Clinical trial NCT06860269: A 3-cohort Randomized Study Evaluating the Role of New Immunotherapeutic Agents and of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Frontline Therapy of Adults With Acute Lymphoblastic Leukemia
Official title: A 3-cohort Randomized Study Evaluating the Role of New Immunotherapeutic Agents and of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Frontline Therapy of Adults With Acute Lymphoblastic Leukemia
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Acute Lymphoblastic Leukemia
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2025-03-06
Enrollment: 1200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 3-cohort stratified multicenter multi-country prospective open-label randomized Phase III trial. In each cohort, participants will be randomized according to a 1:1 ratio (R1, R2 and R3).

Additionnally a phase 2 single arm trial will be performed in SR patients of the Phneg BCP-ALL cohort.

Of note, T-LL patients will be included but not randomized to receive ISA or not.
Primary purpose: TREATMENT

Brief summary: Adult acute lymphoblastic leukemia (ALL) includes Ph-positive (Phpos) ALL, Ph-negative (Phneg) B-cell precursor (BCP) ALL and T-ALL/lymphoblastic lymphoma (LL), accounting for approximately 25, 50 and 25% of all cases, respectively. In younger adults, the results associated with standard therapy have markedly improved in these 3 groups, due to chemotherapy intensification in the BCP and T groups and addition of TKIs in the Phpos group, respectively. This led to reevaluate the role of allogeneic hematopoietic stem cell transplantation (HSCT) in first remission, which is generally now indicated only in higher-risk patients, mostly defined as those with persistent high levels of minimal residual disease (MRD). Nevertheless, event-free survival (EFS) remains at 60-70% at 3 years, meaning there is still room for further improvements.

Fortunately, new immunotherapies have been approved to treat relapsed/refractory (R/R) BCP-ALL patients, including the anti-CD19 bispecific T-cell engager blinatumomab (BLINA, Blincyto®, Amgen). 4 BLINA is also approved for the frontline treatment of patients with persistent high measurable residual disease (MRD) levels after initial therapy (IG/TR MRD ≥0.1% (≥1.10-3

)). BLINA has been also evaluated frontline in combination with TKI in the Phpos group leading to promising outcome improvements. Toxicities associated with these combined treatments seem to be limited and manageable. In the Phpos ALL subset, the third-generation tyrosine kinase inhibitor ponatinib (PONA, Iclusig®, Incyte) has also been evaluated frontline with promising results when compared to 1st or even 2nd generation TKI. In the T-ALL/LL subset, anti-CD38 antibodies, approved to treat patients with multiple myeloma, are potential drugs of interest. The anti-CD38 antibody isatuximab (ISA, Sarclisa®, Immunogen, Sanofi-Aventis) is currently approved to treat myeloma patients in 2nd line. In vitro and in vivo preclinical studies suggest that CD38 is a relevant target in T-ALL and that isatuximab may be useful to eradicate residual disease in this subgroup of patients. Incorporation/combination of these new agents into frontline adult ALL therapy could allow reducing relapse incidence and prolonging survival in these patients, challenging the indication for HSCT in first complete remission (CR).

The present GRAALL-2024 study is a prospective multicenter multi-country 3-cohort randomized clinical trial.

The 3 cohorts are :

GRAALL-2024/B : Phneg BCP-ALL GRAAPH-2024 : Phpos ALL GRAALL-2024/T : T-ALL/LL

Eligible patients will be allocated to one on the 3 study cohorts during a common treatment prephase. The primary objective of the study is to improve the outcome of younger adults with ALL through optimal frontline incorporation of new antibody-based therapies, including BLINA in Phneg/pos BCP-ALL patients and ISA in T-ALL/LL patients, and to refine indication for allogeneic HSCT in first remission in Phneg/pos BCP-ALL patients.


