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A Trial to Compare Ibrutinib Versus Lenalidomide in Combination With MRE-chemotherapy for Adult Patients With Recurrent/Refractory Primary Central Nervous System Lymphoma (PCNSL)

Primary Purpose

Recurrent/RefractoryPrimary Central Nervous System Lymphoma (PCNSL)

Status
Recruiting
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Ibrutinib
Lenalidomide
Methotrexate
Rituximab
Etoposide
PEGylated recombinant human granulocyte colony
Sponsored by
Second Affiliated Hospital, School of Medicine, Zhejiang University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Recurrent/RefractoryPrimary Central Nervous System Lymphoma (PCNSL)

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Participants must be able to understand and be willing to sign a written informed consent document.
  2. Men and woman who are 18-75 years old on the day of consenting to the study.
  3. Histologically documented PCNSL and histologically documented systemic diffuse large B-cell lymphoma (DLBCL).
  4. Patients must have relapsed/refractory PCNSL or relapsed/refractory SCNSL
  5. All patients need to have received at least one prior CNS directed therapy. There is no restriction on the number of recurrences.
  6. Patients with parenchymal lesions must have unequivocal evidence of disease progression on imaging (MRI of the brain or head CT) 21 days prior to study registration.
  7. Participants must have an ECOG performance status of 0-3.
  8. Participants must have adequate bone marrow and organ function shown by:

    1. Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L
    2. Platelets ≥ 75 x 10^9/L and no platelet transfusion within the past 21 days prior to study registration
    3. Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 21 days prior to study registration
    4. International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal
    5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal
    6. Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3 times the upper limit of normal with direct bilirubin within the normal range in patients with well documented Gilbert Syndrome.
    7. Serum creatinine ≤ 2 times the upper limit of normal
  9. Woman of reproductive potential must agree to use highly effective methods of birth control during the period of therapy and for 30 days after the last dose of the study drug. Men who are sexually active must agree to use highly effective contraception during the period of therapy and for 3 months after the last dose.
  10. Patients must be able to tolerate MRI/CT scans.
  11. Participants must have recovered to grade 1 toxicity from prior therapy.
  12. Participants should be able to submit up to 20 unstained formalin-fixed, paraffinembedded (FFPE) slides from the initial tissue diagnosis prior to study registration for confirmation of diagnosis and correlative studies
  13. NOTE: Prior autologous stem cell transplant as well as prior radiation to the CNS does NOT prevent patients from enrollment into the trial.

Exclusion Criteria:

  1. Patients with SCNSL actively receiving treatment for extra-CNS disease are excluded.
  2. Patient has received chemotherapy, monoclonal antibodies or targeted anticancer therapy ≤ 4 weeks or 5 half-lives, whichever is shorter, or 6 weeks for nitrosourea or mitomycin-C prior to starting the study drug, or the patient has not recovered from the side effects of such therapy.
  3. Patient has received external beam radiation therapy to the CNS within 21 days of the first dose of the study drug.
  4. Patient requires more than 8 mg of dexamethasone daily or the equivalent
  5. Patient has an active concurrent malignancy requiring active therapy
  6. The patient has been treated with radio- or toxin-immunoconjugates within 70 days of the first Patient is allergic to components of the study drug.
  7. Patient is using warfarin or any other Coumadin-derivative anticoagulant or vitamin K antagonists. Patients must be off warfarin-derivative anticoagulants for at least seven days prior to starting the study drug. Low molecular weight heparin is allowed. Patients with congenital bleeding diathesis are excluded.
  8. Patient is taking a drug known to be a moderate and strong inhibitor or inducers of the P450 isoenzyme CYP3A. Participants must be off P450/CYP3A inhibitors and inducers for at least two weeks prior to starting the study drug.
  9. Patient is using systemic immunosuppressant therapy, including cyclosporine A, tacrolimus, sirolimus, and other such medications, or chronic administration of > 5 mg/day or prednisone or the equivalent. Participants must be off immunosuppressant therapy for at least 28 days prior to the first dose of the study drug.
  10. Patient has significant abnormalities on screening electrocardiogram (EKG) and active and significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, hypertension, valvular disease, pericarditis, or myocardial infarction within 6 months of screening,
  11. Patient has a known bleeding diathesis (e.g. von Willebrand"s disease) or hemophilia.
  12. Patient is known to have human immunodeficiency virus (HIV) infection.
  13. Patient is known to have a history of active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) as determined by serologic tests.
  14. Patient is known to have an uncontrolled active systemic infection.
  15. Patient underwent major systemic surgery ≤ 4 weeks prior to starting the trial treatment or who has not recovered from the side effects of such surgery, or who plan to have surgery within 2 weeks of the first dose of the study drug.
  16. Patient is unable to swallow capsules or has a disease or condition significantly affecting gastrointestinal function, such as malabsorption syndrome, resection of the stomach or small bowel, or complete bowel obstruction.
  17. Patient has a life-threatening illness, medical condition, or organ system dysfunction that, in the opinion of the investigator, could compromise the subject"s safety or put the study outcomes at undue risk.
  18. Women who are pregnant or nursing (lactating), where pregnancy is defined as a state of a female after conception until the termination of gestation, confirmed by a positive serum hCG laboratory test of > 5 mIU/mL (See section on Pregnancy and Reproduction)
  19. Patient has undergone prior allogenic stem cell transplant (autologous stem cell transplant is NOT an exclusion)
  20. The patient is unwell or unable to participate in all required study evaluations and procedures
  21. Known hypersensitivity to ibrutinib, thalidomide or lenalidomide

