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Zanubrutinib-based Induction and Maintenance Therapy in Young and Fit Patients With Untreated Mantle Cell Lymphoma

Primary Purpose

Mantle Cell Lymphoma

Status
Recruiting
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
R-CHOP/R-DHAOx； Zanubrutib（induction）； ASCT conditioning ； Zanubrutinib（Maintenance）
Sponsored by
Sun Yat-sen University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Mantle Cell Lymphoma

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. 1. Histologically confirmed diagnosis of MCL according to WHO classification
  2. Previously untreated MCL
  3. Suitable for high-dose treatment including high-dose Ara-C
  4. Age ≥ 18 years and ≤ 65 years
  5. Stage II-IV (Ann Arbor)
  6. Measurable disease by computed tomography (CT)/magnetic resonance imaging (MRI). Measurable disease was defined as at least 1 lymph node > 1.5 cm in longest diameter and measurable in 2 perpendicular dimensions; in case of bone marrow infiltration only, bone marrow aspiration and biopsy are mandatory for all staging evaluations
  7. ECOG performance status ≤ 2

  8. The following laboratory values at screening (unless related to MCL):

    • Absolute neutrophil count (ANC) ≥ 1×10⁹/L
    • Platelets ≥ 75×10⁹/L (platelets ≥ 50×10⁹/L with bone marrow involvement)
    • Transaminases (AST and ALT) ≤ 3 × upper limit of normal (ULN)
    • Total bilirubin ≤ 2 × ULN (unless documented Gilbert's syndrome)
    • Calculated creatinine clearance ≥ 30 mL/min
  9. International normalized ratio ≤ 1.5 and activated partial thromboplastin time ≤ 1.5 x upper limit of normal. If a factor inhibitor was present with prolongation of the international normalized ratio or activated partial thromboplastin time.
  10. Sexually active men and women of child-bearing potential must agree to use highly effective contraceptives (eg, condoms, implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence, or sterilized partner) while on study; this should be maintained for 90 days after the last dose of study drug
  11. Life expectancy of> 3 months
  12. Written informed consent form according to GCP and national regulations

Exclusion Criteria:

  1. Known CNS involvement of MCL
  2. Major surgery within 4 weeks of screening
  3. Prior hematopoietic stem cell transplantation
  4. Concomitant or previous malignancies within the last 2 years other than basal cell skin cancer or in situ uterine cervix cancer
  5. Clinically significant cardiovascular disease such as uncontrolled arrhythmias and hypertension , congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification or LVEF below 50%（AHA，2016）
  6. QTcF > 450 msec or other significant electrocardiogram (ECG) abnormalities including second-degree atrioventricular block Type II, or third-degree atrioventricular block
  7. Clinically significant hypersensitivity (eg, anaphylactic or anaphylactoid reactions to the compound of zanubrutinib itself or to the excipients in its formulation)
  8. Requires treatment with strong CYP3A inhibitors or strong CYP3A inducers
  9. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
  10. Patients with unresolved hepatitis B or C infection or known HIV positive infection
  11. Active infection including infections requiring oral or intravenous antimicrobial therapy
  12. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could have compromised the patient's safety, or put the study at risk
  13. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug
  14. Pregnancy or lactation
  15. Participation in another clinical trial within 30 days before enrollment in this study
  16. poor compliance

Sites / Locations

  • Department of Medical Oncology, Sun Yat-sen University Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Zanubrutinib+R-CHOP/R-DHAOx

Arm Description

Induction: Alternating 3× R-CHOP/ 3× R-DHAOx, every 21 days plus oral Zanubrutinib in cycle 1, 3, 5 in combination with R-CHOP: ASCT conditioning Maintenance: Zanubrutinib, 160mg PO BID, continuously for 2 year Zanubrutinib maintenance will start after regeneration of peripheral blood count after the end of the last cycle of induction therapy or ASCT Requirements for start of maintenance: ANC ≥ 1,000 cells/mm³ (1.0 X 109/L); Platelets ≥ 50,000 cells/mm³ (50 X 109/L);

Outcomes

Primary Outcome Measures

MRD negativity rate
To evaluate the MRD negativity rate after Zanubrutinib-based induction therapy in subjects with newly diagnosed, young and fit MCL. The primary endpoint of the trial will be bone marrow minimal residual disease (MRD) negative rate after induction therapy (at the completion of cycle 6 or at premature discontinuation).

Secondary Outcome Measures

Duration of MRD negativity
The time from the first achieving MRD negativity after start of treatment to the MRD convert to positive
Progression free survival (PFS)
The time from start of treatment to progression or death from any cause
Overall survival (OS)
The time from start of treatment to death from any cause

Full Information

First Posted
February 1, 2021
Last Updated
August 24, 2021
Sponsor
Sun Yat-sen University
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1. Study Identification

Unique Protocol Identification Number
NCT04736914
Brief Title
Zanubrutinib-based Induction and Maintenance Therapy in Young and Fit Patients With Untreated Mantle Cell Lymphoma
Official Title
A Perspective Study of Zanubrutinib-based Induction and Maintenance Therapy in Young and Fit Patients With Untreated Mantle Cell Lymphoma (BRIDGE)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2021
Overall Recruitment Status
Recruiting
Study Start Date
January 31, 2021 (Actual)
Primary Completion Date
January 31, 2023 (Anticipated)
Study Completion Date
February 28, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Sun Yat-sen University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a prospective, single-center, single-arm, phase II study of Zanubrutinib-based induction followed by ASCT and Zanubrutinib maintenance (2 years) or followed directly by Zanubrutinib maintenance without ASCT in young and fit patients with untreated MCL. There will be an initial safety run-in phase of 6 patients which will be closely monitored for the observed toxicities during cycle1 in， induction therapy. After completion of safety run-in phase, the investigator will assessed and decided whether to continue the trial as planned. If no unexpected toxicity has been observed, study will expand the sample size to further assess efficacy and safety. Total around 47 patients aged 18-65 years with previously untreated, Ann Arbor stage II-IV, histologically proven MCL will be enrolled to receive alternating 3 cycles R-CHOP + Zanubrutinib /3 cycles R-DHAOx induction. Totally 6 cycles in induction and every 21 days per cycle. Due to lack of published data about BTKi in combination with R-DHAOx, Zanubrutinib is only applied in cycle 1,3,5(R-CHOP), 160mg BID, d1-21, and not in combination with R-DHAOx Patients who achieve remission (≥PR) will be allowed to proceed to ASCT or maintenance. Whether ASCT or not depends on investigator's evaluation and discretion. In patients who do not achieve a remission at end of induction (treatment failure), no study specific treatment is defined; rather, the further salvage treatment is upon the discretion of investigators. Patients remain in study for progression and survival follow-up. Patients will receive Zanubrutinib maintenance for two years in case of remission at ASCT assessment or end of induction assessment. Zanubrutinib is applied oral 160mg BID, continuously for 2 year or until progressive disease, unacceptable toxicity or death, whichever comes first. The primary analysis will be performed after last-patient completes induction treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mantle Cell Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Zanubrutinib Combined with R-CHOP，R-DHAOx
Masking
None (Open Label)
Allocation
N/A
Enrollment
47 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Zanubrutinib+R-CHOP/R-DHAOx
Arm Type
Experimental
Arm Description
Induction: Alternating 3× R-CHOP/ 3× R-DHAOx, every 21 days plus oral Zanubrutinib in cycle 1, 3, 5 in combination with R-CHOP: ASCT conditioning Maintenance: Zanubrutinib, 160mg PO BID, continuously for 2 year Zanubrutinib maintenance will start after regeneration of peripheral blood count after the end of the last cycle of induction therapy or ASCT Requirements for start of maintenance: ANC ≥ 1,000 cells/mm³ (1.0 X 109/L); Platelets ≥ 50,000 cells/mm³ (50 X 109/L);
Intervention Type
Drug
Intervention Name(s)
R-CHOP/R-DHAOx； Zanubrutib（induction）； ASCT conditioning ； Zanubrutinib（Maintenance）
Other Intervention Name(s)
R-CHOP，R-DHAOx，Brukinsa
Intervention Description
Alternating 3× R-CHOP/ 3× R-DHAOx, every 21 days plus oral Zanubrutinib in cycle 1, 3, 5 in combination with R-CHOP: R-CHOP (cycle 1,3,5): Rituximab 375 mg/m2 D1, I.V. Cyclophosphamide 750 mg/m2 D1, I.V. Doxorubicine 50 mg/m2 D1, I.V. Vincristine 1.4mg/m2(max 2mg)D1, I.V. Prednisone 100mg D1-5, oral Zanubrutinib 160mg BID D1-21, oral R-DHAOx (cycle 2,4,6): Dexamethasone 40mg D1-4 oral/I.V. Rituximab 375mg/m2 D1, I.V. Ara-C 2×2g/m2 q12h D2, I.V. Cisplatin 100mg/m2 D1, I.V. Maintenance: Zanubrutinib, 160mg PO BID, continuously for 2 year or until progressive disease。 Zanubrutinib maintenance will start after regeneration of peripheral blood count after the end of the last cycle of induction therapy or ASCT
Primary Outcome Measure Information:
Title
MRD negativity rate
Description
To evaluate the MRD negativity rate after Zanubrutinib-based induction therapy in subjects with newly diagnosed, young and fit MCL. The primary endpoint of the trial will be bone marrow minimal residual disease (MRD) negative rate after induction therapy (at the completion of cycle 6 or at premature discontinuation).
Time Frame
18 weeks
Secondary Outcome Measure Information:
Title
Duration of MRD negativity
Description
The time from the first achieving MRD negativity after start of treatment to the MRD convert to positive
Time Frame
60 months
Title
Progression free survival (PFS)
Description
The time from start of treatment to progression or death from any cause
Time Frame
60 months
Title
Overall survival (OS)
Description
The time from start of treatment to death from any cause
Time Frame
60 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 1. Histologically confirmed diagnosis of MCL according to WHO classification Previously untreated MCL Suitable for high-dose treatment including high-dose Ara-C Age ≥ 18 years and ≤ 65 years Stage II-IV (Ann Arbor) Measurable disease by computed tomography (CT)/magnetic resonance imaging (MRI). Measurable disease was defined as at least 1 lymph node > 1.5 cm in longest diameter and measurable in 2 perpendicular dimensions; in case of bone marrow infiltration only, bone marrow aspiration and biopsy are mandatory for all staging evaluations ECOG performance status ≤ 2 The following laboratory values at screening (unless related to MCL): Absolute neutrophil count (ANC) ≥ 1×10⁹/L Platelets ≥ 75×10⁹/L (platelets ≥ 50×10⁹/L with bone marrow involvement) Transaminases (AST and ALT) ≤ 3 × upper limit of normal (ULN) Total bilirubin ≤ 2 × ULN (unless documented Gilbert's syndrome) Calculated creatinine clearance ≥ 30 mL/min International normalized ratio ≤ 1.5 and activated partial thromboplastin time ≤ 1.5 x upper limit of normal. If a factor inhibitor was present with prolongation of the international normalized ratio or activated partial thromboplastin time. Sexually active men and women of child-bearing potential must agree to use highly effective contraceptives (eg, condoms, implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence, or sterilized partner) while on study; this should be maintained for 90 days after the last dose of study drug Life expectancy of> 3 months Written informed consent form according to GCP and national regulations Exclusion Criteria: Known CNS involvement of MCL Major surgery within 4 weeks of screening Prior hematopoietic stem cell transplantation Concomitant or previous malignancies within the last 2 years other than basal cell skin cancer or in situ uterine cervix cancer Clinically significant cardiovascular disease such as uncontrolled arrhythmias and hypertension , congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification or LVEF below 50%（AHA，2016） QTcF > 450 msec or other significant electrocardiogram (ECG) abnormalities including second-degree atrioventricular block Type II, or third-degree atrioventricular block Clinically significant hypersensitivity (eg, anaphylactic or anaphylactoid reactions to the compound of zanubrutinib itself or to the excipients in its formulation) Requires treatment with strong CYP3A inhibitors or strong CYP3A inducers Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction Patients with unresolved hepatitis B or C infection or known HIV positive infection Active infection including infections requiring oral or intravenous antimicrobial therapy Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could have compromised the patient's safety, or put the study at risk History of stroke or intracranial hemorrhage within 6 months before first dose of study drug Pregnancy or lactation Participation in another clinical trial within 30 days before enrollment in this study poor compliance
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
huang huiqiang
Phone
138 0888 5154
Email
haunghq@sysucc.org.cn
Facility Information:
Facility Name
Department of Medical Oncology, Sun Yat-sen University Cancer Center
City
Guangzhou
State/Province
Guangdong
ZIP/Postal Code
510060
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Huiqiang Huang, Professor
Phone
+86 020 87343350
Email
huanghq@sysucc.org.cn
First Name & Middle Initial & Last Name & Degree
Huiqiang Huang

12. IPD Sharing Statement

Plan to Share IPD
No

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Zanubrutinib-based Induction and Maintenance Therapy in Young and Fit Patients With Untreated Mantle Cell Lymphoma

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