Eligibility criteria: Inclusion Criteria:

1. Patients aged 18 to 65 years old
2. Newly diagnosed ALL or T-LL according to the WHO criteria
3. 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/LL cohorts
4. Not previously treated except with corticosteroids and/or intrathecal therapy (prephase)
5. Eligible for allo-HSCT if Phpos ALL or Phneg BCP-ALL
6. ECOG performance status ≤2
7. 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
8. Patients has signed written inform consent
9. 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
10. Eligible for National Health Insurance (for French patients)

Exclusion Criteria:

Common exclusion criteria :

1. Patient previously treated with systemic chemotherapy, antibody-based therapy or TKI
2. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
3. 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)
4. Patients with LVEF\<50% or other clinically significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)
5. 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
6. Estimated glomerular filtration rate (GFR) \< 50 mL/mn using the MDRD equation
7. Chronic pancreatitis or acute pancreatitis within 6 months before study start
8. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) or active infection with Hepatitis B or C.
9. Concurrent severe diseases which exclude the administration of therapy
10. Treatment with any other investigational agent or participating in another trial within 30 days prior to entering this study
11. Pregnancy and breast feeding
12. Patients unwilling or unable to comply with the protocol
13. Patients under a legal protection regime (guardianship, trusteeship, judicial safeguard)
14. Chronic or current active uncontrolled infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment
15. Current use of prohibited medication
16. Known hypersensitivity or severe reaction to ponatinib (GRAAPH), blinatumomab (GRAAPH and GRAALL-B) , isatuximab (GRAALL-T) or their excipients.
17. Receipt of live (including attenuated) vaccines or anticipation of need for such vaccines during the study

If patients with Phpos ALL:

1. Complete left bundle branch block, right bundle branch block plus left anterior hemiblock, bi-fascicular block
2. History of or presence of clinically significant ventricular or atrial tachyarrhythmias
3. Clinically significant resting bradycardia (\< 50 beats per minute)
4. 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
5. 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)
6. Previous myocardial infarction within the last 12 months
7. Symptomatic peripheral vascular disease
8. History of ischemic stroke or transient ischemic attacks (TIAs) within the last 12 months
9. Significant bleeding disorder or thrombophilia unrelated to the underlying malignancy indication for study participation
10. Gastrointestinal disorders, such as malabsorption syndrome or any other illness that could affect oral absorption

Primary outcomes:
measure: Overall survival
timeFrame: At 5 years
measure: Overall survival
timeFrame: At 5 years
measure: Event-Free Survival
timeFrame: At 5 years
measure: Overall survival
timeFrame: At 5 years
Secondary outcomes:
measure: Overall survival
timeFrame: At 5 years
measure: Event Free Survival
timeFrame: At 5 years
measure: Relapse Free Survival
timeFrame: At 5 years
measure: Hematological complete response rate
timeFrame: At 45 days
measure: Hematological complete response rate
timeFrame: At 4 months
measure: Measurable residual disease (MRD) response
timeFrame: At inclusion
measure: Measurable residual disease (MRD) response - non graft patients
timeFrame: Up to 6 months
measure: Measurable residual disease (MRD) response - graft patients
timeFrame: Through study completion, approximately 5 years
measure: Measurable residual disease (MRD) response
timeFrame: Up to 5 years
measure: Early mortality
timeFrame: At day 30
measure: Early mortality
timeFrame: At day 60
measure: Early mortality
timeFrame: At day 90
measure: Cumulative incidence of relapse (CIR)
timeFrame: At 5 years
measure: Cumulative incidence of non relapse mortality
timeFrame: At 5 years
measure: Transplant-related mortality (TRM)
timeFrame: At 5 years
measure: Graft-versus-host-disease (GvHD) incidence
timeFrame: At 5 years
measure: Number of patients who experience one or more Adverse Event (AEs) or Serious Adverse Event (SAEs)
timeFrame: At 5 years
measure: Rate of patients who experience one or more Adverse Event (AEs) or Serious Adverse Event (SAEs)
timeFrame: At 5 years
measure: Quality of life
timeFrame: Until 5 years
measure: Incremental cost effectiveness and cost utility ratio
timeFrame: At 5 years
Other outcomes:
Locations:
Study officials:
References: