Precision Diagnosis Directing HDACi and TKI Target Therapy for Adult Ph-like ALL

Overview

Ph-like ALL is a recently recognized high-risk subgroup and the optimal therapeutic approaches are poorly characterized. Based on the pediatric-inspired, PEG-L-asparaginase-intensified and MRD-directed PDT-ALL-2016 protocol, this open-label, two-arm, multi-site trial PDT-Ph-like-ALL is aimed to evaluate the safety and effect of oral histone deacetylase inhibitor chidamide and dasatinib for adult Ph-like ALL.

Full Title of Study: “An Open-Label, One-Arm, Multi-Site Trial of Precision Diagnosis Directing Target Total Therapy for Adult Ph-like Acute Lymphoblastic Leukemia”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: August 30, 2023

Detailed Description

Ph-like, or BCR-ABL1-like lymphoblastic leukemia is neoplasm of lymphoblasts committed to the B-cell lineage that lack the BCR-ABL1 translocation but show a pattern of the expression very similar to that seen in BCR-ABL1-positive ALL. Chidamide is a novel oral HDACi with promising activity in non-Hodgkin lymphoma (NHL). Based on the pediatric-inspired, PEG-L-asparaginase-intensified and MRD-directed PDT-ALL-2016 protocol, this open-label, two-arm, multi-site trial is aimed to evaluate the safety and effect of oral histone deacetylase inhibitor (HDACi) chidamide and tyrosine kinase inhibitor (TKI) dasatinib for adult Ph-like ALL/LBL. HDACi chidamide and TKI dasatinib will be added to chidamide and dasatinib group, respectively, from induction therapy to consolidation therapy (total courses of chidamide treatment: 5 courses for allo-HSCT after Consolidation Module-3; 12 courses for patients non-allo-HSCT after Consolidation Module 1-9). Primary study endpoint is event-free survival and secondary study endpoints are complete remission and MRD after induction, adverse event and overall survival. Pretreatment: Dexamethasone, -3 to 0d; Chidamide for chidamide arm: 10mg/d, po qd. Dasatinib for Dasatinib arm: 100mg/d, po qd. Induction:VCR: 1, 8, 15, 22; IDA: 1, 8; CTX: 1g/m2, 1; PEG-asp: 2000-2500IU/m2, 1, 15; Pred: 1-24; MRD assessment: d14, 24, 45, and pre-allo-HSCT. VLCAM (MRD1/d14>1%): CTX, d25; AraC 50mg/m2, d25-31, 26; 6-MP: 25-31, PEG-asp: 26; Consolidation Module: CM1: AraC 2g/m2, q12h, 1-2, Dex: 10mg/m2, 1-2, PEG-asp: 2, 6-MP: 1-7. IT: d1; CM2: MTX 3g/m2, 1, Dex: 10mg/m2, 1-2, PEG-asp: 2; 6-MP: 1-7; IT: d1; CM3: CTX 0.5g/m2, 1-3, PEG-asp: 2, 6-MP: 1-7, IT: d1. Allo-HSCT: after CM3 when donors available. Non-HSCT: finish CM 4-9 and POMP maintenance. CM4-6: repeat CM1-3. Re-Induction: after CM6. CM7-9: repeat CM1-3. Maintenance: POMP-Pred: x12m; VCR x12m; MTX: x24m; 6-MPx24m.

Interventions

  • Drug: Chidamide
    • Chidamide will be administrated at dose of 10mg/day in chidamide arm in PDT-Ph-Like protocol. PDT-Ph-Like protocol for chidamide arm consists of diagnostic test (bone marrow aspiration, flow immunophenotyping, karyotyping,FISH, NGS, Flow-MRD), induction regimen (chidamide, prednisone, vincristine, cyclophosphamide, idarubicin, pegaspargase), consolidation regimen (chidamide, cytarabine, methotrexate, dexamethasone, cyclophosphamide, etoposide, 6-mercaptopurine, pegaspargase), MRD assessment and maintenance regimen, intrathecal injection chemotherapy, radiation therapy for CNS-involved leukemia and allogeneic hematopoietic stem cell transplantation.
  • Drug: Dasatinib
    • Dasatinib will be administrated at a dose of 100mg/day in dasatinib arm in PDT-Ph-Like protocol. PDT-Ph-Like protocol for dasatinib arm consists of diagnostic test (bone marrow aspiration, flow immunophenotyping, karyotyping,FISH, NGS, Flow-MRD), induction regimen (dasatinib, prednisone, vincristine, cyclophosphamide, idarubicin, pegaspargase), consolidation regimen (dasatinib, cytarabine, methotrexate, dexamethasone, cyclophosphamide, etoposide, 6-mercaptopurine, pegaspargase), MRD assessment and maintenance regimen, intrathecal injection chemotherapy, radiation therapy for CNS-involved leukemia and allogeneic hematopoietic stem cell transplantation.

Arms, Groups and Cohorts

  • Experimental: Chidamide
    • Chidamide will be added to chidamide arm Ph-like ALL(CRLF2 high-expression, CRLF2/EPO/JAK2 rearrangement, JAK/IL-7R/SH2B3 mutation, etc).
  • Experimental: Dasatinib
    • Dasatinib at a dose of 100mg/day will be added to Dasatinib arm of Ph-like ALL (CRKL high-expression, ABL1 or ABL2 or CSFR1 or PRGFRB rearrangement, etc).

Clinical Trial Outcome Measures

Primary Measures

  • Event free survival
    • Time Frame: 3 years
    • EFS of Ph-like ALL group

Secondary Measures

  • Minimum residual disease after induction
    • Time Frame: 3 months
    • MRD after 1 course
  • CR after Induction Therapy
    • Time Frame: 3 months
    • CR rate of Ph-like group
  • Death in induction
    • Time Frame: 3 months
  • Adverse events
    • Time Frame: 3 years
    • AE during PDT-Ph-like
  • Relapse
    • Time Frame: 3 years
    • Relapse of Ph-like ALL
  • Relapse free survival
    • Time Frame: 3 years
    • RFS
  • Overall survival
    • Time Frame: 3 years
    • OS

Participating in This Clinical Trial

Inclusion Criteria

  • 14-55 years old; – Ph-like ALL newly diagnosed; – signed written informed consent Exclusion Criteria:

  • Pregnant women; – History of pancreatitis; – History of diabetes; – History of active peptic ulcer disease in the past 6 months; – History of arteriovenous thrombosis in the past 6 months; – Severe active infection; – Allergic to any drugs in PDT-Ph-like-ALL.

Gender Eligibility: All

Minimum Age: 14 Years

Maximum Age: 55 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Nanfang Hospital, Southern Medical University
  • Provider of Information About this Clinical Study
    • Principal Investigator: Hongsheng Zhou. M.D., Ph.D, M.D., Professor – Nanfang Hospital, Southern Medical University
  • Overall Contact(s)
    • Hongshengq Zhou, MD, Ph.D, 86-20-62787349, zhs1@i.smu.edu.cn

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