Phase 3 Randomized, Double-Blind Study of Belrestotug and Dostarlimab Versus Pembrolizumab in PD-L1 High Non-Small Cell Lung Cancer
- Trial ID
- 2023-504753-12-00
- Protocol
- 213823
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3 study is to evaluate the **efficacy** of dostarlimab plus belrestotug compared with pembrolizumab plus placebo in participants with PD-L1 high (TC ≥50%) non-small cell lung cancer (NSCLC). This is clinically relevant as it aims to determine the potential superiority of the investigational combination therapy over the current standard treatment, which could lead to improved outcomes for patients with this specific subtype of lung cancer.
Secondary objectives include:
- To further compare the efficacy of dostarlimab plus belrestotug with pembrolizumab plus placebo in participants with PD-L1 high NSCLC.
- To evaluate the safety and tolerability of dostarlimab plus belrestotug compared with pembrolizumab plus placebo in the same patient population.
- To assess disease and treatment-related symptoms and their impact on function and health-related quality of life (QoL).
- To evaluate the immunogenicity of dostarlimab and belrestotug when administered in combination in participants with PD-L1 high NSCLC.
Participants
The clinical trial involves a total of **482 participants** diagnosed with **non-small cell lung cancer (NSCLC)**. The study population includes both male and female subjects, aged 18 years and older, who are not considered part of a vulnerable population. Participants were selected based on their confirmed diagnosis of locally advanced or metastatic NSCLC, with a requirement for a **PD-L1-high (TC ≥ 50%)** tumor status. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Participants are required to have adequate organ function and an **ECOG performance status** score of 0 or 1. The selection criteria ensure that participants have not received prior systemic therapy for their advanced or metastatic NSCLC, although previous neoadjuvant or adjuvant treatments are permissible under certain conditions. The trial aims to evaluate the efficacy of dostarlimab plus belrestotug compared with pembrolizumab plus placebo in this specific patient population.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, and controlled Phase 3 study designed to evaluate the safety and efficacy of belrestotug in combination with **dostarlimab** compared to a placebo in combination with **pembrolizumab** in participants with previously untreated, locally advanced, unresectable, or metastatic PD-L1 selected non-small cell lung cancer (NSCLC). The trial is expected to commence recruitment on August 15, 2024, and is estimated to conclude by September 6, 2029. The study involves multiple visits, starting with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis, and organ function. Participants must have a histologically or cytologically confirmed diagnosis of NSCLC and meet specific PD-L1 expression levels.
Following the screening, eligible participants will be randomized to receive either the investigational combination of belrestotug and dostarlimab or the control combination of placebo and pembrolizumab. The trial will be conducted in a double-blind manner to ensure unbiased results. The treatment period will last up to 1111 days, during which participants will receive the study drugs via **intravenous use**. Regular follow-up visits will be scheduled to monitor the participants' health, assess the efficacy of the treatment, and record any adverse events. These visits will include assessments of progression-free survival (PFS) and overall survival (OS) as primary endpoints, along with secondary endpoints such as objective response rate (ORR) and duration of response (DOR).
The end-of-study visit will occur after the completion of the treatment period or upon early termination. Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or if they choose to withdraw consent. The study will also terminate early for any participant who becomes pregnant or fails to comply with the study protocol. The expected length of participant involvement is approximately three years, with the possibility of extension based on individual response and safety assessments. The trial aims to provide comprehensive data on the efficacy and safety of the investigational treatment regimen in a specific subset of NSCLC patients.
Treatment
The clinical trial involves the administration of **JEMPERLI** (dostarlimab), a **concentrate for solution for infusion**. Dostarlimab is a monoclonal antibody targeting PD-1, used in the treatment of certain cancers. The pharmaceutical form is a solution for infusion, with a concentration of 500 mg per vial. The route of administration is **intravenous use**, and the dosing schedule is determined based on the study protocol, with a maximum treatment period of 1111 days. The product is manufactured by GlaxoSmithKline (Ireland) Limited and is authorized for use in the European Union.
