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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.

Dexamethasone will be added in Pre-phase Regimen, Induction-Regimen, Consolidation-Module of PDT-ALL-LBL protocol.

Vincristine will be added to Induction-Regimen, Consolidation-Module and Maintenance-Module of PDT-ALL-LBL protocol.

vincristine

CTX will be added to Induction-Regimen, Consolidation-Module and Maintenance-Module of PDT-ALL-LBL protocol.

IDA will be added to Induction-Regimen and Consolidation-Module of PDT-ALL-LBL protocol.

PEG-ASP will be added to Induction-Regimen and Consolidation-Module of PDT-ALL-LBL protocol.

Adriamycin will be added to Consolidation-Module of PDT-ALL-LBL protocol.

Adriamycin

Methotrexate will be added to Consolidation-Module of PDT-ALL-LBL protocol.

Mercaptopurine will be added to Consolidation-Module and Maintenance-Module of PDT-ALL-LBL protocol.

6-mercaptopurine.

VP-16 will be added to Consolidation-Module of PDT-ALL-LBL protocol.

AraC will be added to Consolidation-Module of PDT-ALL-LBL protocol.

Bone marrow aspiration and additional tests will be performed in all module of PDT-ALL-LBL protocol.

Bone marrow aspiration

Intrathecal injection of chemotherapy will be performed in PDT-ALL-LBL protocol.

Intrathecal injection

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

Radiation therapy

Next-Generation-Sequencing (NGS) will be performed in PDT-ALL-LBL protocol.

Allo-HSCT will be added to LBL patients with available donor in PDT-ALL-LBL protocol.

allogeneic hematopoietic stem cell transplantation

Flow-MRD will be added to PDT-ALL-LBL for bone marrow and cerebrospinal fluid samples.

Flow-MRD

FISH will be added to PDT-ALL-LBL for bone marrow samples.

FISH

Flow immunophenotyping will be performed in PDT-ALL-LBL protocol.

Flow immunophenotyping

Karyotyping will be performed in PDT-ALL-LBL protocol.

Karyotyping

HDACi chidamide will be added to induction regimen, consolidation and maintenance module of PDT-ALL-LBL.

Chidamide

PET-scan will be performed for T-LBL patients for MRD assessment in PDT-ALL-LBL.

PET-CT scan

Hongsheng Zhou

Qifa Liu, MD

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.

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.

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

An Open-Label, One-Arm, Multi-Site Trial of Precision Diagnosis Directing Histone Deacetylase Inhibitor Chidamide Total Therapy for Adult T-lymphoblastic Lymphoma/Leukemia

3 years EFS of LBL/ALL patients enrolled in PDT-ALL-LBL

MRD after induction regimen of PDT-ALL-LBL protocol

CR after induction regimen of PDT-ALL-LBL protocol

Dearth during induction regimen of PDT-ALL-LBL

AE of 3 years of LBL patients enrolled in PDT-ALL-LBL

Cumulative incidence relapse rate of 3 years of LBL patients enrolled in PDT-ALL-LBL protocol

3 years RFS of LBL patients enrolled in PDT-ALL-LBL protocol

3 years OS of LBL patients enrolled in PDT-ALL-LBL protocol

Nanfang Hospital, Southern Medical University

M.D., Professor

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.

Chidamide will be administrated at a dose of 10mg/day in PDT-ETP-ALL protocol.

Dexamethasone will be added in Pre-phase Regimen, Induction-Regimen, Consolidation-Module of PDT-ETP-ALL protocol.

Vincristine will be added to Induction-Regimen, Consolidation-Module and Maintenance-Module of PDT-ETP-ALL protocol.

CTX will be added to Induction-Regimen, Consolidation-Module and Maintenance-Module of PDT-ETP-ALL protocol.

IDA will be added to Induction-Regimen and Consolidation-Module of PDT-ETP-ALL protocol.

PEG-ASP will be added to Induction-Regimen and Consolidation-Module of PDT-ETP-ALL protocol.

Adriamycin will be added to Consolidation-Module of PDT-ETP-ALL protocol.

Methotrexate will be added to consolidation module of PDT-ETP-ALL protocol.

