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

Leukemia, Acute Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03553238
• Other study ID #: PDT-ETP-ALL
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: February 14, 2016
• Est. completion date: August 30, 2020

Study information

• Verified date: June 2018
• Source: Nanfang Hospital of Southern Medical University
• Contact: Hongsheng Zhou, MD, Ph.D
• Phone: +862062787349
• Email: zhs1[@]i.smu.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 70
• Est. completion date: August 30, 2020
• Est. primary completion date: May 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 14 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Acute
• Leukemia, Lymphoblastic
• Leukemia, T Cell
• Leukemia, T-Cell
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Chidamide
Chidamide will be administrated at a dose of 10mg/day in PDT-ETP-ALL protocol.
• Dexamethasone
Dexamethasone will be added in Pre-phase Regimen, Induction-Regimen, Consolidation-Module of PDT-ETP-ALL protocol.
• vincristine
Vincristine will be added to Induction-Regimen, Consolidation-Module and Maintenance-Module of PDT-ETP-ALL protocol.
• Cyclophosphamide
CTX will be added to Induction-Regimen, Consolidation-Module and Maintenance-Module of PDT-ETP-ALL protocol.
• Idarubicin
IDA will be added to Induction-Regimen and Consolidation-Module of PDT-ETP-ALL protocol.
• Pegaspargase
PEG-ASP will be added to Induction-Regimen and Consolidation-Module of PDT-ETP-ALL protocol.
• Adriamycin
Adriamycin will be added to Consolidation-Module of PDT-ETP-ALL protocol.
• Methotrexate
Methotrexate will be added to consolidation module of PDT-ETP-ALL protocol.
• 6-Mercaptopurine
Mercaptopurine will be added to Consolidation-Module and Maintenance-Module of PDT-ETP-ALL protocol.
• Etoposide
VP-16 will be added to Consolidation-Module of PDT-ETP-ALL protocol.
• Cytarabine
AraC will be added to Consolidation-Module of PDT-ETP-ALL protocol.

Procedure:
• Bone marrow aspiration
Bone marrow aspiration and additional tests will be performed in all module of PDT-ETP-ALL protocol.
• Intrathecal injection
Intrathecal injection chemotherapy will be performed in PDT-ETP-ALL protocol.

Radiation:
• Radiation therapy
Radiation therapy will be performed for mediastinum and/or central nervous system leukemia in PDT-ETP-ALL protocol.

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.

Diagnostic Test:
• Flow-MRD
Flow-MRD will be added to PDT-ETP-ALL for bone marrow and cerebrospinal fluid samples.
• FISH
FISH will be performed in PDT-ETP-ALL for bone marrow samples.
• Flow immunophenotyping
Flow immunophenotyping will be performed in PDT-ETP-ALL protocol.
• Karyotyping
Karyotyping will be performed in PDT-ETP-ALL protocol.

Locations

Country	Name	City	State
China	Nanfang Hospital, Southern Medical University	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Nanfang Hospital of Southern Medical University

Country where clinical trial is conducted

China, 

References & Publications (4)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event free survival		3 years
Secondary	Minimum residual disease after induction		3 months
Secondary	CR after Induction Therapy		3 years
Secondary	Death in induction		3 month
Secondary	Adverse events		3 years
Secondary	Relapse		3 years
Secondary	Relapse free survival		3 years
Secondary	Overall survival		3 years