GRAALL 2024 - 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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

5 Jan 2026 → ongoing

Decision date (initial)

2025-01-27

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

INCYTE · SANOFI · AMGEN · [DGOS-INCA] : PHRC-K20-100

External identifiers

EU CT number

2024-511437-35-00

ClinicalTrials.gov

NCT06860269

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Primary objective
• • GRAALL-2024/B
o HR patients (phase 3): To improve the outcome of younger adults with HR Ph-negative BCP-ALL through early frontline incorporation of blinatumomab and refined indications for allogeneic HSCT.
o SR patients (phase 2): To improve the outcome of younger adults with SR Ph-negative BCP-ALL through frontline incorporation of blinatumomab
• GRAALL-2024/T (phase 3): To improve the outcome of younger adults with T-ALL through early frontline incorporation of isatuximab
• GRAAPH-2024 (phase 3): To improve the outcome of younger adults with Ph-positive B-ALL through early frontline incorporation of blinatumomab, ponatinib, and refined indications for allogeneic HSCT.

Secondary objectives 3

1. 1) Safety profiles
2. 2) Patient-related outcomes (PROs) and quality-of-life (QoL)
3. 3) Cost effectiveness and utility

Conditions and MedDRA coding

Patients aged 18-65 years old with newly diagnosed previously untreated ALL or T-LL.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1. Patients aged 18 to 65 years old
2. 2. Newly diagnosed ALL or T-LL according to the WHO criteria
3. 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 cohorts
4. 4. Not previously treated except with corticosteroids and/or intrathecal therapy (prephase)
5. 5. ECOG performance status ≤2
6. 6. 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
7. 7. Patients has signed written inform consent document
8. 8. 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. 9.Eligible for national health insurance (for french patients)

Exclusion criteria 18

1. 1. Patient previously treated with systemic chemotherapy for ALL, antibody-based therapy or TKI
2. 2. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
3. 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. 4. Patients with LVEF<50% or other clinically significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)
5. 5. 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
6. 6. 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
7. 7. Estimated glomerular filtration rate (GFR) < 50 mL/mn using the MDRD equation
8. 8. Chronic pancreatitis or acute pancreatitis within 6 months before study start
9. 9. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) or active infection with Hepatitis B or C.
10. 10. Concurrent severe diseases which exclude the administration of therapy
11. 11. Treatment with any other investigational agent or participating in another trial within 30 days prior to entering this study
12. 12. Pregnancy and breast feeding
13. 13. Patients unwilling or unable to comply with the protocol
14. 14. Patients under a legal protection regime (guardianship, trusteeship, judicial safeguard)
15. 15. Chronic or current active uncontrolled infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment
16. 16. Current use of prohibited medication (see Section 7.11) (only GRAAPH)
17. 17. Known hypersensitivity or severe reaction to ponatinib, blinatumomab, isatuximab or their excipients .
18. 18. Receipt of live (including attenuated) vaccines or anticipation of need for such vaccines during the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. • GRAALL-2024/B o HR patients (phase 3) :OS o SR patients (phase 2) : OS • GRAALL-2024/T (phase 3) : EFS • GRAAPH-2024 (phase 3) : OS

Secondary endpoints 12

1. • OS and RFS in the T-ALL cohorts
2. • EFS and RFS in the Phneg/pos ALL cohorts
3. • Hematological CR rate
4. • MRD response (IG/TR and BCR::ABL1 markers) after each treatment cycles
5. • Early mortality at day 30, 60 and 90
6. • Cumulative incidence of relapse (CIR) and cumulative incidence of non-relapse mortality (CINRM)
7. • Transplant-related mortality (TRM) and graft-versus-host-disease (GvHD) incidence.
8. • Safety: number and rate of patients who experience one or more AEs/SAEs Quality-of-Life measured by the generic EQ5D 5L instrument Incremental cost effectiveness and cost utility ratio defined as the difference in total costs divided by the difference in survival and in quality adjusted life years
9. Sensitivity analyses: • EFS/RFS, CIR, CINRM and OS after censoring patients receiving allo-HSCT in first remission at transplant time
10. Sensitivity analyses: • EFS/RFS, CIR, CINRM and OS after censoring outcomes at the time of initiation of any subsequent anti-leukemic therapy other than therapies planned in the protocol
11. Subgroup analyses: • Age subgroups (older than 45y, 55y)
12. Subgroup analyses: • ALL subgroups according to genomic classification and antigen target expression

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Nicolas Boissel

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Nicolas Boissel

Locations

2 EU/EEA countries · 72 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 2 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 43 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications