Phase III Study of Tucidinostat in Combination With R-CHOP in Patients With Newly Diagnosed Double-Expressor DLBCL (DEB)

Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter Study of Tucidinostat in Combination With R-CHOP in Patients With Newly Diagnosed MYC/BCL2 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Diffuse Large B-cell Lymphoma
• Intervention / Treatment: Drug: R-CHOP(Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone); Drug: Tucidinostat; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 423
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Weili Zhao, Professor; Phone Number: 86-13910677109; Email: zhaoweili_sih@163.com
• Study Contact Backup: Name: Kunkun Dai, Manager; Phone Number: 86-18956067368; Email: daikunkun@chipscreen.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China
      • Peking university cancer hospital
  • Shanghai
    • Shanghai, Shanghai, China
      • Shanghai JiaoTong University School of Medicine，Ruijin Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CR-CHOP	Drug: R-CHOP(Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone); R-CHOP : rituximab 375 mg/m2 IV, cyclophosphamide 750 mg/m2 IV, doxorubicin 50 mg/m2 IV, vincristine 1.4 mg/m2 IV [maximum total 2 mg], and prednisone [or equivalent] 100 mg orally as the background therapy for 6 cycles (21 days/cycle).; Drug: Tucidinostat; Tucidinostat ：30 mg was given orally after breakfast on day 1, day 4, day 8, day 11 in a 21-day cycle，for 6 cycles. After cycle 6 patients who are evaluated as complete response will receive 24 weeks additional administrations of Tucidinostat on day 1, day 4, day 8, day 11 in a 21-day cycle.
Placebo Comparator: R-CHOP	Drug: R-CHOP(Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone); R-CHOP : rituximab 375 mg/m2 IV, cyclophosphamide 750 mg/m2 IV, doxorubicin 50 mg/m2 IV, vincristine 1.4 mg/m2 IV [maximum total 2 mg], and prednisone [or equivalent] 100 mg orally as the background therapy for 6 cycles (21 days/cycle).; Drug: Placebo; Placebo：30 mg was given orally after breakfast on day 1, day 4, day 8, day 11 in a 21-day cycle，for 6 cycles. After cycle 6 patients who are evaluated as complete response will receive 24 weeks additional administrations of placebo on day 1, day 4, day 8, day 11 in a 21-day cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event Free Survival (EFS)	Defined as the duration from the date of randomization to the date of disease progression, relapse from CR , initiation of subsequent systemic antilymphoma therapy for residual disease, or death, whichever occurs first.	Up to approximately 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response Rate(CRR)	Defined as the proportion of subjects with measurable disease who achieve CR.	Up to approximately 3 years
Progression-Free Survival (PFS)	Defined as the duration from the date of randomization to the date of progression, relapse from CR, or death, whichever occurred first.	Up to approximately 5 years
Overall Survival (OS)	defined as the duration from the date of randomization to the date of the participant's death	Up to approximately 5 years
Disease-Free Survival (DFS)	Defined for patients achieving CR as the period from the date of the initial CR until the date of relapse or death from any cause.	Up to approximately 5 years
Safety of Tucidinostat when combined with R-CHOP	All adverse events occurring during or after the first treatment will be summarized by treatment arm and NCI CTCAE grade.	Up to approximately 5 years

Collaborators and Investigators

• Sponsor: Chipscreen Biosciences, Ltd.
• Investigators: Principal Investigator: Weili Zhao, Professor, Shanghai JiaoTong University School of Medicine，Ruijin Hospital; Principal Investigator: Jun Zhu, Professor, Peking University Cancer Hospital & Institute

Study record dates

Study Major Dates

• Study Start (Actual): May 21, 2020
• Primary Completion (Actual): July 5, 2023
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: January 14, 2020
• First Submitted That Met QC Criteria: January 14, 2020
• First Posted (Actual): January 18, 2020

Study Record Updates

• Last Update Posted (Actual): September 6, 2023
• Last Update Submitted That Met QC Criteria: September 5, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Cyclophosphamide; Rituximab; Prednisone; Doxorubicin; Vincristine
• Other Study ID Numbers: CDM302

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No