorder or nonmalignant systemic disease in the opinion of the treating investigator
- Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
- Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption
- Has had an allogenic tissue/solid organ transplant
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 07 May 2020 | 40 |
 Estonia | Not Recruiting | 07 May 2020 | 8 |
 France | Not Recruiting | 07 May 2020 | 29 |
 Germany | Not Recruiting | 07 May 2020 | 39 |
 Hungary | Not Recruiting | 07 May 2020 | 13 |
 Italy | Not Recruiting | 07 May 2020 | 28 |
 Latvia | Not Recruiting | 07 May 2020 | 14 |
 Lithuania | Not Recruiting | 07 May 2020 | 10 |
 Norway | Not Recruiting | 07 May 2020 | 10 |
 Poland | Not Recruiting | 07 May 2020 | 18 |
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 |
|---|---|---|---|---|---|---|
CISPLATIN | Other | — | INTRAVENOUS INFUSION | 75 | 9 | SUB07483MIG |
MK-7339, Olaparib Placebo | Placebo | N/A | — | — | — | N/A |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 10 | 52 | PRD6651400 |
DURVALUMAB | Comparator | — | INTRAVENOUS INFUSION | 10 | 52 | SUB176342 |
PEMETREXED | Other | — | INTRAVENOUS INFUSION | 500 | 9 | SUB09655MIG |
ETOPOSIDE | Other | — | INTRAVENOUS INFUSION | 50 | 9 | SUB07337MIG |
Olaparib | Test | FILM-COATED TABLET | ORAL | 600 | 52 | PRD9414227 |
CARBOPLATIN | Other | — | INTRAVENOUS INFUSION | 900 | 9 | SUB06614MIG |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 200 | 61 | PRD4323105 |
Olaparib | Test | FILM-COATED TABLET | ORAL | 600 | 52 | PRD9414228 |