Efficacy of Tislelizumab Versus Placebo in Patients with Molecular Residual Disease Post-Curative Therapy: A Randomized Controlled Trial
- Trial ID
- 2023-503316-33-00
- Protocol
- 2023/3720 UMBRELLA
- Sponsor
- Institut Gustave Roussy
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the study is to assess the **efficacy** of **tislelizumab** compared to placebo, as measured by **disease-free survival (DFS)** in patients with a positive status for **molecular residual disease (MRD)** [MRD (+)] between 3 to 4.5 months after the completion of standard curative-intent therapy. This evaluation is clinically relevant as it aims to determine the potential of tislelizumab to improve DFS, which is a critical endpoint in assessing the effectiveness of cancer therapies in preventing disease recurrence.
Secondary objectives include:
- Estimation of DFS in subjects without MRD [MRD (-)] between 3 to 4.5 months after standard therapy.
- Estimation of overall survival (OS) at 12, 24, and 48 months.
- Estimation of the percentage of MRD (+) subjects completing standard therapy.
- Estimation of the elapsed time between MRD detection and relapse detection via imaging.
- Estimation of MRD assessment failure.
- For MRD (+) subjects, estimation of the time to become MRD (-) between 3 to 4.5 months post-therapy.
- Evaluation of the safety and tolerability of tislelizumab according to the NCI-CTCAE version 5.
- Evaluation of Health-Related Quality of Life (HRQoL) using EORTC QLQ-C30 and EuroQol EQ-5D-5.
- Cost-effectiveness analysis.
Participants
The clinical trial involves **patients** with a positive status for molecular residual disease (MRD) 3 to 4.5 months after the completion of standard curative treatment. The study population includes both male and female participants aged 18 years and older. 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 trial population was selected based on their completion of standard curative-intent therapy within the specified timeframe and their ability to comply with study visits and procedures. Participants must have adequate organ function and must not have received prior immunotherapy. The trial includes individuals with specific cancer histologies, such as TNM stage II-III non-small cell lung cancer (NSCLC), stage II-III colorectal cancer, stage I-III pancreatic cancer, and grade 3 limb or trunk wall soft-tissue sarcoma. The sponsor has not provided information on the total number of participants. Participants' lifestyle considerations include the requirement for females of childbearing potential and nonsterile males to use highly effective methods of birth control during the study and for a specified period after the last dose of the trial drug. The trial also involves a vulnerable population, as indicated by the inclusion of individuals with a positive or negative circulating tumor DNA (ctDNA) test result prior to randomization.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **tislelizumab** compared to placebo in patients with a positive status for **molecular residual disease** (MRD) following standard curative-intent therapy. This is a randomized, double-blind, controlled trial with an estimated duration extending until June 2026. The trial will involve participants who have completed standard treatment for a minimum of 3 months and a maximum of 4.5 months prior to enrollment. The primary endpoint is disease-free survival (DFS) for MRD-positive patients, defined as the time from randomization to relapse or death. Secondary endpoints include overall survival (OS) and the incidence of treatment-emergent adverse events (TEAEs).
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and adequate organ function. Following randomization, participants will receive either **tislelizumab** or placebo via intravenous infusion. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and compliance with the study protocol. These visits will include assessments such as imaging studies, laboratory tests, and completion of quality of life questionnaires. The end-of-study visit will mark the conclusion of the participant's involvement, during which final evaluations will be conducted.
The expected length of participant involvement is up to 24 months, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with study procedures. Participants are required to adhere to contraceptive guidelines throughout the study and for a specified period after the last dose of the trial drug. The trial aims to provide comprehensive data on the potential benefits and risks of **tislelizumab** in this patient population, contributing to the understanding of its role in managing MRD-positive cancer patients.
Treatment
The clinical trial involves the administration of **Tislelizumab**, an experimental medication, which is a **solution for infusion**. Tislelizumab is a protein-based therapeutic agent developed by BeiGene, identified by the sponsor product code BGB-A317. The medication is administered intravenously, with a maximum daily dose of 400 mg and a total maximum dose of 3600 mg over a treatment period of up to 24 months. The dosing schedule is designed to ensure optimal therapeutic exposure while monitoring participant compliance through regular assessments and infusion records.
In addition to Tislelizumab, the study utilizes **CHLORURE DE SODIUM FRESENIUS 0.9%**, a **solution for injection** serving as a non-experimental treatment. This sodium chloride solution, produced by Fresenius Kabi France S.A.S., is used as a placebo comparator in the trial. It is administered via intravenous injection or infusion, with a maximum daily dose of 5 mg and a total maximum dose of 120 mg over the same 24-month treatment period. The use of this placebo allows for the assessment of Tislelizumab's efficacy in comparison to standard saline solution, ensuring the integrity of the trial's outcomes.
Efficacy
The efficacy of **Tislelizumab** in the clinical trial will be assessed primarily through the measurement of **disease-free survival (DFS)** in patients with molecular residual disease (MRD) positive status. DFS is defined as the time from randomization to relapse or death, whichever occurs first. The DFS rate will be evaluated at multiple timepoints, specifically at 12, 24, 48, and 60 months. Secondary endpoints include DFS for MRD negative patients, overall survival (OS) defined as the time from randomization to death from any cause at the same timepoints, and the percentage of MRD positive subjects assessed between 3 to 4.5 months after completion of standard curative-intent therapy.
Additional secondary endpoints involve the time from detection of MRD to relapse as documented per RECIST v1.1, the percentage of subjects with MRD assessment failure, and the time from baseline to detection of MRD negative status in subjects initially MRD positive. The incidence and severity of treatment-emergent adverse events (TEAEs), including both non-serious and serious adverse events, will be recorded, with particular attention to TEAEs leading to dose interruptions or discontinuation. Patient-reported outcomes will be collected using the EORTC QLQ-C30 and EuroQol EQ-5D-5L questionnaires at baseline and at months 6, 12, 18, and 24. Economic evaluations will include incremental costs, quality-adjusted life years (QALY), and incremental cost-effectiveness ratio (ICER) expressed in euros per QALY.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18 years,
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1,
- Subjects must have adequate organ function as indicated by the following laboratory values (For MRD+ patients, laboratory results must be obtained within 7 days prior to C1D1): a) Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, haemoglobin ≥90 g/L. Note: Patients must not have required a blood transfusion or growth factor support ≤ 14 days before sample collection. b) International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x upper limit of normal (ULN). c) Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN. d) Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 3 x ULN for patients with Gilbert's syndrome). e) Aspartate and alanine aminotransferase (AST and ALT) ≤ 3 x ULN f)Creatinine clearance ≥30 mL/min for participants with creatinine levels above institutional normal (≥ULN). Creatinine clearance should be calculated per the Cockcroft-Gault formula (or local institutional standard method)
- Subjects with a social security in compliance with the French law relating to biomedical research (Article L.1121-11 of French Public Health Code),
- Subjects should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol,
- Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the trial, and ≥ 120 days after the last dose of the trial drug and have a negative serum pregnancy test ≤ 7 days of the first dose of the trial drug. A barrier contraceptive method (e.g., condom) is also required. A woman is considered of childbearing potential following menarche and until becoming post-menopausal (≥ 12 months of non-therapy-induced amenorrhea) unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral oophorectomy and bilateral salpingectomy with surgery at least 1 month before the first dose of study drug or confirmed by follicle stimulating hormone (FSH) test >40 mIU/mL and estradiol <40 pg/mL (<140 pmol/L).
- Nonsterile males must be willing to use a highly effective method of birth control for the duration of the study and for ≥ 120 days after the last dose of the trial drug. A barrier contraceptive method (e.g., condom) is also required.(...)The following methods are considered as unacceptable methods (non-exhaustive list): periodic abstinence (calendar, symptothermal, post-ovulation methods) and withdrawal (coitus interruptus).