Mercaptopurine will be added to Consolidation-Module and Maintenance-Module of PDT-ETP-ALL protocol.

6-Mercaptopurine

VP-16 will be added to Consolidation-Module of PDT-ETP-ALL protocol.

AraC will be added to Consolidation-Module of PDT-ETP-ALL protocol.

Bone marrow aspiration and additional tests will be performed in all module of PDT-ETP-ALL protocol.

Intrathecal injection chemotherapy will be performed in PDT-ETP-ALL protocol.

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

Next-Generation-Sequencing (NGS) will be performed in PDT-ETP-ALL protocol.

Allo-HSCT will be performed for patients with available donor in PDT-ETP-ALL protocol.

Flow-MRD will be added to PDT-ETP-ALL for bone marrow and cerebrospinal fluid samples.

FISH will be performed in PDT-ETP-ALL for bone marrow samples.

Flow immunophenotyping will be performed in PDT-ETP-ALL protocol.

Karyotyping will be performed in PDT-ETP-ALL protocol.

Hongsheng Zhou, MD, Ph.D

Hongsheng Zhou, MD, PhD

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.

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.

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

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

Skin and Connective Tissue Diseases

Symptoms and General Pathology

Nervous System Diseases

Breast Neoplasms

Neoplasm Metastasis

Meningeal Carcinomatosis

Meningeal Neoplasms

Breast Diseases

Skin Diseases

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Trastuzumab

Tucatinib

Capecitabine

Antineoplastic Agents, Immunological

Protein Kinase Inhibitors

Intra-CSF trastuzumab: 150 mg weekly Tucatinib: 300 mg orally twice daily Capecitabine: 1000 mg/m² orally twice daily on days 1-14 of each 21-day cycle

Tucatinib Oral Tablet

1000 mg/m², twice daily on days 1-14 of each 21-day cycle

Capecitabine tablets

Intrathecal by lumbar puncture or Ommaya Reservoir, 150 mg weekly

Trastuzumab Injection

Telma ROQUE, PhD

Jérôme LEMONNIER, PhD

Laura SALABERT, MD

George EMILE, MD

Xavier DURANDO, Prof

Isabelle DESMOULINS, MD

Louis LARROUQUERE, MD

Amélie DARLIX, MD

Caroline BAILLEUX, MD

Christelle JOUANNAUD, MD

Jean-Christophe THERY, MD

Philippe TRENZ, MD

Nicolas EPAILLARD, MD

Louis LARROUQUERE

The goal of this clinical trial is to evaluate the efficacy of tucatinib and capecitabine in combination with intrathecal trastuzumab on overall survival rate at 12 months in HER2-positive metastatic breast cancer (MBC) patients with proven leptomeningeal evolution and requiring intrathecal therapy.

Capecitabine, Tucatinib, and Intrathecal Trastuzumab for Breast Cancer Patients With Leptomeningeal Disease

Multicentric Single Arm Phase II Study Evaluating the Efficacy of Association of Tucatinib, Capecitabine and Intra-CSF Trastuzumab in HER2 Amplified Breast Cancer Patients With Leptomeningeal Metastases

Individual Participant Data will not be shared at an individual level. Those data will be part of the study database including all enrolled patients.

12-month overall survival will be defined as the proportion of patients alive 12 months after treatment initiation.

Clinical neurological symptoms relief will be defined as complete or partial diminution of symptoms associated to leptomeningeal metastasis using the neurologic assessment in neuro-oncology (NANO) scale, a standardized questionnaire designed to measure neurological function in oncology.

The questionnaire includes 5 domains scored 0-3 (gait, strength, visual fields, language, and level of consciousness) and 4 domains scored 0-2 (ataxia of upper extremities, sensation, facial strength, and behavior). Scores are sum up to a maximum of 23 points with high-scale values representing impaired neurological performances.

The progression-free survival (PFS) is the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse.

The overall survival (OS) is the length of time from inclusion in the study that patients are still alive.

Developed by the EORTC, this self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials.

The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease.

All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.

This EORTC brain cancer specific questionnaire is intended to supplement the QLQ-C30.

