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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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An Open-Label, One-Arm, Multi-Site Trial of Precision Diagnosis Directing Histone Deacetylase Inhibitor Chidamide Target Total Therapy for Adult Early T-cell Progenitor Acute Lymphoblastic Leukemia/Lymphoma

Conditions
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Leukemia, Acute, Leukemia, T Cell, Leukemia, Lymphoblastic

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


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ETP-ALL<br>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. | Drug: Chidamide<br>* Chidamide will be administrated at a dose of 10mg/day in PDT-ETP-ALL protocol.<br>* Other names: HDACi chidamide;Drug: Dexamethasone<br>* Dexamethasone will be added in Pre-phase Regimen, Induction-Regimen, Consolidation-Module of PDT-ETP-ALL protocol.<br>* Other names: DXM;Drug: vincristine<br>* Vincristine will be added to Induction-Regimen, Consolidation-Module and Maintenance-Module of PDT-ETP-ALL protocol.<br>* Other names: VCR;Drug: Cyclophosphamide<br>* CTX will be added to Induction-Regimen, Consolidation-Module and Maintenance-Module of PDT-ETP-ALL protocol.<br>* Other names: CTX;Drug: Idarubicin<br>* IDA will be added to Induction-Regimen and Consolidation-Module of PDT-ETP-ALL protocol.<br>* Other names: IDA;Drug: Pegaspargase<br>* PEG-ASP will be added to Induction-Regimen and Consolidation-Module of PDT-ETP-ALL protocol.<br>* Other names: PEG-ASP;Drug: Adriamycin<br>* Adriamycin will be added to Consolidation-Module of PDT-ETP-ALL protocol.<br>* Other names: ADR;Drug: Methotrexate<br>* Methotrexate will be added to consolidation module of PDT-ETP-ALL protocol.<br>* Other names: MTX;Drug: 6-Mercaptopurine<br>* Mercaptopurine will be added to Consolidation-Module and Maintenance-Module of PDT-ETP-ALL protocol.<br>* Other names: 6-MP;Drug: Etoposide<br>* VP-16 will be added to Consolidation-Module of PDT-ETP-ALL protocol.<br>* Other names: VP-16;Drug: Cytarabine<br>* AraC will be added to Consolidation-Module of PDT-ETP-ALL protocol.<br>* Other names: AraC;Procedure: Bone marrow aspiration<br>* Bone marrow aspiration and additional tests will be performed in all module of PDT-ETP-ALL protocol.<br>* Other names: BM test;Procedure: Intrathecal injection<br>* Intrathecal injection chemotherapy will be performed in PDT-ETP-ALL protocol.<br>* Other names: IT;Radiation: Radiation therapy<br>* Radiation therapy will be performed for mediastinum and/or central nervous system leukemia in PDT-ETP-ALL protocol.<br>* Other names: RT;Genetic: NGS<br>* Next-Generation-Sequencing (NGS) will be performed in PDT-ETP-ALL protocol.<br>Procedure: allogeneic hematopoietic stem cell transplantation<br>* Allo-HSCT will be performed for patients with available donor in PDT-ETP-ALL protocol.<br>* Other names: allo-HSCT;Diagnostic Test: Flow-MRD<br>* Flow-MRD will be added to PDT-ETP-ALL for bone marrow and cerebrospinal fluid samples.<br>Diagnostic Test: FISH<br>* FISH will be performed in PDT-ETP-ALL for bone marrow samples.<br>Diagnostic Test: Flow immunophenotyping<br>* Flow immunophenotyping will be performed in PDT-ETP-ALL protocol.<br>Diagnostic Test: Karyotyping<br>* Karyotyping will be performed in PDT-ETP-ALL protocol.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimum residual disease after induction |  | 3 months | 
| CR after Induction Therapy |  | 3 years | 
| Death in induction |  | 3 month | 
| Adverse events |  | 3 years | 
| Relapse |  | 3 years | 
| Relapse free survival |  | 3 years | 
| Overall survival |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Early T-cell Precursor, Acute Lymphoblastic Leukemia, Histone Deacetylase Inhibitor, Chidamide