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

NCT ID: NCT02611492

Last Updated: 2019-10-21

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE3

Total Enrollment

265 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-04-30

Study Completion Date

2025-12-31

Brief Summary

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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)

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Detailed Description

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Conditions

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Philadelphia Chromosome Positive Adult Acute Lymphoblastic Leukemia

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Intensive Arm (A)

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

\+ Post-SCT Maintenance

Group Type ACTIVE_COMPARATOR

Nilotinib

Intervention Type DRUG

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

Methotrexate

Intervention Type DRUG

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

Aracytine (Ara C)

Intervention Type 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)

Intervention Type DRUG

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

Depomedrol

Intervention Type DRUG

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

Dexamethasone

Intervention Type DRUG

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

Vincristine

Intervention Type DRUG

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

Imatinib

Intervention Type DRUG

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

6 Mercaptopurine (6MP)

Intervention Type DRUG

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

Light Arm (B)

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

\+ Post-SCT Maintenance

Group Type EXPERIMENTAL

Nilotinib

Intervention Type DRUG

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

Methotrexate

Intervention Type DRUG

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

Granulocyte Colony-Stimulating Factor (G-CSF)

Intervention Type DRUG

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

Depomedrol

Intervention Type DRUG

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

Dexamethasone

Intervention Type DRUG

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

Vincristine

Intervention Type DRUG

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

Imatinib

Intervention Type DRUG

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

6 Mercaptopurine (6MP)

Intervention Type DRUG

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

Interventions

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Nilotinib

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

Intervention Type DRUG

Methotrexate

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

Intervention Type 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

Intervention Type 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

Intervention Type 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

Intervention Type DRUG

Dexamethasone

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

Intervention Type DRUG

Vincristine

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

Intervention Type DRUG

Imatinib

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

Intervention Type DRUG

6 Mercaptopurine (6MP)

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

Intervention Type DRUG

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Maximum Eligible Age

59 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Locations

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Hopital Saint Louis

Paris, , France

Site Status RECRUITING

Countries

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France

Central Contacts

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Hervé Dombret, MDPhD

Role: CONTACT

+33 (0)1 57 27 68 47

Véronique Lhéritier

Role: CONTACT

+33(0)4 78 86 22 39

Facility Contacts

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Hervé Dombret, MDPhD

Role: primary

+33 (0)1 57 27 68 47

References

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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.

Reference Type DERIVED
PMID: 38452207 (View on PubMed)

Other Identifiers

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AOM12629_1

Identifier Type: -

Identifier Source: org_study_id

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