- Completion of surgical and peri-operative treatments as per international guidelines
- Subject must have completed standard curative-intent therapy for minimum 2 months and maximum 5 months and must not have standard treatment at least 2 months before blood sampling for ctDNA analyses
- Patients must not have blood transfusion at least 3 months before blood sampling for ctDNA analyses
- Histology: TNM stage II-III NSCLC, Stage II-III colorectal cancer, stage I-III pancreatic cancer, histologically confirmed high-risk soft tissue sarcoma defined as either (a) an FNCLCC Grade 3 tumor (or an equivalent high-grade tumor by another recognized grading system), or (b) a specific sarcoma subtype associated with a high risk of systemic relapse (and typically not graded under standard sarcoma grading systems), such as, desmoplastic small round cell tumor (DSRCT) , alveolar soft part sarcoma (ASPS), clear cell sarcoma, malignant peripheral nerve sheath tumor (MPNST), retroperitoneal leiomyosarcoma, or epithelioid sarcoma (c) FNCLCC Grade 2 sarcomas with documented high-risk pathological features (e.g., presence of tumor necrosis), considered by the investigator as having aggressive clinical behavior and equivalent to Grade 3. This classification must be justified and documented in the pathology report and/or medical records
- Subjects must have sufficient amount of archived primary tumor material for ctDNA and translational research analyses that will be conducted as defined in the protocol,
- Subjects must have a valid (positive or negative) ctDNA test result prior to randomization,
- Subjects must not have had prior immunotherapy (anti-PD-1 or anti-PD-L1),
- No evidence of disease on imaging
- Subject must not have standard treatment at least 2 months before blood sampling for ctDNA analyses.
Exclusion Criteria
- Participation in another clinical trial with an investigational product during the last 2 to 5 months and while on study treatment
- Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study or within 5 months after the last dose of the study drugs (except anti-COVID-19 vaccines)
- Active or history of autoimmune disease or immune deficiency, with the exception of history of treated autoimmune-related hypothyroidism and Type 1 diabetes mellitus on insulin regimen
- History of idiopathic pulmonary fibrosis (including pneumonitis or interstitial lung disease), drug-induced pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis (history of radiation pneumonitis in the radiation field (fibrosis) is permitted).
- Patients who underwent major surgery within 28 days prior to inclusion or until the surgical wound is fully healed
- Patients with known HIV infection may be eligible provided they are on effective antiretroviral therapy, have controlled HIV infection with undetectable or adequately suppressed viral load, adequate CD4 count, no active or recent opportunistic infection, and no clinically significant drug-drug interaction with study treatment.
- Patients with active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
- Active tuberculosis
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
- Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
- Any condition which in the Investigator’s opinion makes it undesirable for the subject to participate in a clinical trial or which would jeopardize compliance with the protocol,
- Significant cardiovascular disease, such as: • History of myocardial infarction, acute coronary syndromes or coronary angioplasty/stenting/bypass grafting within the past 6 months, o Congestive Heart Failure (CHF) NYHA class III or IV or history of CHF NYHA class III or IV, unless an echocardiogram or multi-gated acquisition scan performed within 3 months day 1 reveals a left ventricular ejection fraction ≥ 55%
- Uncontrolled hypertension defined by systolic pressure > 150 and/or diastolic pressure > 110 mmHg, with or without anti-hypertensive medication. Patients with initial blood pressure elevations are eligible if initiation or adjustment of anti-hypertensive medication lowers blood pressure to meet entry criteria
- History of stroke or transient ischemic attack within 6 months prior to randomization
- Pregnant or breastfeeding women
- Subjects under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.
- Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin−2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment
- Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate and thalidomide) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: o Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids as premedication for hypersensitivity reaction (e.g., CT scan premedication)) are eligible for the study after Principal investigator approval has been obtained o Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study o Patients who received intranasal, inhaled, topical or local steroid injections (e.g., intra articular injection)
- Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > Grade 1.
- Known intolerance the study drugs or any of their excipients
- Patients with prior allogeneic stem cell or solid organ transplantation
- Patients with confirmed EGFR exon 19 deletions or exon 21 L858R substitutions are excluded from the study, due to the potential benefit from adjuvant osimertinib treatment, which represents a standard of care for these genetic profiles in non-small cell lung cancer (NSCLC). Similarly, patients with confirmed ALK rearrangements are also excluded, as adjuvant alectinib is recommended as a standard treatment for this molecular subtype
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 30 Jun 2024 | 717 |
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 |
|---|---|---|---|---|---|---|
Tislelizumab | Test | SOLUTION FOR INFUSION | INTRAVENOUS | 400 | 24 | PRD5423108 |
CHLORURE DE SODIUM FRESENIUS 0,9 %, solution injectable | Placebo | SOLUTION INJECTABLE | IV INJECTION, IV INFUSION | 5 | 24 | PRD4961336 |