**KEYTRUDA** (pembrolizumab) is used as a comparator treatment in this study. It is also a **concentrate for solution for infusion**, with a concentration of 25 mg/mL. Pembrolizumab is a monoclonal antibody that targets PD-1, similar to dostarlimab, and is used in the treatment of various cancers. The administration is via **intravenous use**, and the dosing schedule aligns with the study protocol, with a maximum treatment period of 1111 days. This product is manufactured by Merck Sharp & Dohme B.V. and is authorized for use in the European Union.
The study also includes a **placebo** group, where participants receive 0.9% Sodium Chloride for Injection. This serves as a control to evaluate the efficacy of the experimental treatments. The placebo is administered in a manner consistent with the active treatments, ensuring blinding and maintaining the integrity of the study design.
Additionally, the trial involves the use of a **human IgG1 kappa monoclonal antibody against TIGIT**, identified by the sponsor product code GSK4428859. This investigational product is provided as a **solution for infusion** and is administered intravenously. The dosing schedule and treatment duration are consistent with the study protocol, with a maximum treatment period of 1111 days. This product is developed by GlaxoSmithKline and is part of the experimental treatment arm in combination with dostarlimab.
Efficacy
The efficacy of the investigational treatment in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** per RECIST 1.1 by Blinded Independent Central Review (BICR), defined as the time from the date of randomization to the date of first documented disease progression or death due to any cause, whichever occurs first, and **Overall Survival (OS)**, defined as the time from the date of randomization to the date of death due to any cause.
Secondary endpoints encompass a range of measures, including **Objective Response Rate (ORR)**, defined as the percentage of participants with a confirmed Complete Response (CR) or Partial Response (PR) per RECIST 1.1 by investigator assessment, and **Molecular Response Rate (MRR)**, defined as the percentage of participants with a molecular response, indicated by a ≥ 50% reduction in circulating tumor DNA (ctDNA) levels relative to baseline. Additional secondary endpoints include PFS per RECIST 1.1 by investigator assessment, **Duration of Response (DOR)**, **Time to First Subsequent Therapy (TFST)**, and the incidence of Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events of Special Interest (AESIs).
Furthermore, the trial will evaluate the Time to Deterioration (TTD) in lung cancer symptoms and physical functioning, as assessed by the NSCLC Symptom Assessment Questionnaire (SAQ) total score and the EORTC QLQ-C30 physical functioning domain, respectively. The occurrence of Anti-Drug Antibodies (ADA) to dostarlimab and belrestotug will also be monitored. These efficacy parameters will be measured and collected at specified timepoints throughout the trial, with data analysis conducted according to the predefined statistical plan.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Is capable of giving signed informed consent as described in Appendix 6 ( Protocol Section 10.6.3), which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
- Is, at the time of signing the ICF, at least 18 years old or the legal age of consent in the jurisdiction in which the study is taking place.
- Has a histologically or cytologically confirmed diagnosis of 1 of the following: a. Locally advanced, unresectable NSCLC (not eligible for curative surgery and/or definitive radiotherapy with or without chemotherapy), or b. Metastatic NSCLC. NOTE: Squamous or nonsquamous histology is permitted. Mixed tumors will be categorized by the predominant cell type; if small cell or neuroendocrine elements are present, the participant is ineligible.
- Has not received prior systemic therapy for their locally advanced or metastatic NSCLC. NOTE: Completion of treatment with cytotoxic chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed if therapy was completed at least 6 months prior to the diagnosis of locally advanced or metastatic disease. Prior treatment with neoadjuvant/adjuvant immunotherapy for resectable disease is permitted if at least 12 months have passed since the last dose of immunotherapy prior to the diagnosis of locally advanced or metastatic disease and no permanent discontinuation of prior immunotherapy treatment due to toxicity.
- Provides a tumor tissue sample obtained at the time of or after the initial diagnosis of locally advanced or metastatic NSCLC. Although a fresh tumor tissue sample obtained during screening is preferred, an archival tumor specimen (collected within 2 years prior to screening*) is acceptable. Tumor tissue must be from a site not previously irradiated. Biopsies obtained prior to the administration of any systemic therapy administered for the treatment of a participant’s tumor (such as neoadjuvant/adjuvant therapy) are not acceptable. Needle or excisional biopsies or resected tissue is required. Cytological specimens such as fine needle aspirates, bone marrow samples, or cell blocks are not acceptable, nor are bone specimens. *NOTE: If multiple specimens are available, the most recent archival tumor specimen should be submitted.
- Has a PD-L1-high (TC ≥ 50%) tumor as determined by the PD-L1 CDx Assay at a central laboratory.
- Has measurable disease (at least 1 target lesion) based on RECIST 1.1, as determined by the investigator. Measurable lesions that have been previously irradiated and have been shown to be progressing following irradiation may be considered as target lesions. NOTE: It is preferable not to have a lymph node as a singular target lesion.
- Has an ECOG PS score of 0 or 1
- Has adequate organ function: System Laboratory Values Hematologic ANC ≥1.5x109/L Hemoglobin ≥9 g/dL Platelets ≥100x109/L Hepatic Total bilirubin ≤1.5x ULN For participants with Gilbert’s Syndrome (only if direct bilirubin ≤35%) ≤3.0x ULN ALT and AST ≤2.5x ULN For participants with liver metastases ≤5x ULN Renal eGFRa ≥30 mL/min Abbreviations: ALT = alanine aminotransferase; ANC = Absolute neutrophil count; AST = aspartate aminotransferase; eGFR = estimated glomerular filtration rate; ULN = upper limit of normal. eGFR to be calculated as individualized eGFR using the CKD-EPI + Mosteller formulas (Protocol Appendix 4).
- If of childbearing potential, female participants must be willing to use contraception. Contraceptive use by female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. • A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies: o Is a WONCBP as defined in Protocol Appendix 1. Or o Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), as described in Appendix 1, during the Intervention Period and for at least 4 months after the last dose of study intervention. Female participant agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this timeframe. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention. o A WOCBP must not be pregnant; this will generally be confirmed via a negative highly sensitive serum pregnancy test within 7 days before the first dose of study intervention. In rare cases where it is suspected that hCG is elevated in the absence of pregnancy (e.g., due to a tumor producing hCG), an ultrasound must be performed to rule out pregnancy. • Additional requirements for pregnancy testing during and after study intervention administration are located in Section 8.3.8. • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk of inclusion of a woman with an early undetected pregnancy.
Exclusion Criteria
- Has NSCLC with a tumor that harbors any of the following molecular alterations: a. EGFR mutations that are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19, exon 20 insertion mutation, and exon 21 [L858R] substitution mutation). All participants with nonsquamous histology must have been tested for EGFR mutation status using a tissue-based test; use of an approved test is strongly encouraged. Participants with squamous histology do not need to be tested for EGFR mutation status. Participants with nonsquamous histology and unknown or indeterminate EGFR status are excluded. b. ALK translocations that are sensitive to available targeted inhibitor therapy. All participants with nonsquamous histology must have been tested for ALK fusion mutation status using a tissue-based test; use of an approved test is strongly encouraged. Participants with squamous histology do not need to be tested for ALK fusion mutation status. Participants with nonsquamous histology and unknown or indeterminate ALK status are excluded. c. Any other known genomic aberrations or oncogenic driver mutations for which an approved targeted therapy is available for first line treatment of locally advanced or metastatic NSCLC.
- Has had surgery within 4 weeks of the first dose of study intervention and has not recovered from AEs (i.e., has any ongoing surgery-related events equal or higher than Grade 1)/complications related to surgery or has received lung radiation therapy of >30 Gy within 6 months of the first dose of study intervention.
- Has received prior therapy with any immune checkpoint inhibitors, including antibodies or drugs targeting PD-(L)1, CTLA-4, TIGIT, or other checkpoint pathways. NOTE: Participants may be enrolled if received neoadjuvant/adjuvant immunotherapy for resectable disease and at least 12 months has passed since last dose of prior immunotherapy to the diagnosis of locally advanced or metastatic disease and no permanent discontinuation of prior immunotherapy treatment due to toxicity.
