Precision Diagnosis Directing HDACi Chidamide Target Therapy for Adult ETP-ALL
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2/Phase 3 |
Detailed 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: ETP-ALL 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
Chidamide will be administrated at a dose of 10mg/day in PDT-ETP-ALL protocol.
Other Names:
Drug: Dexamethasone
Dexamethasone will be added in Pre-phase Regimen, Induction-Regimen, Consolidation-Module of PDT-ETP-ALL protocol.
Other Names:
Drug: vincristine
Vincristine will be added to Induction-Regimen, Consolidation-Module and Maintenance-Module of PDT-ETP-ALL protocol.
Other Names:
Drug: Cyclophosphamide
CTX will be added to Induction-Regimen, Consolidation-Module and Maintenance-Module of PDT-ETP-ALL protocol.
Other Names:
Drug: Idarubicin
IDA will be added to Induction-Regimen and Consolidation-Module of PDT-ETP-ALL protocol.
Other Names:
Drug: Pegaspargase
PEG-ASP will be added to Induction-Regimen and Consolidation-Module of PDT-ETP-ALL protocol.
Other Names:
Drug: Adriamycin
Adriamycin will be added to Consolidation-Module of PDT-ETP-ALL protocol.
Other Names:
Drug: Methotrexate
Methotrexate will be added to consolidation module of PDT-ETP-ALL protocol.
Other Names:
Drug: 6-Mercaptopurine
Mercaptopurine will be added to Consolidation-Module and Maintenance-Module of PDT-ETP-ALL protocol.
Other Names:
Drug: Etoposide
VP-16 will be added to Consolidation-Module of PDT-ETP-ALL protocol.
Other Names:
Drug: Cytarabine
AraC will be added to Consolidation-Module of PDT-ETP-ALL protocol.
Other Names:
Procedure: Bone marrow aspiration
Bone marrow aspiration and additional tests will be performed in all module of PDT-ETP-ALL protocol.
Other Names:
Procedure: Intrathecal injection
Intrathecal injection chemotherapy will be performed in PDT-ETP-ALL protocol.
Other Names:
Radiation: Radiation therapy
Radiation therapy will be performed for mediastinum and/or central nervous system leukemia in PDT-ETP-ALL protocol.
Other Names:
Genetic: NGS
Next-Generation-Sequencing (NGS) will be performed in PDT-ETP-ALL protocol.
Procedure: allogeneic hematopoietic stem cell transplantation
Allo-HSCT will be performed for patients with available donor in PDT-ETP-ALL protocol.
Other Names:
Diagnostic Test: Flow-MRD
Flow-MRD will be added to PDT-ETP-ALL for bone marrow and cerebrospinal fluid samples.
Diagnostic Test: FISH
FISH will be performed in PDT-ETP-ALL for bone marrow samples.
Diagnostic Test: Flow immunophenotyping
Flow immunophenotyping will be performed in PDT-ETP-ALL protocol.
Diagnostic Test: Karyotyping
Karyotyping will be performed in PDT-ETP-ALL protocol.
|
Outcome Measures
Primary Outcome Measures
- Event free survival [3 years]
Secondary Outcome Measures
- 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]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
14-55 years old;
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ETP-ALL newly diagnosed;
-
signed written informed consent
Exclusion Criteria:
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Pregnant women;
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History of pancreatitis;
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History of diabetes;
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History of active peptic ulcer disease in the past 6 months;
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History of arteriovenous thrombosis in the past 6 months;
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Severe active infection;
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Allergic to any drugs in PDT-ETP-ALL.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Nanfang Hospital, Southern Medical University | Guangzhou | Guangdong | China | 510515 |
Sponsors and Collaborators
- Nanfang Hospital of Southern Medical University
Investigators
- Study Director: Hongsheng Zhou, MD, PhD, Nanfang Hospital, Southern Medical University, CHINA
Study Documents (Full-Text)
None provided.More Information
Publications
- Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405. doi: 10.1182/blood-2016-03-643544. Epub 2016 Apr 11. Review.
- Bond J, Graux C, Lhermitte L, Lara D, Cluzeau T, Leguay T, Cieslak A, Trinquand A, Pastoret C, Belhocine M, Spicuglia S, Lheritier V, Leprêtre S, Thomas X, Huguet F, Ifrah N, Dombret H, Macintyre E, Boissel N, Asnafi V. Early Response-Based Therapy Stratification Improves Survival in Adult Early Thymic Precursor Acute Lymphoblastic Leukemia: A Group for Research on Adult Acute Lymphoblastic Leukemia Study. J Clin Oncol. 2017 Aug 10;35(23):2683-2691. doi: 10.1200/JCO.2016.71.8585. Epub 2017 Jun 12.
- Koch U, Radtke F. Mechanisms of T cell development and transformation. Annu Rev Cell Dev Biol. 2011;27:539-62. doi: 10.1146/annurev-cellbio-092910-154008. Epub 2011 Jul 5. Review.
- Yu S, Zhou X, Steinke FC, Liu C, Chen SC, Zagorodna O, Jing X, Yokota Y, Meyerholz DK, Mullighan CG, Knudson CM, Zhao DM, Xue HH. The TCF-1 and LEF-1 transcription factors have cooperative and opposing roles in T cell development and malignancy. Immunity. 2012 Nov 16;37(5):813-26. doi: 10.1016/j.immuni.2012.08.009. Epub 2012 Oct 25. Erratum in: Immunity. 2014 Jan 16;40(1):166.
- PDT-ETP-ALL