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

NCT02611492 | Unknown Phase 3 DMC

• 1 other identifier: AOM12629_1
• Study Type: interventional
• Target: 265
• Locations: 1 country
• Sites: 1

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)

Conditions

Philadelphia Chromosome Positive Adult Acute Lymphoblastic Leukemia

Outcome Measures

Primary Outcomes (1)

• Major Molecular Response (MMolR)

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

  4 cycles (4 months)

Secondary Outcomes (8)

• Complete remission after cycle 1

  day 28

• Cumulative incidence of treatment- and transplantation-related mortality

  2 years

• Cumulative incidence of relapse

  10 years

• Relapse free survival

  10 years

• Event-free survival

  10 years

Study Arms (2)

Intensive Arm (A)

ACTIVE COMPARATOR

4 cycles + 2 interphases +Hematopoietic Stem Cell Transplantation (SCT) \+ Post-SCT Maintenance

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)

EXPERIMENTAL

4 cycles + 2 interphases +Hematopoietic Stem Cell Transplantation (SCT) \+ Post-SCT Maintenance

Drug: Nilotinib; Drug: Methotrexate; Drug: Granulocyte Colony-Stimulating Factor (G-CSF); Drug: Depomedrol; Drug: Dexamethasone; Drug: Vincristine; Drug: Imatinib; Drug: 6 Mercaptopurine (6MP)

Interventions

Nilotinib DRUG

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

Intensive Arm (A); Light Arm (B)

Methotrexate DRUG

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

Intensive Arm (A); Light Arm (B)

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

Intensive Arm (A)

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

Intensive Arm (A); Light Arm (B)

Depomedrol 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

Intensive Arm (A); Light Arm (B)

Dexamethasone DRUG

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

Intensive Arm (A); Light Arm (B)

Vincristine DRUG

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

Intensive Arm (A); Light Arm (B)

Imatinib DRUG

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

Intensive Arm (A); Light Arm (B)

6 Mercaptopurine (6MP) DRUG

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

Intensive Arm (A); Light Arm (B)

Eligibility Criteria

• Age: 18 Years - 59 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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
• 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.

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Hopital Saint Louis

Paris, 75010, France

RECRUITING

Related Publications (1)

• 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.

  PMID: 38452207 DERIVED

MeSH Terms

Interventions

nilotinib; Methotrexate; Cytarabine; Granulocyte Colony-Stimulating Factor; Dexamethasone; Vincristine; Imatinib Mesylate; Mercaptopurine

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Indolizidines; Indolizines; Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Sulfhydryl Compounds; Sulfur Compounds; Purines

Central Study Contacts

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 19, 2015
• First Posted: November 20, 2015
• Study Start: April 1, 2016
• Primary Completion: December 1, 2020
• Study Completion: December 1, 2025
• Last Updated: October 21, 2019

Record last verified: 2019-09

Locations

FR (1)