- Has never smoked, defined as smoking <100 tobacco cigarettes in a lifetime
- Has an invasive malignancy or history of invasive malignancy other than the disease under study within the last 5 years, except as noted below: a. Participants may be enrolled in the study with a history of any other invasive malignancy for which the participant was definitively treated, from which the participant has been disease-free for at least 2 years, and which, in the opinion of the principal investigator and medical monitor, is not expected to affect the evaluation of the effects of the study intervention on the currently targeted malignancy. b. Participants with curatively treated basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, and/or in situ breast cancer may be enrolled in the study.
- Has known brain metastases meeting any of the following criteria: a. Symptomatic b. Untreated (NOTE: asymptomatic brain metastases are exclusionary if untreated) c. Actively progressing d. Any leptomeningeal disease (regardless of symptomatology, treatment status, or stability) NOTE: Participants with non leptomeningeal brain metastases who have received prior therapy for brain metastases and have radiographically stable CNS disease for at least 4 weeks (confirmed by 2 brain scans taken at least 4 weeks apart, with at least 1 scan collected after treatment of brain metastases) may participate, provided they are neurologically stable for at least 2 weeks following treatment for brain metastases (i.e., any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have returned to baseline or resolved) and prior to the first dose of study intervention. Corticosteroids must be discontinued at least 3 days prior to the first dose of study intervention.
- Has autoimmune disease or syndrome (current or history thereof) that required systemic treatment within the past 2 years. Replacement therapies (e.g., insulin, thyroxine, or physiologic doses of corticosteroids for treatment of adrenal or pituitary insufficiency) are not considered systemic treatments and are allowed. NOTE: Participants with controlled T1DM are eligible if the participant otherwise meets entry criteria.
- Has received systemic steroid therapy within 3 days prior to the first dose of study intervention or is receiving any other form of immunosuppressive medication. Replacement therapy is not considered a form of systemic therapy. Note the following: a. Corticosteroid use is allowed as premedication for hypersensitivity reactions (e.g., IV contrast allergies/reactions). b. Use of topical, inhaled, or intranasal corticosteroids, local steroid injection, or steroid eye drops is allowed. c. Participants who receive daily steroid replacement therapy are an exception to this criterion. Daily prednisone at doses of ≤10 mg is an example of replacement therapy and are permitted in this study. Equivalent hydrocortisone doses are also permitted if administered as a replacement therapy.
- Has received any live vaccine within 30 days prior to first dose of study intervention. NOTE: mRNA and adenoviral-based COVID-19 vaccines are considered non-live. Study participants can be vaccinated against COVID-19 using vaccines authorized via the appropriate regulatory mechanisms (e.g., Emergency Use Authorization, Conditional Marketing Authorization, or Marketing Authorization Application). Refer to Protocol Section 6.9 and Appendix 5 (Section 10.5.1.4) for further information regarding COVID 19 vaccination recommendations and data to be collected in the eCRF.
- Has any history of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis.
- Has advanced, symptomatic, or visceral spread and is considered to be at imminent risk of life-threatening complications (including, but not limited to, participants with massive uncontrolled effusions [e.g., pleural, pericardial, peritoneal]).
- Has symptomatic ascites, pleural effusion, or pericardial effusion. A participant who is clinically stable following treatment of these conditions (including therapeutic thoracocentesis, paracentesis, or pericardiocentesis) is eligible if the participant otherwise meets entry criteria.
- Has active inflammatory bowel disease, acute diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, or peritoneal carcinomatosis.
- Has a history or evidence of cardiac abnormalities within the 6 months prior to enrollment, including: a. Serious, uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities including second degree (Type II) or third degree AV block. b. Cardiomyopathy, myocarditis, myocardial infarction, acute coronary syndromes (including angina pectoris), coronary angioplasty, stenting, or bypass grafting. c. Congestive heart failure (Class III or IV) as defined by the New York Heart Association functional classification system (Appendix 8) [NYHA, 1994]. d. Symptomatic pericarditis. NOTE: Participants with troponin and/or NT-proBNP/BNP values ≥2x ULN will require review by a cardiologist or locally appropriate specialist to identify underlying conditions that may meet exclusion criteria or that may require increased monitoring during study participation. In addition, cardiologist or locally appropriate specialist review should be considered for potentially significant ECG abnormalities such as AV block (except for first degree), new cardiac arrhythmias, or frequent PVCs. The sponsor is to be informed regarding these participants.
