Clinical trial NCT03709719: Blinatumomab in High-risk B-cell Precursor Acute Lymphoblastic Leukemia
Official title: A Phase II Study to Evaluate the Safety and the Efficacy of a Blinatumomab Based Consolidation and Maintenance in Patients With High-risk B-cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL). GRAALL-QUEST
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia, Adult B-Cell
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2018-10-17
Enrollment: 95
Sex: ALL
Minimum age (years): 18
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The GRAALL-QUEST study is a Phase 2 study nested in the GRAALL-2014/B study (NCT02617004). The GRAALL-QUEST study evaluates the safety and the efficacy of blinatumomab-containing consolidation and maintenance therapy in patients aged 18-59 years old with high-risk B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first complete hematologic remission after one induction course of standard chemotherapy and no central nervous system (CNS) involvement at diagnosis.

High-risk patients are defined as patients with KMT2A/MLL gene rearrangement, and/or IKZF1 (Ikaros) intra-genic deletion and/or high post-induction Ig-TCR minimal residual disease (MRD) level (≥10-4). In such patients not receiving blinatumomab, 3-year hematologic relapse incidence and relapse-free survival (RFS) are estimated at 60-65% and 50% only, respectively, on the basis of historical results.

A large subset of these high-risk patients (i.e. those with post-induction MRD level ≥10-3 and/or post-consolidation MRD level ≥10-4), but not all, will also be considered as candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first hematologic remission. The primary objective of the GRAALL-QUEST study is to evaluate the efficacy of adding blinatumomab to consolidation and eventually maintenance therapy in term of Relapse Free Survival (RFS). Secondary objectives are overall survival, comparison of RFS and Overall Survival (OS) in transplanted versus non-transplanted patients, MRD response and safety. Blinatumomab will be given as monthly cycles at the daily dose of 28 microg/d continuous IV infusion, together with 3 triple intra-thecal (IT) chemotherapy injections. The first cycle will start after completion of the first consolidation chemotherapy phase (corresponding to the MRD2 time-point). Patients receiving allo-HSCT will receive successive blinatumomab cycles until allo-HSCT. Patients not receiving allo-HSCT will receive a first blinatumomab cycle (cycle 1) during the second consolidation chemotherapy phase, followed by late intensification, then the third consolidation chemotherapy phase including another blinatumomab cycle (cycle 2) and maintenance chemotherapy including three additional blinatumomab cycles (cycles 3 to 5), for a total of 5 blinatumomab cycles maximum.


Eligibility criteria: Inclusion Criteria:

* Included in GRAALL-2014/B

  1. Whose blood and bone marrow explorations have been completed before the steroids prephase
  2. Aged 18 to 59 years old with not previously treated B-lineage-ALL (including intrathecal injections) newly diagnosed according to the WHO 2008 definition with \> 20% bone marrow blasts
  3. Whose karyotype shows no t(9;22) and/or the absence in molecular biology of BCR-ABL marker
  4. With Eastern Cooperative Oncology Group (ECOG) performance status \< 3
  5. With or without central nervous system (CNS) or testis involvement
  6. Without other evolving cancer (except basal cell carcinoma of the skin or "in situ" carcinoma of the cervix) or its treatment should be finished at least since 6 months
  7. Having signed a written informed consent
  8. With efficient contraception for women of childbearing age (excluding estrogens and IUS)
  9. With health insurance coverage
  10. Who have received or being receiving the steroid prephase
* With High Risk (HR) B-ALL
* ECOG ≤ 3
* In Complete Remission after one or two induction cures and having received the three blocks of consolidation N°1
* With or without allogeneic donor

Exclusion Criteria:

* With ECOG status \> 3 after consolidation 1
* With abnormal laboratory values as defined below after consolidation 1

  1. Aspartate transaminase (AST) (SGOT) and/or alanine transaminase (ALT) (SGPT) ≥ 5 x ULN
  2. Total bilirubin ≥ 1.5 x ULN
  3. Creatinine ≥ 1.5 x ULN or creatinine clearance \< 50 ml/min
  4. Serum amylase and lipase ≥ 1.5 x ULN
* With active uncontrolled infection, any other concurrent disease or medical condition that is deemed to interfere with the conduct of the study as judged by the investigator
* New York Heart Association (NYHA) Functional Classification 3-4 cardiac disease
* Infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HBsAg positive) or hepatitis C virus (anti-HCV positive)

Primary outcomes:
measure: Disease Free Survival Y3
timeFrame: 3 years
Secondary outcomes:
measure: OS Y3
timeFrame: 3 years
measure: CIR Y3
timeFrame: 3 years
measure: NRM
timeFrame: 3 years
measure: MRD1
timeFrame: after induction or on day 1 of first consolidation
measure: MRD2
timeFrame: on day 1 of second consolidation
measure: MRD3
timeFrame: on day 1 of late intensification(or at pre Allo-SCT evaluation)
measure: MRD4
timeFrame: on day 1 of maintenance phase (or at day 100 after Allo-SCT)
Other outcomes:
Locations:
city: Paris
country: France
facility: Hopital saint Louis
Study officials:
References: