Clinical Trials /

A Phase III Randomized Trial of the Reduction of Chemotherapy in Philadelphia Chromosome-positive ALL of Young Adults

NCT02611492

Description:

The Primary objective is to assess the non-inferiority of the experimental arm (arm B) compared to the control arm (arm A) in terms of Major Molecular Response (MMolR) after the 4th cycle (MRD4) in patients aged 18-59 years old with de novo Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL)

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Suspended

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Phase III Randomized Trial of the Reduction of Chemotherapy in Philadelphia Chromosome-positive ALL of Young Adults
  • Official Title: A Phase III Study, Randomized, to Evaluate the Reduction of Chemotherapy Intensity in Association With Nilotinib (Tasigna®) in Philadelphia Chromosome-positive (Ph+) ALL of Young Adults (18-59 Years Old) (GRAAPH-2014)

Clinical Trial IDs

  • ORG STUDY ID: AOM12629_1
  • NCT ID: NCT02611492

Conditions

  • Philadelphia Chromosome Positive Adult Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
NilotinibIntensive Arm (A)
MethotrexateIntensive Arm (A)
Aracytine (Ara C)Intensive Arm (A)
Granulocyte Colony-Stimulating Factor (G-CSF)Intensive Arm (A)
DepomedrolIntensive Arm (A)
DexamethasoneIntensive Arm (A)
VincristineIntensive Arm (A)
ImatinibIntensive Arm (A)
6 Mercaptopurine (6MP)Intensive Arm (A)

Purpose

The Primary objective is to assess the non-inferiority of the experimental arm (arm B) compared to the control arm (arm A) in terms of Major Molecular Response (MMolR) after the 4th cycle (MRD4) in patients aged 18-59 years old with de novo Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL)

Trial Arms

NameTypeDescriptionInterventions
Intensive Arm (A)Active Comparator4 cycles + 2 interphases +Hematopoietic Stem Cell Transplantation (SCT) + Post-SCT Maintenance
  • Nilotinib
  • Methotrexate
  • Aracytine (Ara C)
  • Granulocyte Colony-Stimulating Factor (G-CSF)
  • Depomedrol
  • Dexamethasone
  • Vincristine
  • Imatinib
  • 6 Mercaptopurine (6MP)
Light Arm (B)Experimental4 cycles + 2 interphases +Hematopoietic Stem Cell Transplantation (SCT) + Post-SCT Maintenance
  • Nilotinib
  • Methotrexate
  • Granulocyte Colony-Stimulating Factor (G-CSF)
  • Depomedrol
  • Dexamethasone
  • Vincristine
  • Imatinib
  • 6 Mercaptopurine (6MP)

Eligibility Criteria

        Inclusion Criteria:

        Patient

          1. Whose blood and bone marrow explorations have been completed before the steroids
             prephase

          2. Aged 18-59 years old with newly-diagnosed non previously treated Ph+ ALL according to
             WHO 2008 criteria (confirmed diagnosis of the Philadelphia chromosome defined by the
             reciprocal translocation of chromosomes 9 and 22, t(9;22) and/or presence of the
             BCR-ABL molecular maker)

          3. With ≥ 20% bone marrow blasts

          4. With Eastern Cooperative Oncology Group (ECOG) Performans Status ≤ 3

          5. With or without central nervous system (CNS) or testis involvement

          6. Without evolving cancer (except basal cell carcinoma of the skin or "in situ"
             carcinoma of the cervix) or its chemo- or radio-therapy should be finished at least
             since 6 months.

          7. Having received no previous treatment for this hematological disease (including IT
             injection)

          8. Having signed written informed consent

          9. With efficient contraception for women of childbearing age (excluding estrogens and
             IUD)

         10. With health insurance coverage

         11. Who have received (or being receiving) the recommended steroid prephase.

        Note 1: Secondary ALL (antecedent of chemo- or radio-therapy) can be included Note 2: In
        case of high vascular risk (see section "study management") the patient will not be able to
        receive nilotinib unless an ultra sound Doppler of the neck and lower limbs has been
        performed during the pre-phase and treatment validated by the medical coordinators of the
        protocol via the secretariat.

        Exclusion Criteria:

        Patient:

          1. Previously treated with Tyrosine Kinase Inhibitor (TKI)

          2. With another active malignancy

          3. With general or visceral contra-indication to intensive therapy (except if considered
             related to the ALL):

               1. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2.5 x
                  upper limit of normal range (ULN)

               2. Total bilirubin > 1.5 x ULN

               3. Creatinine > 1.5 x ULN or creatinine clearance <50 mL/mn

               4. Serum amylase or lipase > 1.5 x ULN or antecedents of acute pancreatitis

          4. With heart failure, including at least one of the following criteria:

               1. Left ventricular ejection fraction (LVEF) <50% or below the lowest normal
                  threshold, as determined by ECG or heart failure (NYHA grade III or IV)

               2. Impossibility to measure the QT interval on ECG

               3. Complete left bundle branch block

               4. Pacemaker

               5. Congenital long QT syndrome of known familial antecedents of long QT syndrome

               6. Antecedents or current ventricular or atrial tachyarrhythmia, clinically
                  significant

               7. Baseline bradycardia (<50 bpm) clinically significant

               8. Corrected QT interval (QTc)> 450 msec established on the mean of 3 baseline ECG

               9. Antecedents of myocardial infarct in the past 6 months

              10. Instable angor within the past 12 months

              11. Any heart condition clinically significant (i.e. congestive heart failure,
                  uncontrolled hypertension)

          5. Active uncontrolled infection, any other concurrent disease deemed to interfere with
             the conduct of the study as judged by the investigator

          6. Severe evolving infection, or known HIV or Human T-Lymphotropic Virus type I (HTLV1)
             seropositivity, or active infection by hepatitis B or C virus

          7. Pregnant (beta-HCG) or nursing woman

          8. Women of childbearing potential not willing to use an effective form of contraception
             during participation in the study and at least three months thereafter. Patient not
             willing to ensure not to beget a child during participation in the study and at least
             three months thereafter.

          9. Having received an investigational treatment or participation in another trial within
             30 days prior to entering this study.

         10. Not able to bear with the procedures or the frequency of visits planned in the trial.

         11. Unable to consent, under tutelage or curators, or judiciary safeguard
      
Maximum Eligible Age:59 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Major Molecular Response (MMolR)
Time Frame:4 cycles (4 months)
Safety Issue:
Description:defined as a breakpoint cluster region (BCR)-Abelson (ABL) ratio < 0.1% in the bone marrow sample of MRD4

Secondary Outcome Measures

Measure:Complete remission after cycle 1
Time Frame:day 28
Safety Issue:
Description:
Measure:Cumulative incidence of treatment- and transplantation-related mortality
Time Frame:2 years
Safety Issue:
Description:
Measure:Cumulative incidence of relapse
Time Frame:10 years
Safety Issue:
Description:
Measure:Relapse free survival
Time Frame:10 years
Safety Issue:
Description:
Measure:Event-free survival
Time Frame:10 years
Safety Issue:
Description:
Measure:overall survival
Time Frame:10 years
Safety Issue:
Description:
Measure:T315I mutation
Time Frame:10 years
Safety Issue:
Description:mutations will be assessed by Reverse transcription Quantitative Polymerase Chain Reaction (RQ-PCR) sequencing in case of progression or relapse
Measure:Toxicity
Time Frame:12 months
Safety Issue:
Description:

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Assistance Publique - Hôpitaux de Paris

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