- Has current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. NOTE: Stable chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria.
- Has any infectious diseases described below: a. A severe infection requiring IV antibiotics or requiring hospitalization for infection or complication of infection or severe pneumonia within 4 weeks prior to randomization. b. Active tuberculosis (i.e., history of exposure or history of positive tuberculosis test, plus presence of clinical symptoms or physical or radiographic findings). c. Has a known HIV infection AND meets at least 1 of the following criteria: i. Has documented evidence of plasma HIV-1 RNA ≥ 50 c/mL within 3 months prior to or at screening. In the 3 to 12 months prior to screening, plasma HIV-1 RNA levels consistently <50 c/mL are required for enrollment; if multiple instances of plasma HIV-1 RNA values ≥ 50 c/mL occurred in the 3 to 12 months prior to screening, the participant is not eligible for enrollment unless, per the investigator’s assessment, the elevations were neither persistent nor associated with antiretroviral resistance; OR ii. Has not had CD4 cell counts measured in the past 12 months (i.e., at least 2 separate measurements taken a minimum of 28 days apart, 1 of which must be conducted at screening); OR iii. Has had any CD4 cell count values ≤ 350 cells/mm3 in the past 12 months; OR iv. Has had 1 or more changes in their combination antiretroviral therapy regimen (except for switches as allowed per details provided in Protocol Appendix 9) or has received an antiretroviral therapy regimen that is inconsistent with locally recommended guidelines during the 3 months prior to screening; OR v. Has a history of HIV-associated non-Hodgkin lymphoma within 5 years prior to screening; OR vi. Has received treatment with an HIV 1 immunotherapeutic vaccine within 90 days of screening. NOTE: Participants with history of CDC Stage 3 disease (also known as AIDS defining disease [CDC, 2014]) are eligible (provided all other applicable criteria are met) if the AIDS-defining disease has been treated and cured or is stable for at least 3 months prior to screening. Cutaneous Karposi’s Sarcoma not requiring systemic therapy is not exclusionary.] d. Tests positive for HCV antibodies and HCV RNA. e. Untreated chronic hepatitis B or chronic HBV inactive carriers with HBV DNA >500 IU/mL (or >2500 copies/mL) at screening. NOTE: See Protocol Appendix 2 for additional information on management of participants with HBV, additional procedures, and dose modification guidelines in case of HBV reactivation.
- Has a history of severe hypersensitivity to mAbs or to any of the excipients in the formulations of the components of the study interventions.
- Has any serious and/or unstable pre-existing medical (aside from malignancy), psychiatric, or other condition that could, in the opinion of the investigator, interfere with the participant’s safety, obtaining informed consent, or compliance with the study procedures.
- Is, at the time of signing the ICF, a regular user (including recreational use) of any illicit drugs or has a recent history (within the last year) of substance abuse (including alcohol) that, in the opinion of the investigator, would interfere with the evaluation of the study intervention or interpretation of safety.
- Is currently participating in or has participated in a study of an investigational therapy within 4 weeks prior to the first dose of study intervention.
- Has a history of allogeneic tissue/stem cell transplant or solid organ transplant.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 15 Aug 2024 | 7 |
 Bulgaria | Not Recruiting | 15 Aug 2024 | 2 |
 Croatia | Not Recruiting | 15 Aug 2024 | 32 |
 Czechia | Not Recruiting | 15 Aug 2024 | 15 |
 Estonia | Not Recruiting | 15 Aug 2024 | 9 |
 Finland | Not Recruiting | 15 Aug 2024 | 2 |
 France | Not Recruiting | 15 Aug 2024 | 4 |
 Germany | Not Recruiting | 15 Aug 2024 | 25 |
 Greece | Not Recruiting | 15 Aug 2024 | 25 |
 Hungary | Not Recruiting | 15 Aug 2024 | 32 |
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 |
|---|---|---|---|---|---|---|
0.9% Sodium Chloride for Injection | Placebo | N/A | — | — | — | N/A |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 00 | 1111 | PRD4323105 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion. | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 00 | 1111 | PRD12081132 |
JEMPERLI 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 00 | 1111 | PRD8877508 |