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Trial record 15 of 80 for:    "Adult Acute Lymphocytic Leukemia" | "Antineoplastic Agents, Hormonal"

A Phase III Randomized Trial of the Reduction of Chemotherapy in Philadelphia Chromosome-positive ALL of Young Adults (GRAAPH2014)

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ClinicalTrials.gov Identifier: NCT02611492
Recruitment Status : Recruiting
First Posted : November 20, 2015
Last Update Posted : October 21, 2019
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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)

Condition or disease Intervention/treatment Phase
Philadelphia Chromosome Positive Adult Acute Lymphoblastic Leukemia Drug: Nilotinib Drug: Methotrexate Drug: Aracytine (Ara C) Drug: Granulocyte Colony-Stimulating Factor (G-CSF) Drug: Depomedrol Drug: Dexamethasone Drug: Vincristine Drug: Imatinib Drug: 6 Mercaptopurine (6MP) Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 265 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : April 2016
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Intensive Arm (A)

4 cycles + 2 interphases +Hematopoietic Stem Cell Transplantation (SCT)

+ Post-SCT Maintenance

Drug: Nilotinib
400 mg/12h per os D1 to D28 cycles 1-4 300 mg/12h per os D1-D14 interphase

Drug: Methotrexate
1 g/m2 continuous Intravenous Infusion (CIV) D1 cycles 2 and 4 25 mg/m2 per os D1, D8 interphase

Drug: Aracytine (Ara C)
Age<45 years: 3 mg/m2/12h D2, D3 cycles 2 and 4 Age>=45 years: 1.5 mg/m2/12h D2, D3 cycles 2 and 4

Drug: Granulocyte Colony-Stimulating Factor (G-CSF)
5µg/kg/d (SC) D6 until neutrophils > 1 G/L D15 cycles 1 and 3; D6 cycles 2 and 4

Drug: Depomedrol
40 mg + methotrexate 15 mg + Aracytine (AraC) 40mg IT cycle 1: D1, D8, D15 IT cycles 2 and 4: D9 IT cycle 3: D1

Drug: Dexamethasone
40 mg per os, D1-D2, D8-D9, D15-D16, D22-D23, cycles 1 and 3

Drug: Vincristine
2 mg total dose IV, D1 D8 D15 D22 cycles 1 and 3

Drug: Imatinib
300 mg/12h per os in post-SCT maintenance therapy for during at least 2 years

Drug: 6 Mercaptopurine (6MP)
60 mg/m2 per os, D1 to D14, interphase

Experimental: Light Arm (B)

4 cycles + 2 interphases +Hematopoietic Stem Cell Transplantation (SCT)

+ Post-SCT Maintenance

Drug: Nilotinib
400 mg/12h per os D1 to D28 cycles 1-4 300 mg/12h per os D1-D14 interphase

Drug: Methotrexate
1 g/m2 continuous Intravenous Infusion (CIV) D1 cycles 2 and 4 25 mg/m2 per os D1, D8 interphase

Drug: Granulocyte Colony-Stimulating Factor (G-CSF)
5µg/kg/d (SC) D6 until neutrophils > 1 G/L D15 cycles 1 and 3; D6 cycles 2 and 4

Drug: Depomedrol
40 mg + methotrexate 15 mg + Aracytine (AraC) 40mg IT cycle 1: D1, D8, D15 IT cycles 2 and 4: D9 IT cycle 3: D1

Drug: Dexamethasone
40 mg per os, D1-D2, D8-D9, D15-D16, D22-D23, cycles 1 and 3

Drug: Vincristine
2 mg total dose IV, D1 D8 D15 D22 cycles 1 and 3

Drug: Imatinib
300 mg/12h per os in post-SCT maintenance therapy for during at least 2 years

Drug: 6 Mercaptopurine (6MP)
60 mg/m2 per os, D1 to D14, interphase




Primary Outcome Measures :
  1. Major Molecular Response (MMolR) [ Time Frame: 4 cycles (4 months) ]
    defined as a breakpoint cluster region (BCR)-Abelson (ABL) ratio < 0.1% in the bone marrow sample of MRD4


Secondary Outcome Measures :
  1. Complete remission after cycle 1 [ Time Frame: day 28 ]
  2. Cumulative incidence of treatment- and transplantation-related mortality [ Time Frame: 2 years ]
  3. Cumulative incidence of relapse [ Time Frame: 10 years ]
  4. Relapse free survival [ Time Frame: 10 years ]
  5. Event-free survival [ Time Frame: 10 years ]
  6. overall survival [ Time Frame: 10 years ]
  7. T315I mutation [ Time Frame: 10 years ]
    mutations will be assessed by Reverse transcription Quantitative Polymerase Chain Reaction (RQ-PCR) sequencing in case of progression or relapse

  8. Toxicity [ Time Frame: 12 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 59 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02611492


Contacts
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Contact: Hervé Dombret, MDPhD +33 (0)1 57 27 68 47 herve.dombret@aphp.fr
Contact: Véronique Lhéritier +33(0)4 78 86 22 39 veronique.lheritier@chu-lyon.fr

Locations
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France
Hopital Saint Louis Recruiting
Paris, France, 75010
Contact: Hervé Dombret, MDPhD    +33 (0)1 57 27 68 47    herve.dombret@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02611492     History of Changes
Other Study ID Numbers: AOM12629_1
First Posted: November 20, 2015    Key Record Dates
Last Update Posted: October 21, 2019
Last Verified: September 2019
Additional relevant MeSH terms:
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Antineoplastic Agents, Hormonal
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Philadelphia Chromosome
Leukemia, Lymphoid
Leukemia
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes
Cytarabine
Dexamethasone
Methylprednisolone Acetate
Methotrexate
Vincristine
Mercaptopurine
Sargramostim
Lenograstim
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones