Phase 2 Study of Chemoimmunotherapy with Pembrolizumab and Olaparib Maintenance in Extensive-Stage Small-Cell Lung Cancer
- Trial ID
- 2024-514666-39-00
- Protocol
- IRST162.14
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2 trial is to evaluate the **efficacy** of chemo-immunotherapy induction followed by maintenance with **pembrolizumab** and **olaparib** in patients with Extensive-Stage Small-Cell Lung Cancer (ES-SCLC) as a first-line treatment. This is assessed in terms of **Progression-free Survival (PFS)** from registration. The clinical relevance of this objective lies in its potential to improve treatment outcomes and extend the duration of disease control in ES-SCLC, a condition known for its aggressive nature and limited treatment options.
Secondary objectives include:
- Evaluating the clinical activity as assessed by the overall objective response rate (ORR) and the immune-related objective response rate (irORR).
- Assessing 6, 12, and 24 months **Progression-free Survival** from registration.
- Evaluating the **Overall Survival (OS)** from registration.
- Determining the safety and tolerability of pembrolizumab in combination with chemotherapy and olaparib.
Participants
The clinical trial focuses on participants diagnosed with **Extensive-Stage Small-Cell Lung Cancer (ES SCLC)**. The study population includes both male and female subjects, aged 18 years and older, who have a cytologically or histologically confirmed diagnosis of ES SCLC. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population. Participants must have a life expectancy of at least 12 weeks and the ability to comply with the study protocol. The trial excludes individuals with prior systemic treatment for ES SCLC, although those who have received prior chemo-radiotherapy for limited-stage SCLC with a treatment-free interval of at least 6 months may be eligible. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a **chemo-immunotherapy** induction followed by maintenance therapy with **pembrolizumab** and **olaparib** in patients with Extensive-Stage Small-Cell Lung Cancer (ES-SCLC). This is a Phase II, randomized, double-blind, controlled trial. The trial aims to assess the primary endpoint of progression-free survival (PFS) from registration, with secondary endpoints including objective response rate (ORR), immune-related ORR, PFS at 6, 12, and 24 months, overall survival (OS), and safety profile. The estimated duration of the trial is from March 27, 2023, to September 1, 2026.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as life expectancy, organ function, and absence of prior systemic treatment for ES-SCLC. Following successful screening, participants will be randomized to receive either the investigational treatment or a control. Study visits will include regular follow-up assessments to monitor treatment efficacy and safety, with specific intervals determined by the study protocol. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement is up to 735 days, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or any other reason deemed appropriate by the investigator. Participants will be closely monitored throughout the trial to ensure adherence to the protocol and to address any adverse events promptly.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Pembrolizumab**, marketed as KEYTRUDA, is a **concentrate for solution for infusion**. It is administered via **intravenous infusion** at a dosage of 200 mg every three weeks, with a maximum treatment period of 735 days. Pembrolizumab is a protein-based therapeutic agent developed by Merck Sharp & Dohme B.V. and is used as part of the chemo-immunotherapy induction phase followed by maintenance therapy in the trial.
**Olaparib** is provided in the form of **film-coated tablets** and is administered orally. The maximum daily dose is 600 mg, with a total maximum dose of 12,600 mg over a treatment period of 651 days. Olaparib is a chemical-based medication developed by Merck & Co. Inc., and it is used in combination with pembrolizumab during the maintenance phase of the trial.
**Cisplatin**, marketed as Cisplatino Sandoz, is a **solution for infusion** administered via infusion. The maximum daily dose is 75 mg/m², with a total maximum dose of 600 mg over a treatment period of 84 days. Cisplatin is a chemical-based agent provided by Sandoz S.P.A. and serves as a standard-of-care therapy in the trial.
**Etoposide**, marketed as ETOPOSIDE TEVA, is provided as an **injection** and administered via infusion. The maximum daily dose is 100 mg/m², with a total maximum dose of 2,400 mg over 84 days. Etoposide is a chemical-based medication developed by TEVA PHARMA B.V. and is used as a comparator treatment in the study.
**Carboplatin**, marketed as CARBOPLATINO TEVA, is also provided as an **injection** and administered via infusion. The maximum daily dose is 750 mg, with a total maximum dose of 3,000 mg over 84 days. Carboplatin is a chemical-based agent from TEVA PHARMA B.V. and is included as part of the standard-of-care therapy in the trial.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to evaluate the efficacy of the chemo-immunotherapy induction followed by maintenance with pembrolizumab and olaparib in patients with extensive-stage small-cell lung cancer (ES-SCLC).
Efficacy
The efficacy of the clinical trial will be assessed primarily through **Progression-free Survival (PFS)**, which is the main objective of the study. This parameter will be measured from the time of registration to the point of disease progression or death from any cause. Secondary endpoints include the **Objective Response Rate (ORR)**, **Immune-related Objective Response Rate (irORR)**, **Progression-free Survival (PFS) at 6, 12, and 24 months**, and **Overall Survival (OS)**. Additionally, the safety profile of the treatment will be evaluated.
The trial involves a translational approach to first-line chemo-immunotherapy followed by maintenance with pembrolizumab and olaparib in patients with Extensive-Stage Small-Cell Lung Cancer (ES-SCLC). The efficacy parameters will be collected and analyzed at specified intervals throughout the study duration, which is estimated to conclude by September 2026. The trial will utilize validated scales and laboratory tests to ensure accurate and reliable data collection. The study aims to provide comprehensive insights into the efficacy of the treatment regimen in improving survival outcomes for patients with ES-SCLC.
Inclusion and Exclusion Criteria
Inclusion Criteria
- The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
- Male/female participants who are at least 18 years of age on the day of signing informed consent
- Cytologically/histologically confirmed diagnosis of SCLC per the Veterans Administration Lung Study Group (VALG) staging system will be enrolled in this study. Patients must have extensive stage (ES) SCLC defined as Stage IV (T any, N any, M 1a/b/c) by the American Joint Committee on Cancer, Eighth Edition
- Possibility of obtaining tissue sample, via a biopsy of the primary tumour or metastatic tumour tissue, within the 6 weeks prior to study entry. An archival biopsy is acceptable as long as there has been no intervening anticancer treatment since the time the biopsy was obtained to enrolment in this clinical study and as long as it was within 6 weeks of study entry. Tissue sample would consist of formalin-fixed, paraffin-embedded tumour tissue blocks, or, from formalin-fixed paraffin-embedded tumor tissue block, at least five re-cut, unstained sections of 5 μM thickness for immunohistochemical analysis and five unstained sections of 10 μM thickness for NGS, presented on slides or cell-block
- No prior systemic treatment for ES-SCLC. Patients who have received prior chemo-radiotherapy for limited-stage SCLC must have been treated with curative intent and experienced a treatmentfree interval of at least 6 months since the last chemotherapy, radiotherapy, or chemoradiotherapy cycle from diagnosis of ES-SCLC
- Patients with thoracic radiotherapy clinically indicated (e.g. mediastinal syndrome) could be enrolled providing they receive radiotherapy not before 15 days since the start of the experimental treatment. Patients who received radiation therapy to the lung fields that is > 30 Gy within 6 months of the first dose of trial treatment, will be excluded
- Presence of target lesions by RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of registration
- Patients with paraneoplastic syndromes can be enrolled if an autoimmune origin can be excluded. Autoimmune origin will be defined according to local practice
- Life expectancy ≥12 weeks
- Capacity to swallow
- Ability to comply with the study protocol, in the investigator's judgment
- Have adequate organ function as defined in the following table (Table 1). Specimens must be collected within 10 days prior to the registration day
- Negative human immunodeficiency virus (HIV) test at screening
- Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening. The HBV DNA test will be performed only for patients who have a positive total HBcAb test
- Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test
- Male participants: Male patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception (see appendix F for acceptable methods) if they are of childbearing potential
- Female participants: A female participant is eligible to participate if she is not pregnant (see Appendix F), not breastfeeding, and at least one of the following conditions applies: a) Not a woman of childbearing potential (WOCBP) as defined in Appendix F OR b) A WOCBP who agrees to follow the contraceptive guidance in Appendix F during the treatment period and for at least 120 days after the last dose of study treatment.
Exclusion Criteria
- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention
- Active or history of autoimmune disease or immune deficiency which has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs), including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: Patients with a history of autoimmune-related hypothyroidism who are on thyroidreplacement hormone are eligible for the study. Patiens with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: - Rash must cover less than 10% of body surface area; - Disease is well controlled at baseline and requires only low-potency topical corticosteroids; - No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months; - Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), druginduced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest IRST162.14 – THOR Pag. 36 of 100 Prot_v.2.0_05.02.24 computerized tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
- Prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease
- Live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist®) are live attenuated vaccines and are not allowed
- Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g. unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome. In case of significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident), acute events must happen not before than 3 months prior to initiation of study treatment
- Major surgical procedure within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
- History of malignancy other than SCLC within 3 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate >90%), such as, adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, Stage I uterine cancer or non-muscle-invasive urothelial carcinoma (Ta – Tis – T1)
- History of (non-infectious) pneumonitis that required steroids or has current pneumonitis
- Active infection requiring systemic therapy
- Known history of active TB (Bacillus Tuberculosis)
- Treatment with investigational therapy within 28 days prior to initiation of study treatment
- Patient who has received prior therapy with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, anti-CTLA-4, anti-OX 40, anti-CD137, anti-CD27
- Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment
- Any previous treatment with a PARP inhibitor, including Olaparib
- Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks
- Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents
- Has severe hypersensitivity (≥Grade 3) to pembrolizumab, olaparib and/or any of their excipients
- History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
- Known allergy or hypersensitivity to carboplatin or etoposide
- History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
- Has had an allogenic tissue/solid organ transplant
- A WOCBP who has a positive urine pregnancy test within 72 hours prior to registration (see Appendix C). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 27 Mar 2023 | 60 |
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 |
|---|---|---|---|---|---|---|
Olaparib | Test | FILM-COATED TABLET | ORAL | 600 | 651 | PRD9414228 |
ETOPOSIDE TEVA 20 mg/ml, concentrato per soluzione per infusione | Other | CONCENTRATO PER SOLUZIONE PER INFUSIONE | INFUSION | 100 | 84 | PRD644794 |
Cisplatino Sandoz 1 mg/ml – Concentrato per soluzione per infusione | Other | CONCENTRATO PER SOLUZIONE PER INFUSIONE | INFUSION | 75 | 84 | PRD773633 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 200 | 735 | PRD4323105 |
Olaparib | Test | FILM-COATED TABLET | ORAL | 600 | 651 | PRD9414227 |
CARBOPLATINO TEVA 10 mg/ml | Other | INJECTION | INFUSION | 750 | 84 | PRD667156 |