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

NCT06860269 | Recruiting Phase 2 DMC

• 1 other identifier: APHP210356
• Study Type: interventional
• Target: 1,200
• Locations: 1 country
• Sites: 1

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.

Conditions

Acute Lymphoblastic Leukemia

Outcome Measures

Primary Outcomes (4)

• Overall survival

  For GRAAL-2024/B HR patients (phase 3)

  At 5 years

• Overall survival

  For GRAAL-2024/B SR patients (phase 2)

  At 5 years

• Event-Free Survival

  For GRAAL-2024/T patients (phase 3)

  At 5 years

• Overall survival

  For GRAAPH-2024 patients (phase 3) - Phpos ALL

  At 5 years

Secondary Outcomes (20)

• Overall survival

  At 5 years

• Event Free Survival

  At 5 years

• Relapse Free Survival

  At 5 years

• Hematological complete response rate

  At 45 days

• Hematological complete response rate

  At 4 months

Study Arms (9)

GRAALL-2024/B Very High Risk - SOC

NO INTERVENTION

Phneg BCP-ALL cohort Standard of Care : ALLO HSCT

GRAALL-2024/B High Risk - SOC

ACTIVE COMPARATOR

Phneg BCP-ALL cohort

Other: Randomization 1 + Allo HSCT

GRAALL-2024/B High risk - Blina

EXPERIMENTAL

Phneg BCP-ALL cohort

Drug: Randomization + Blinatumomab + chemotherapy

GRAALL-2024/B Standard Risk - SOC

NO INTERVENTION

Phneg BCP-ALL cohort Standard of Care : Blinatumomab + chemotherapy

GRAALL-2024/T - SOC

ACTIVE COMPARATOR

T-ALL cohort

Other: Randomization + Standard frontline T-ALL chemotherapy backbone

GRAALL-2024/T - Isa

EXPERIMENTAL

T-ALL cohort

Drug: Randomization + Isatuximab + Standard frontline T-ALL chemotherapy backbone

GRAAL-2024/T - T-cell lymphoblastic lymphoma - SOC

NO INTERVENTION

Non randomized - standard care

GRAAPH-2024 - SOC

ACTIVE COMPARATOR

Phpos ALL cohort

Other: Randomization 2 + Allo HSCT

GRAAPH-2024 - Blina/Pona

EXPERIMENTAL

Phpos ALL cohort

Drug: Randomization + Blinatumomab + Ponatinib + chemotherapy

Interventions

Randomization + Blinatumomab + chemotherapy DRUG

Rando 1 : BLINA will be given at 28 µg/day IVC from D1 to D28 for 2 to 4 cycles (first cycle starts with 9 µg/day for 7 days)

GRAALL-2024/B High risk - Blina

Randomization + Isatuximab + Standard frontline T-ALL chemotherapy backbone DRUG

Rando 3 : ISA will be given at 10 mg/kg IV for a maximum of 28 infusions starting at induction up to maintenance phase.

GRAALL-2024/T - Isa

Randomization + Standard frontline T-ALL chemotherapy backbone OTHER

Rando 3 : standard of care

GRAALL-2024/T - SOC

Randomization + Blinatumomab + Ponatinib + chemotherapy DRUG

Rando 2 : * PONA will be given at 45 mg/day PO during 2 cycles, 30 mg/day during 2 additional cycles, and 15 mg/day during maintenance phase or after alloHSCT * BLINA will be given at 28 µg/day IVC from D1 to D28 for 2 to 5 cycles (first cycle starts with 9 µg/day for 7 days). Patients allografted will receive two courses before transplant.

GRAAPH-2024 - Blina/Pona

Randomization 1 + Allo HSCT OTHER

Rando 1 : standard of care - Allogeneic Hematopoietic Stem Cell Transplantation

GRAALL-2024/B High Risk - SOC

Randomization 2 + Allo HSCT OTHER

Rando 2 : standard of care

GRAAPH-2024 - SOC

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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/LL cohorts
• Not previously treated except with corticosteroids and/or intrathecal therapy (prephase)
• Eligible for allo-HSCT if Phpos ALL or Phneg BCP-ALL
• 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
• 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
• Eligible for National Health Insurance (for French patients)

You may not qualify if:

• Patient previously treated with systemic chemotherapy, 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)
• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Hôpital Saint Louis

Paris, France

RECRUITING

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

Random Allocation; blinatumomab; Drug Therapy; isatuximab; ponatinib

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Epidemiologic Research Design; Epidemiologic Methods; Investigative Techniques; Research Design; Methods; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health; Therapeutics

Central Study Contacts

Nicolas Boissel, MD PhD

CONTACT

1 42 49 96 43; nicolas.boissel@aphp.fr

Jérôme Lambert, MD PhD

CONTACT

0142499742; jerome.lambert@u-paris.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: January 16, 2025
• First Posted: March 6, 2025
• Study Start: May 6, 2025
• Primary Completion (Estimated): March 15, 2035
• Study Completion (Estimated): March 15, 2035
• Last Updated: February 10, 2026

Record last verified: 2026-02

Locations

FR (1)