Clinical trial NCT02611492: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Philadelphia Chromosome Positive Adult Acute Lymphoblastic Leukemia
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2015-11-20
Enrollment: 265
Sex: ALL
Minimum age (years): 18
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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)


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

Primary outcomes:
measure: Major Molecular Response (MMolR)
timeFrame: 4 cycles (4 months)
Secondary outcomes:
measure: Complete remission after cycle 1
timeFrame: day 28
measure: Cumulative incidence of treatment- and transplantation-related mortality
timeFrame: 2 years
measure: Cumulative incidence of relapse
timeFrame: 10 years
measure: Relapse free survival
timeFrame: 10 years
measure: Event-free survival
timeFrame: 10 years
measure: overall survival
timeFrame: 10 years
measure: T315I mutation
timeFrame: 10 years
measure: Toxicity
timeFrame: 12 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Hopital Saint Louis
Study officials:
References: