Evaluation of Blinatumomab, Isatuximab, and Ponatinib in Frontline Therapy for Adults with Acute Lymphoblastic Leukemia and T-Lymphoblastic Lymphoma
- Trial ID
- 2024-511437-35-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the GRAALL 2024 study is to enhance the clinical outcomes of younger adults with various subtypes of **acute lymphoblastic leukemia** (ALL) through the early incorporation of novel immunotherapeutic agents and refined indications for allogeneic hematopoietic stem cell transplantation (HSCT). Specifically, for high-risk (HR) patients with Philadelphia chromosome-negative B-cell precursor ALL (BCP-ALL), the study aims to improve outcomes by integrating blinatumomab and optimizing HSCT indications. For standard-risk (SR) patients with the same subtype, the focus is on the frontline incorporation of blinatumomab. In patients with T-cell ALL (T-ALL), the study seeks to improve outcomes through the early use of isatuximab. Additionally, for patients with Philadelphia chromosome-positive B-ALL, the study evaluates the early use of blinatumomab and ponatinib, alongside refined HSCT indications. These objectives are clinically relevant as they aim to improve survival rates and treatment efficacy in a population with historically poor outcomes.
Secondary objectives include evaluating the safety profiles of the treatments, assessing patient-related outcomes (PROs) and quality of life (QoL), and determining the cost-effectiveness and utility of the therapeutic strategies employed in the study. These secondary objectives are crucial for understanding the broader impact of the treatments beyond clinical efficacy, including their safety, patient satisfaction, and economic viability.
Participants
The clinical trial involves a total of **100 participants** who are aged between **18 to 65 years**. The study population includes both male and female subjects who have been newly diagnosed with previously untreated **acute lymphoblastic leukemia (ALL)** or T-cell lymphoblastic lymphoma (T-LL). Participants were selected based on specific criteria, including their diagnosis according to WHO standards and their eligibility for allogeneic hematopoietic stem cell transplantation (HSCT) if applicable. The trial does not include a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. Lifestyle considerations such as diet and physical activity are not specified, but participants must be willing to comply with the study's protocol requirements, including scheduled visits and treatment regimens. The trial does not specify any particular lifestyle habits or restrictions beyond the use of effective contraception for participants of child-bearing potential. The sponsor has not provided additional information regarding other lifestyle factors or health status beyond the inclusion criteria.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of new immunotherapeutic agents and allogeneic hematopoietic stem cell transplantation (HSCT) in the frontline therapy of adults with **acute lymphoblastic leukemia** (ALL). This trial is structured as a randomized, controlled study with a double-blind design to ensure unbiased results. The trial is expected to commence on October 15, 2024, and conclude by October 14, 2034, with a total duration of approximately 10 years. Participants will be involved in the study for a maximum treatment period of 140 days, depending on the cohort and treatment arm they are assigned to.
The study will include several key visits: an initial screening visit to confirm eligibility, multiple follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess overall outcomes. The inclusion visit will involve comprehensive assessments, including immunophenotypic, cytogenetic, and molecular evaluations to classify patients into specific cohorts such as Ph-positive ALL, Ph-negative BCP-ALL, or T-ALL. Follow-up visits will be scheduled at regular intervals to evaluate primary endpoints such as overall survival (OS) and event-free survival (EFS), as well as secondary endpoints like hematological complete remission (CR) rate and minimal residual disease (MRD) response.
Participants are expected to adhere to the study protocol, including scheduled visits and treatment regimens. Conditions that may lead to early termination from the study include non-compliance with the protocol, adverse events, or withdrawal of consent. The trial aims to improve outcomes for younger adults with high-risk Ph-negative BCP-ALL, standard-risk Ph-negative BCP-ALL, T-ALL, and Ph-positive B-ALL through the incorporation of agents such as **blinatumomab**, **ponatinib**, and **isatuximab**. The study will also refine indications for allogeneic HSCT, aiming to enhance survival rates and quality of life for participants.
Treatment
The clinical trial involves the administration of **BLINCYTO**, which contains the active substance **blinatumomab**. This medication is provided as a powder for concentrate and solution for infusion, specifically formulated for intravenous administration. The maximum daily dose is 28 micrograms, with a total maximum dose of 3.92 milligrams over a treatment period of up to 140 days. The pharmaceutical form is a solution for infusion, and the medication is produced by Amgen Europe B.V. **Blinatumomab** is a recombinant antibody derivative targeting human CD19 and CD3, classified under the ATC code L01FX07.
**Iclusig**, containing the active substance **ponatinib**, is administered in the form of film-coated tablets. The route of administration is oral, with a maximum daily dose of 45 milligrams and a total maximum dose of 14.7 grams over a 30-day treatment period. The tablets are manufactured by Incyte Biosciences Distribution B.V. **Ponatinib** is a chemical compound, and its ATC classification is L01EA05.
**SARCLISA**, with the active substance **isatuximab**, is provided as a concentrate for solution for infusion. This medication is administered intravenously, with a maximum daily dose of 10 milligrams per kilogram and a total maximum dose of 300 milligrams per kilogram over a 30-day treatment period. The solution for infusion is produced by Sanofi Winthrop Industrie. **Isatuximab** is a humanized monoclonal antibody against CD38, classified under the ATC code L01FC02.
Throughout the trial, participant compliance with the dosing schedules will be monitored to ensure adherence to the treatment protocols. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided.