The QLQ-BN20 contains 20 items organized into four scales (three items each: future uncertainty, visual disorder, motor dysfunction, and communication deficit), and seven single items (headaches, seizures, drowsiness, hair loss, itchy skin, weakness of legs, and bladder control). All items are rated on a four-point Likert-type scale (1 = "not at all", 2 = "a little", 3 = "quite a bit", and 4 = "very much"), and are linearly transformed to a 0-100 scale, with higher scores indicating more severe symptoms.

Intra-cerebrospinal fluid (CSF) response at 4 weeks will be defined by absence, evaluated by the cytologist, of tumor cells in the intra-cerebrospinal fluid of the patient.

Duration of LM response is the length of time from first intracranial objective response and disease progression.

For this outcome, disease progression is defined as the length of time during and after the treatment of a disease that a patient lives with the leptomeningeal metastases but they does not get worse.

The Montreal Cognitive Assessment (MoCA) is a widely used screening assessment for detecting cognitive dysfunctions.

The test is a 30-point test assesses different cognitive domains: attention and concentration (5 points), executive functions (4 points), memory (2 points), language (5 points), visuospatial skills (4 points), conceptual thinking (1 point), calculations (3 points), and orientation (6 points). MoCA scores range between 0 and 30, a score of 26 or over is considered normal.

The National Cancer Institute-Common Terminology Criteria for Adverse Events version 5 (NCI-CTCAE v5) is widely accepted in the community of oncology research as the leading rating scale for adverse events. This scale, divided into 5 grades (1 = "mild", 2 = "moderate", 3 = "severe", 4 = "life-threatening", and 5 = "death") determined by the investigator, will make it possible to assess the severity of the disorders.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Precision Diagnosis Directing HDACi Chidamide Target Therapy for Adult T-LBL/ALL	NCT03564704	Leukemia Leukemia, Acute Adult Lymphobla... Leukemia, Lymph... Leukemia, T Cel... Adult Acute Lym... Lymphoblastic L... Lymphoblastic L...	Dexamethasone vincristine Cyclophosphamid... Idarubicin Pegaspargase Adriamycin Methotrexate 6-mercaptopurin... Etoposide Cytarabine Bone marrow asp... Intrathecal inj... Radiation thera... NGS allogeneic hema... Flow-MRD FISH Flow immunophen... Karyotyping Chidamide PET-CT scan	14 Years - 55 Years	Nanfang Hospital, Southern Medical University
Precision Diagnosis Directing HDACi Chidamide Target Therapy for Adult ETP-ALL	NCT03553238	Leukemia, Acute Leukemia, T Cel... Leukemia, Lymph...	Chidamide Dexamethasone vincristine Cyclophosphamid... Idarubicin Pegaspargase Adriamycin Methotrexate 6-Mercaptopurin... Etoposide Cytarabine Bone marrow asp... Intrathecal inj... Radiation thera... NGS allogeneic hema... Flow-MRD FISH Flow immunophen... Karyotyping	14 Years - 55 Years	Nanfang Hospital, Southern Medical University
Precision Diagnosis Directing HDACi Chidamide Target Therapy for Adult ETP-ALL	NCT03553238	Leukemia, Acute Leukemia, T Cel... Leukemia, Lymph...	Chidamide Dexamethasone vincristine Cyclophosphamid... Idarubicin Pegaspargase Adriamycin Methotrexate 6-Mercaptopurin... Etoposide Cytarabine Bone marrow asp... Intrathecal inj... Radiation thera... NGS allogeneic hema... Flow-MRD FISH Flow immunophen... Karyotyping	14 Years - 55 Years	Nanfang Hospital, Southern Medical University
Capecitabine, Tucatinib, and Intrathecal Trastuzumab for Breast Cancer Patients With Leptomeningeal Disease	NCT05800275	Leptomeningeal ... Leptomeningeal ... HER2-positive M...	Tucatinib Oral ... Capecitabine ta... Trastuzumab Inj...	18 Years -	UNICANCER
A Study for Improving the Outcome of Childhood Acute Promyeloid Leukemia	NCT02200978	Childhood Acute...	ATO RIF ATRA mitoxantrone Ara-C MTX 6MP intrathecal inj...	- 16 Years	South China Children's Leukemia Group

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