Precision Diagnosis Directing HDACi Chidamide Target Therapy for Adult T-LBL/ALL

Study Overview
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Brief Summary
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Based on the pediatric-inspired, PEG-L-asparaginase-intensified and MRD-directed PDT-ALL-2016 protocol, this open-label, one-arm, multi-site trial PDT-ALL-LBL is aimed to evaluate the safety and effect of oral histone deacetylase inhibitor chidamide for adult T-ALL/LBL. Compared to PDT-ALL-2016 for B-ALL, HDACi chidamide will be administrated from induction therapy to maintenance therapy, along with higher dose of consolidation regimen of cytarabine, methotrexate, cyclophosphamide.

Detailed Description
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T-lymphoblastic lymphoma/leukemia is a neoplasm of lymphoblasts committed to the T-cell lineage, typically composed of small to medium-sized blast with scant cytoplasm, moderately condensed to dispersed chromatin, and inconspicuous nucleoli, involving bone marrow and blood or presenting with primary involvement of the thymus or of nodal or extranodal sites. T-ALL/LBL is generally considered a higher-risk disease than B-ALL. Compared to B-ALL, T-LBL/ALL is associated with a higher risk of induction failure, early relapse, and isolated CNS relapse. Chidamide is a novel oral HDACi with promising activity in non-Hodgkin lymphoma (NHL). Chidamide, a new oral isotype-selective HDACi, approved in China for the treatment of R/R PTCL in December 2014. 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-ALL-LBL is aimed to evaluate the safety and effect of oral histone deacetylase inhibitor chidamide for adult T-ALL/LBL. Compared to PDT-ALL-2016 for B-ALL, HDACi chidamide will be administrated from induction therapy to maintenance therapy, along with higher dose of consolidation regimen of cytarabine, methotrexate, cyclophosphamide. The intervention of PDT-ALL-LBL consists of diagnostic test (bone marrow aspiration, flow immunophenotyping, karyotyping，FISH, NGS, Flow-MRD), induction regimen (chidamide, dexamethasone, vincristine, cyclophosphamide, Idarubicin, pegaspargase), consolidation regimen (chidamide, prednisone, cytarabine, methotrexate, cyclophosphamide, etoposide, adriamycin, 6-mercaptopurine, pegaspargase), MRD assessment (MRD1/d14, MRD2/d24, MRD3/d45, MRD4/pre-allo-HSCT) and maintenance regimen (chidamide, vincristine, methotrexate, 6-mercaptopurine), intrathecal injection, radiation therapy (for mediastinum- and/or central nervous system-involved lymphoma/leukemia) and allogeneic hematopoietic stem cell transplantation for patients with donor. Induction Regimen-Pretreatment: dexamethasone, -3d to 0d; Induction regimen VICLD: VCR: d1, d8, d15, d22; IDA: d1, d8; CTX: 1g/m2, 1; PEG-asp: 2000-2500IU/m2, 1, 15; dexamethasone: 1-24; chidamide: 10mg/d, po, qd. Flow-based MRD assessment: d14, d24 during induction regimen, d45, and pre-HSCT. Salvage regimen VLCAM (MRD1/d24>1%): CTX, d25; AraC 50mg/m2, d25-31; 6-MP: 25-31, PEG-asp: 2500IU/m2, d26. Consolidation Module (CM)-CM1: AraC 3g/m2, q12h, d1-2, Dex: 10mg/m2, d1-2, PEG-asp: 2, 6-MP: d1-7, chidamide, po qd; CM2: MTX 5g/m2, 1, Dex: 10mg/m2, 1-2, PEG-asp: d2, 6-MP: 1-7, chidamide, po qd; CM3: CTX 1g/m2, 1-3, PEG-asp: 2, 6-MP: 1-7, chidamide, po qd. CM4-6: repeat CM 1-3. Re-Induction: VICLD after CM6. CM7-9: repeat CM1-3. Allo-HSCT: after CM3 when matched-related-donor (MRD), haploidentical related donor (HRD) or matched-unrelated-donor (MUD) available. Non-allo-HSCT: finish CM4-9 and CPOMP maintenance. Maintenance Module-CPOMP: chidamide, po qd for 24 months; Pred: for 12 months; VCR for 12 months; MTX: for 24m 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 Total Therapy for Adult T-lymphoblastic Lymphoma/Leukemia

Conditions
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Adult Acute Lymphoblastic Leukemia, Lymphoblastic Lymphoma, Lymphoblastic Leukemia, Leukemia, Leukemia, Acute, Adult Lymphoblastic Lymphoma, Leukemia, Lymphoblastic, Leukemia, T Cell

Intervention / Treatment
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* 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
* Drug: Chidamide
* Diagnostic Test: PET-CT scan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 14-55 years old; LBL/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-ALL-LBL protocol.

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: PDT-ALL-LBL<br>The intervention of PDT-ALL-LBL 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 (methotrexate, cytarabine, dexamethasone), radiation therapy (for mediastinum- and/or central nervous system-involved lymphoma/leukemia) and allogeneic hematopoietic stem cell transplantation for patients with donor. | Drug: Dexamethasone<br>* Dexamethasone will be added in Pre-phase Regimen, Induction-Regimen, Consolidation-Module of PDT-ALL-LBL protocol.<br>* Other names: DXM;Drug: vincristine<br>* Vincristine will be added to Induction-Regimen, Consolidation-Module and Maintenance-Module of PDT-ALL-LBL protocol.<br>* Other names: VCR;Drug: Cyclophosphamide<br>* CTX will be added to Induction-Regimen, Consolidation-Module and Maintenance-Module of PDT-ALL-LBL protocol.<br>* Other names: CTX;Drug: Idarubicin<br>* IDA will be added to Induction-Regimen and Consolidation-Module of PDT-ALL-LBL protocol.<br>* Other names: IDA;Drug: Pegaspargase<br>* PEG-ASP will be added to Induction-Regimen and Consolidation-Module of PDT-ALL-LBL protocol.<br>* Other names: PEG-ASP;Drug: Adriamycin<br>* Adriamycin will be added to Consolidation-Module of PDT-ALL-LBL protocol.<br>* Other names: ADR;Drug: Methotrexate<br>* Methotrexate will be added to Consolidation-Module of PDT-ALL-LBL protocol.<br>* Other names: MTX;Drug: 6-mercaptopurine.<br>* Mercaptopurine will be added to Consolidation-Module and Maintenance-Module of PDT-ALL-LBL protocol.<br>* Other names: 6-MP;Drug: Etoposide<br>* VP-16 will be added to Consolidation-Module of PDT-ALL-LBL protocol.<br>* Other names: VP-16;Drug: Cytarabine<br>* AraC will be added to Consolidation-Module of PDT-ALL-LBL protocol.<br>* Other names: AraC;Procedure: Bone marrow aspiration<br>* Bone marrow aspiration and additional tests will be performed in all module of PDT-ALL-LBL protocol.<br>* Other names: BM smear;Procedure: Intrathecal injection<br>* Intrathecal injection of chemotherapy will be performed in PDT-ALL-LBL protocol.<br>* Other names: IT;Radiation: Radiation therapy<br>* Radiation therapy will be performed for mediastinum and/or central nervous system leukemia/lymphoma in PDT-ALL-LBL protocol.<br>* Other names: RT;Genetic: NGS<br>* Next-Generation-Sequencing (NGS) will be performed in PDT-ALL-LBL protocol.<br>Procedure: allogeneic hematopoietic stem cell transplantation<br>* Allo-HSCT will be added to LBL patients with available donor in PDT-ALL-LBL protocol.<br>* Other names: Allo-HSCT;Diagnostic Test: Flow-MRD<br>* Flow-MRD will be added to PDT-ALL-LBL for bone marrow and cerebrospinal fluid samples.<br>Diagnostic Test: FISH<br>* FISH will be added to PDT-ALL-LBL for bone marrow samples.<br>Diagnostic Test: Flow immunophenotyping<br>* Flow immunophenotyping will be performed in PDT-ALL-LBL protocol.<br>Diagnostic Test: Karyotyping<br>* Karyotyping will be performed in PDT-ALL-LBL protocol.<br>Drug: Chidamide<br>* HDACi chidamide will be added to induction regimen, consolidation and maintenance module of PDT-ALL-LBL.<br>* Other names: HDACi Chidamide;Diagnostic Test: PET-CT scan<br>* PET-scan will be performed for T-LBL patients for MRD assessment in PDT-ALL-LBL.<br>* Other names: PET-CT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free-Survival | 3 years EFS of LBL/ALL patients enrolled in PDT-ALL-LBL | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimum residual disease after induction | MRD after induction regimen of PDT-ALL-LBL protocol | 3 months | 
| CR after Induction Therapy | CR after induction regimen of PDT-ALL-LBL protocol | 3 months | 
| Death in induction | Dearth during induction regimen of PDT-ALL-LBL | 3 months | 
| Adverse events | AE of 3 years of LBL patients enrolled in PDT-ALL-LBL | 3 years | 
| Relapse | Cumulative incidence relapse rate of 3 years of LBL patients enrolled in PDT-ALL-LBL protocol | 3 years | 
| Relapse free survival | 3 years RFS of LBL patients enrolled in PDT-ALL-LBL protocol | 3 years | 
| Overall survival | 3 years OS of LBL patients enrolled in PDT-ALL-LBL protocol | 3 years |