Efficacy
The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoints include overall survival (OS) for high-risk (HR) and standard-risk (SR) patients in the GRAALL-2024/B cohort, event-free survival (EFS) for the GRAALL-2024/T cohort, and OS for the GRAAPH-2024 cohort. Secondary endpoints encompass a range of measures such as OS and relapse-free survival (RFS) in the T-ALL cohorts, EFS and RFS in the Ph-negative/positive ALL cohorts, hematological complete remission (CR) rate, and minimal residual disease (MRD) response using IG/TR and BCR::ABL1 markers after each treatment cycle. Additional secondary endpoints include early mortality at days 30, 60, and 90, cumulative incidence of relapse (CIR), cumulative incidence of non-relapse mortality (CINRM), transplant-related mortality (TRM), and graft-versus-host disease (GvHD) incidence.
Safety will be evaluated by the number and rate of patients experiencing adverse events (AEs) or serious adverse events (SAEs). Quality of life will be measured using the EQ5D 5L instrument. Economic evaluations will include incremental cost-effectiveness and cost-utility ratios, defined as the difference in total costs divided by the difference in survival and quality-adjusted life years. Sensitivity analyses will be conducted to assess EFS/RFS, CIR, CINRM, and OS after censoring patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first remission at transplant time, and after censoring outcomes at the initiation of any subsequent anti-leukemic therapy not planned in the protocol. Subgroup analyses will be performed based on age (e.g., older than 45 years, 55 years) and acute lymphoblastic leukemia (ALL) subgroups according to genomic classification and antigen target expression.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients aged 18 to 65 years old
- Newly diagnosed ALL or T-LL according to the WHO criteria
- Immunophenotypic, cytogenetic and/or FISH and molecular evaluation performed and allowing classifying the patient in one of the Phpos ALL, Phneg BCP-ALL or T-ALL cohorts
- Not previously treated except with corticosteroids and/or intrathecal therapy (prephase)
- ECOG performance status ≤2
- Patient willing and able to understand the protocol requirements and comply with the treatment schedule, scheduled visits, electronic patient outcome reporting, exams and other requirements of the study
- Patients has signed written inform consent document
- Willingness of women of child-bearing potential (WOCBP) and male subjects whose sexual partners are WOCBP to use an effective form of contraception, i.e. methods with a failure rate of <1% per year when used consistently and correctly, during the study and at least 6 months thereafter
- 9.Eligible for national health insurance (for french patients)
Exclusion Criteria
- Patient previously treated with systemic chemotherapy for ALL, antibody-based therapy or TKI
- Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
- History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, coordination/movement disorder, autoimmune disease with CNS involvement, psychosis (with the exception of CNS leukemia that is well controlled with intrathecal therapy)
- Patients with LVEF<50% or other clinically significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)
- If patients with Phpos ALL (only GRAAPH): • Complete left bundle branch block, right bundle branch block plus left anterior hemiblock, bi-fascicular block • History of or presence of clinically significant ventricular or atrial tachyarrhythmias • Clinically significant resting bradycardia (< 50 beats per minute) • Congenital long QT syndrome or QTcF > 470 msec on screening ECG. If QTc > 470 msec and electrolytes are not within normal ranges before ponatinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion • Currently taking drug(s) that are known to have a risk of causing prolonged QTc or TdP unless the drug(s) can be changed to acceptable alternatives (ie, an alternate class of agents that do not affect the cardiac conduction system), or the participant can safely discontinue the drug(s) • Previous myocardial infarction within the last 12 months • Symptomatic peripheral vascular disease • History of ischemic stroke or transient ischemic attacks (TIAs) within the last 12 months • Significant bleeding disorder or thrombophilia unrelated to the underlying malignancy indication for study participation • Gastrointestinal disorders, such as malabsorption syndrome or any other illness that could affect oral absorption
- Prior documented chronic liver disease. Inadequate hepatic functions defined as AST or ALT > 5 x the institutional upper limit of normal (ULN), or > 5 x ULN unless if considered due to leukemia. Total bilirubin > 1.5 x ULN unless if considered due to leukemia or Gilbert/Meulengracht
- Estimated glomerular filtration rate (GFR) < 50 mL/mn using the MDRD equation
- Chronic pancreatitis or acute pancreatitis within 6 months before study start
- Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) or active infection with Hepatitis B or C.
- Concurrent severe diseases which exclude the administration of therapy
- Treatment with any other investigational agent or participating in another trial within 30 days prior to entering this study
- Pregnancy and breast feeding
- Patients unwilling or unable to comply with the protocol
- Patients under a legal protection regime (guardianship, trusteeship, judicial safeguard)
- Chronic or current active uncontrolled infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment
- Current use of prohibited medication (see Section 7.11) (only GRAAPH)
- Known hypersensitivity or severe reaction to ponatinib, blinatumomab, isatuximab or their excipients .
- Receipt of live (including attenuated) vaccines or anticipation of need for such vaccines during the study
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 15 Oct 2024 | 100 |
 France | Recruiting | 15 Oct 2024 | 1000 |
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 |
|---|---|---|---|---|---|---|
SARCLISA 20mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 10 | 30 | PRD8132767 |
SARCLISA 20mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 10 | 30 | PRD8132765 |
BLINCYTO 38.5 micrograms powder for concentrate and solution for solution for infusion. | Test | POWDER FOR CONCENTRATE AND SOLUTION FOR SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 28 | 140 | PRD3418637 |
Iclusig 15 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 45 | 30 | PRD4872106 |