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Philadelphia Chromosome Positive Adult Acute Lymphoblastic LeukemiaPhase 3GRAAPH2014NCT02611492

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

A Phase 3 study testing Nilotinib, Methotrexate and Aracytine (Ara C) in people with Philadelphia Chromosome Positive Adult Acute Lymphoblastic Leukemia, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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) Read more about this study

Who is it for?
Ages 18 to 59 years
What is being tested?
Nilotinib, Methotrexate and Aracytine (Ara C)
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
265 participants
Where
1 siteFrance
Study dates
Apr 2016to Dec 2025
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 59 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • Patient
  • Whose blood and bone marrow explorations have been completed before the steroids prephase
  • 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)
  • With ≥ 20% bone marrow blasts
  • With Eastern Cooperative Oncology Group (ECOG) Performans Status ≤ 3
  • With or without central nervous system (CNS) or testis involvement
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  • 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.
  • Having received no previous treatment for this hematological disease (including IT injection)
  • Having signed written informed consent
  • With efficient contraception for women of childbearing age (excluding estrogens and IUD)
  • With health insurance coverage
  • 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.

Who cannot join

  • Patient:
  • Previously treated with Tyrosine Kinase Inhibitor (TKI)
  • With another active malignancy
  • With general or visceral contra-indication to intensive therapy (except if considered related to the ALL):
  • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2.5 x upper limit of normal range (ULN)
  • Total bilirubin > 1.5 x ULN
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  • Creatinine > 1.5 x ULN or creatinine clearance <50 mL/mn
  • Serum amylase or lipase > 1.5 x ULN or antecedents of acute pancreatitis
  • With heart failure, including at least one of the following criteria:
  • Left ventricular ejection fraction (LVEF) <50% or below the lowest normal threshold, as determined by ECG or heart failure (NYHA grade III or IV)
  • Impossibility to measure the QT interval on ECG
  • Complete left bundle branch block
  • Pacemaker
  • Congenital long QT syndrome of known familial antecedents of long QT syndrome
  • Antecedents or current ventricular or atrial tachyarrhythmia, clinically significant
  • Baseline bradycardia (<50 bpm) clinically significant
  • Corrected QT interval (QTc)> 450 msec established on the mean of 3 baseline ECG
  • Antecedents of myocardial infarct in the past 6 months
  • Instable angor within the past 12 months
  • Any heart condition clinically significant (i.e. congestive heart failure, uncontrolled hypertension)
  • Active uncontrolled infection, any other concurrent disease deemed to interfere with the conduct of the study as judged by the investigator
  • Severe evolving infection, or known HIV or Human T-Lymphotropic Virus type I (HTLV1) seropositivity, or active infection by hepatitis B or C virus
  • Pregnant (beta-HCG) or nursing woman
  • 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.
  • Having received an investigational treatment or participation in another trial within 30 days prior to entering this study.
  • Not able to bear with the procedures or the frequency of visits planned in the trial.
  • Unable to consent, under tutelage or curators, or judiciary safeguard

Trial locations and contacts

1 site in 1 country.

Hervé Dombret, MDPhD contact

+33 (0)1 57 27 68 47

herve.dombret@aphp.fr

Véronique Lhéritier contact

+33(0)4 78 86 22 39

veronique.lheritier@chu-lyon.fr

France1 site, 1 recruiting

  • Hopital Saint Louis

    Paris, 75010

    Hervé Dombret, MDPhD, +33 (0)1 57 27 68 47, herve.dombret@aphp.fr

    Recruiting

Other trials in France

About this study

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)

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)

Being tested
Nilotinib, Methotrexate, Aracytine (Ara C), Granulocyte Colony-Stimulating Factor (G-CSF), Depomedrol

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NilotinibDrug

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

  • MethotrexateDrug

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

  • Aracytine (Ara C)Drug

    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

  • Granulocyte Colony-Stimulating Factor (G-CSF)Drug

    5µg/kg/d (SC) D6 until neutrophils > 1 G/L D15 cycles 1 and 3; D6 cycles 2 and 4

  • DepomedrolDrug

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

  • DexamethasoneDrug

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

  • VincristineDrug

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

  • ImatinibDrug

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

  • 6 Mercaptopurine (6MP)Drug

    60 mg/m2 per os, D1 to D14, interphase

Study groups in NCT02611492
Study groupRoleWhat they receive
Intensive Arm (A)Active comparator4 cycles + 2 interphases +Hematopoietic Stem Cell Transplantation (SCT) + Post-SCT Maintenance
Receives: 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)
Light Arm (B)Experimental4 cycles + 2 interphases +Hematopoietic Stem Cell Transplantation (SCT) + Post-SCT Maintenance
Receives: Drug: Nilotinib; Drug: Methotrexate; Drug: Granulocyte Colony-Stimulating Factor (G-CSF); Drug: Depomedrol; Drug: Dexamethasone; Drug: Vincristine; Drug: Imatinib; Drug: 6 Mercaptopurine (6MP)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Major Molecular Response (MMolR)

    defined as a breakpoint cluster region (BCR)-Abelson (ABL) ratio < 0.1% in the bone marrow sample of MRD4

    Measured: 4 cycles (4 months)

Secondary outcomes (8)

  1. Complete remission after cycle 1

    Measured: day 28

  2. Cumulative incidence of treatment- and transplantation-related mortality

    Measured: 2 years

  3. Cumulative incidence of relapse

    Measured: 10 years

  4. Relapse free survival

    Measured: 10 years

  5. Event-free survival

    Measured: 10 years

  6. overall survival

    Measured: 10 years

  7. T315I mutation

    mutations will be assessed by Reverse transcription Quantitative Polymerase Chain Reaction (RQ-PCR) sequencing in case of progression or relapse

    Measured: 10 years

  8. Toxicity

    Measured: 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Nov 2015 (estimated)
  2. Study startApr 2016
  3. Primary completionDec 2020 (estimated)
  4. Study completionDec 2025 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
265 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02611492
Sponsor's protocol ID
AOM12629_1
Acronym
GRAAPH2014
Status last verified
Sep 2019
First submitted
19 Nov 2015
Last updated
21 Oct 2019
Results posted
No
Data monitoring committee
Yes

Publications

  • Chalandon Y, Rousselot P, Chevret S, Cayuela JM, Kim R, Huguet F, Chevallier P, Graux C, Thiebaut-Bertrand A, Chantepie S, Thomas X, Vincent L, Berthon C, Hicheri Y, Raffoux E, Escoffre-Barbe M, Plantier I, Joris M, Turlure P, Pasquier F, Belhabri A, Guepin GR, Blum S, Gregor M, Lafage-Pochitaloff M, Quessada J, Lheritier V, Clappier E, Boissel N, Dombret H. Nilotinib with or without cytarabine for Philadelphia-positive acute lymphoblastic leukemia. Blood. 2024 Jun 6;143(23):2363-2372. doi: 10.1182/blood.2023023502.

    PubMed 38452207

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Nilotinib, Methotrexate and Aracytine (Ara C) in people with Philadelphia Chromosome Positive Adult Acute Lymphoblastic Leukemia, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 21 Oct 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Hervé Dombret, MDPhD (+33 (0)1 57 27 68 47, herve.dombret@aphp.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Major Molecular Response (MMolR) (time frame: 4 cycles (4 months)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02611492, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Oct 2019.

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