Precision Diagnosis Directing HDACi Chidamide Target Therapy for Adult ETP-ALL

Nanfang Hospital, Southern Medical University

Status and phase: Unknown; Phase 3; Phase 2

Conditions: Leukemia, Lymphoblastic; Leukemia, Acute; Leukemia, T Cell

Treatments: Drug: Methotrexate; Drug: 6-Mercaptopurine; Drug: Chidamide; Procedure: allogeneic hematopoietic stem cell transplantation; Diagnostic Test: Flow-MRD; Diagnostic Test: Karyotyping; Radiation: Radiation therapy; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Etoposide; Drug: Adriamycin; Procedure: Bone marrow aspiration; Diagnostic Test: FISH; Drug: Dexamethasone; Procedure: Intrathecal injection; Drug: Idarubicin; Diagnostic Test: Flow immunophenotyping; Drug: vincristine; Drug: Pegaspargase; Genetic: NGS

Study type: Interventional

Funder types: Other

Identifiers

NCT03553238

PDT-ETP-ALL

Details and patient eligibility

About

ETP-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, one-arm, multi-site trial is aimed to evaluate the safety and effect of a novel oral histone deacetylase inhibitor chidamide for adult ETP-ALL/LBL in CHINA.

Full description

Early T-cell precursor (ETP) lymphoblastic leukemia (ETP-ALL) is a neoplasm composed of cells committed to the T-cell lineage but with an unique immunophenotype indicating only limited early T differentiation. In the highly orchestrated development of T cell fate specification under physiological condition, the most immature early thymic progenitors (ETPs) retain multilineage potentials. ETP-ALL blasts have a characteristic immunophenotype, with reduced/absent expression of T-lymphoid markers CD1a, CD5, CD8; and positivity for at least one HSC and/or myeloid antigen CD34, CD117, HLA-DR, CD13, CD33, CD11b, CD65. Recent study shed light on the genetic landscape of adult ETP-ALL, which revealed that more than 40% adult ETP-ALL harbored histone modification mutations. 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, one-arm, multi-site trial is aimed to evaluate the safety and effect of a novel oral histone deacetylase inhibitor chidamide for adult ETP-ALL/LBL. HDACi chidamide at a dose of 10mg/day will be added to ETP-ALL group 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 of PDT-ETP-ALL is event-free survival of ETP-ALL group and secondary study endpoints are complete remission and MRD after induction, adverse event and overall survival of ETP-ALL group.

Pretreatment: Dexamethasone, -3 to 0d;

Induction:VCR: 1, 8, 15, 22; IDA: 1, 8; CTX: 1g/m2, 1, 8; PEG-asp: 2000-2500IU/m2, 1, 15; Dex: 1-24, chidamide: 10mg/d, po, qd.

MRD: d14, 24, 45, and pre-allo-HSCT.

VLCAM (MRD1/d14>1%): CTX, d25; AraC 2g/m2, q12h, d25, 26; 6-MP: 25-31, PEG-asp: 26; chidamide: 10mg/d, po, qd.

Consolidation Module:

CM-1: AraC 3g/m2, q12h, 1-2, Dex: 10mg/m2, 1-2, PEG-asp: 2, 6-MP: 1-7. IT: d1, chidamide: 10mg/d, po, qd.

CM-2: MTX 5g/m2, 1, Dex: 10mg/m2, 1-2, PEG-asp: 2; 6-MP: 1-7; IT: d1; chidamide: 10mg/d, po, qd.

CM-3: CTX 0.5g/m2, 1-3, PEG-asp: 2, Doxorubicin: 40mg/m2, 4, 6-MP: 1-7, IT: d1;chidamide: 10mg/d, po, qd.

Allo-HSCT: after CM-3 when donors available. Non-HSCT: finish CM 4-9 and POMP maintenance.

CM 4-6: repeat CM 1-3. Re-Induction: after CM-6. CM 7-9: repeat CM1-3.

Maintenance: CPOMP-chidamide 10mg/d, po, qd; Pred for 12 months; VCR for 12 months; MTX for 24 months; 6-MP for 24 months.

Enrollment: 70 estimated patients

Sex: All

Ages: 14 to 55 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 14-55 years old;
• ETP-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-ETP-ALL.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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70 participants in 1 patient group

ETP-ALL

Experimental group

Description:

Chidamide at a dose of 10mg/day will be added to PDT-ETP-ALL protocol. The intervention of PDT-ETP-ALL consists of diagnostic test (bone marrow aspiration, flow immunophenotyping, Karyotyping ，FISH, NGS, Flow-MRD, PET-CT scan), induction regimen (chidamide, dexamethasone, vincristine, cyclophosphamide, idarubicin, pegaspargase), consolidation regimen (chidamide, prednisone, cytarabine, methotrexate, cyclophosphamide, etoposide, adriamycin, 6-mercaptopurine, pegaspargase), MRD assessment and maintenance regimen (chidamide, prednisone, vincristine, methotrexate, 6-mercaptopurine), intrathecal injection chemotherapy, radiation therapy (for mediastinum- and/or central nervous system-involved lymphoma/leukemia) and allogeneic hematopoietic stem cell transplantation for patients with donor.

Treatment:

Drug: Pegaspargase

Drug: vincristine

Drug: Idarubicin

Diagnostic Test: Flow-MRD

Procedure: Intrathecal injection

Drug: Dexamethasone

Diagnostic Test: Karyotyping

Procedure: Bone marrow aspiration

Drug: Adriamycin

Diagnostic Test: Flow immunophenotyping

Drug: Etoposide

Genetic: NGS

Drug: Cytarabine

Drug: Cyclophosphamide

Radiation: Radiation therapy

Diagnostic Test: FISH

Procedure: allogeneic hematopoietic stem cell transplantation

Drug: 6-Mercaptopurine

Drug: Chidamide

Drug: Methotrexate