Phase III Study of Tucidinostat in Combination With R-CHOP in Patients With Newly Diagnosed Double-Expressor DLBCL
Phase III Study of Tucidinostat in Combination With R-CHOP in Patients With Newly Diagnosed Double-Expressor DLBCL
Tucidinostat (formerly known as chidamide) is an oral subtype-selective histone deacetylase
 inhibitor. This Randomized, Double-blind, Placebo-controlled Phase 3 trail is studying the
 efficacy and safety of Tucidinostat, in Combination with Rituximab, Cyclophosphamide,
 Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Subjects With Newly Diagnosed MYC/BCL2
 Double-Expressor Diffuse Large B-cell Lymphoma.
The primary objective is to evaluate if the addition of Tucidinostat to rituximab,
 cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) prolongs event-free
 survival (EFS) compared with R-CHOP alone in subjects with newly diagnosed MYC/BCL2
 Double-Expressor subtype of DLBCL selected by IHC and FISH.
Inclusion Criteria:

 -  Each potential subject must satisfy all of the following criteria to be enrolled in
 the study.

 1. Male or female, age ≥ 18 years and ≤80 years.

 2. No prior treatment for diffuse large B cell lymphoma(DLBCL), including
 hemotherapy, immunotherapy; radiotherapy (excluding local radiotherapy);
 monoclonal antibody therapy; surgical treatment (excluding biopsy)

 3. Histological or cytological confirmation of DLBCL

 1. CD20-positive DLBCL;

 2. Myc≥40% as well as Bcl-2≥50% through immunohistochemistry;

 3. Not with double (BCL-2 and c-MYC gene rearrangement) or triple (BCL-2, BCL-6, and
 c-MYC gene rearrangement) hit by FISH.

 The verification of DLBCL will be based on local pathology report.15-20 unstained slides
 must be sent to the central laboratory for retrospective confirmation.

 4.At least one positive lesion according to the Lugano Classification by fluorodeoxyglucose
 (FDG) positron emission tomography (PET)-computed tomography(CT).

 5.Lymphoma International PrognosisIndex (IPI) score of 2,3,4. 6.Eastern Cooperative
 Oncology Group performance status grade of 0, 1, or 2. 7.Laboratory criteria are as follows
 except that caused by lymphoma assessed by the investigator (without receiving any
 supportive treatment for the following parameters within 2 weeks from the last dose prior
 to study entry):

 (1)Hematology values:Hemoglobin (Hb)≥90g/L ; Absolute neutrophil count (ANC) ≥1.5×109/L ;
 platelets ≥90×109/L (2)Biochemical values: Serum creatinine ≤1.5×upper limit of
 normal(ULN); Total bilirubin ≤1.5 × ULN; Alanine aminotransferase (ALT), Aspartate
 aminotransferase (AST) ≤2.5×ULN(ALT,AST≦5×ULN if liver involved).

 8.Expected survival≥6 months. 9.All patients must have signed an informed consent document.

 Exclusion Criteria:

 -  Any potential subject who meets any of the following criteria will be excluded from
 participating in the study.

 1. Presence of CNS involvement.

 2. Patients with primary DLBCL of the central nervous system (CNS),or secondary
 lymphoma of the central nervous system, or Primary mediastinal (thymic) large
 B-cell lymphoma, or Primary effusion lymphoma, or B-cell lymphoma,
 unclassifiable, with features intermediate between DLBCL and classical Hodgkin
 lymphoma, or Primary cutaneous DLBCL, leg type, or indolent lymphoma, or Burkitt
 lymphoma, or EBV-positive mucocutaneous ulcer, or DLBCL associated with chronic
 inflammation, or Lymphomatoid granulomatosis, or Intravascular large B-cell
 lymphoma, or ALK-positive large B-cell lymphoma, or Plasmablastic lymphoma, or
 HHV8-positive DLBCL, NOS, or primary testicular DLBCL.

 3. Patients with transformed lymphoma.

 4. History of organ transplantation or hematopoietic stem cell transplantation.

 5. Patients planned for autologous or allogeneic transplant as consolidation in
 first line.

 6. Patients with any other malignancy, except patients with a history of curatively
 treated basal or squamous cell carcinoma or in situ carcinoma of the cervix at
 any time prior to the study are eligible.

 7. Prior treatment with cytotoxic drugs for another condition (e.g., rheumatoid
 arthritis) or prior use of an anti-CD20 antibody within 5 years of the start of
 Cycle 1.

 8. Prior use of any monoclonal antibody within 3 months of the start of Cycle 1.

 9. Any investigational therapy within 3 months prior to the start of Cycle 1.

 10. History of severe allergic or anaphylactic reactions to humanized or murine
 monoclonal antibodies or known sensitivity or allergy to murine products.

 11. Contraindication to any of the individual components of CHOP.

 12. Corticosteroid use > 30 mg/day of prednisone or equivalent, for purposes other
 than lymphoma symptom control:

 1. Patients receiving corticosteroid treatment with ≤ 30 mg/day of prednisone or
 equivalent must be documented to be on a stable dose of at least 4 weeks'
 duration prior to randomization (Cycle 1, Day 1).

 2. If glucocorticoid treatment is urgently required for lymphoma symptom control
 prior to the start of study treatment, prednisone 100 mg or equivalent could be
 given for a maximum of 5 days, but all tumor assessments must be completed prior
 to start of glucocorticoid treatment.

 13.Ongoing serious central nervous system disease or peripheral neuropathy, such as
 progressive multifocal leukoencephalopathy.

 14.Have uncontrolled or significant cardiovascular disease, including:

 1. Grade II or higher Congestive heart failure, unstable angina pectoris, myocardial
 infarction (New York Heart Association Functional Classification ) within 6
 months prior to study entry; or arrhythmia requiring treatment, or Left
 Ventricular Ejection Fraction (LVEF) < 50% during screening stage.

 2. Primary cardiomyopathy (dilated cardiomyopathy, hypertrophic cardiomyocyte,
 arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy,
 et,al).

 3. History of significant QT interval prolongation, or Corrected QT Interval
 QTc≥450ms(male), QTc≥470ms（female）at screening.

 4. Symptomatic coronary heart disease requiring treatment.

 5. Any other cardiovascular disease which is inappropriate for the study according
 to investigators' judgment.

 15.History of interstitial lung disease(ILD), or with ongoing signs and symptoms by CT
 or MRI at the time of screening.

 16.Patients with factors that could affect oral medication (such as dysphagia, chronic
 diarrhea, intestinal obstruction etc), or undergone gastrectomy.

 17.History of deep vein thrombosis or pulmonary embolism. 18.History of active
 bleeding within 2 months prior to the start of Cycle 1;or patients receiving
 anticoagulation therapy; or patients with evidence of bleeding potential according to
 investigators' judgment ( esophageal varices, active ulcer, or fecal occult blood test
 positive etc. ). Patients with bleeding led by lymphoma according to investigators'
 judgment are eligible.

 19.6 weeks or less from the last major surgery that involved crucial organs, or with any
 other factors impede postoperative recovery according to investigators' judgment.

 20.Known active infection, or active and uncontrolled hepatitis B infection(HBV), hepatitis
 C Virus(HCV), human immunodeficiency virus (HIV)/AIDS (Acquired Immune Deficiency
 Syndrome), or any other serious infection. (active infection defined as any major episode
 of infection requiring systemic treatment; Patients with occult or prior HBV may be
 included if HBV DNA is undetectable.) 21.Any mental or cognitive disorder, that would
 impair the ability to understand the informed consent document, or limit compliance with
 study requirements/ treatment.

 22.Drug or alcohol abuse. 23.Women of childbearing potential and men who are sexually
 active not willing to practice a highly effective method of birth control during and after
 the study consistent with local regulations regarding the use of birth control methods for
 subjects participating in clinical trials.These restrictions apply for 12 months after the
 last dose of rituximab or 12 weeks after the last dose of study drug, whichever is later.
 Pregnancy or lactation.

 24.Any other condition which is inappropriate for the study according to investigators'
 judgment.