Sites / Locations

  • Department of Hematology, the Second Affiliated Hospital, Zhejiang University School of MedicineRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

I-MRE

L-MRE

MRE

Arm Description

Ibrutinib 560 mg/day daily (starting dose) between days 4 and 28 of each cycle for six cycles. Then Ibrutinib is continued until disease progression, intolerable toxicity, death or up to two years. Methotrexate (standard hydration/leucovorin support) 3.5 g/m2 (0.5 g/m2 in 15 min+ 3 g/m2 in 3-hr infusion) d2. Rituximab 375 mg/m2 conventional infusion d1.Etoposide 250 mg/m2 over 3 hours on day3. Every 4 weeks for 1 cycle, 6 cycles will be prescribed as protocol.

Oral lenalidomide 25mg/day (starting dose) between days 4 and 24 of each cycle for six cycles.Then lenalidomide is continued until disease progression, intolerable toxicity, death or up to two years. Methotrexate (standard hydration/leucovorin support) 3.5 g/m2 (0.5 g/m2 in 15 min+ 3 g/m2 in 3-hr infusion) d2. Rituximab 375 mg/m2 conventional infusion d1. Etoposide 250 mg/m2 over 3 hours on day3. Every 4 weeks for 1 cycle, 6 cycles will be prescribed as protocol.

Methotrexate (standard hydration/leucovorin support) 3.5 g/m2 (0.5 g/m2 in 15 min+ 3 g/m2 in 3-hr infusion) d2. Rituximab 375 mg/m2 conventional infusion d1. Etoposide 250 mg/m2 over 3 hours on day3. Every 4 weeks for 1 cycle, 6 cycles will be prescribed as protocol. Patients who will not achieve SD or better after the 4th course, as well as those who will experience Progressive Disease (PD) at any time will be randomly allocated to the Experimental groups.

Outcomes

Primary Outcome Measures

Progression-free survival (PFS)
From date of randomization until recurrence/disease progression, unacceptable toxicity, death or discontinuation for any other reason, whichever comes first assessed up to 2 yrs

Secondary Outcome Measures

Objective response rate (ORR)
To determine efficacy
Overall survival (OS)
To determine efficacy
Number of patients with adverse events
Number of participants with treatment- and non-treatment related adverse events as assessed by CTCAE

Full Information

First Posted
October 15, 2019
Last Updated
July 14, 2021
Sponsor
Second Affiliated Hospital, School of Medicine, Zhejiang University
Collaborators
Ruijin Hospital, The First Affiliated Hospital of Nanchang University, Fujian Medical University Union Hospital, RenJi Hospital, Shanghai Tong Ren Hospital, Shandong Provincial Hospital, Cancer Hospital of Guangxi Medical University, Sir Run Run Shaw Hospital, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Ningbo Medical Center Lihuili Hospital, Yinzhou Hospital Affiliated to Medical School of Ningbo University, Zhejiang University
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1. Study Identification

Unique Protocol Identification Number
NCT04129710
Brief Title
A Trial to Compare Ibrutinib Versus Lenalidomide in Combination With MRE-chemotherapy for Adult Patients With Recurrent/Refractory Primary Central Nervous System Lymphoma (PCNSL)
Official Title
An Open-label, Multicenter,Randomized Phase 2 Trial to Compare the Efficacy and Safety of Ibrutinib Versus Lenalidomide in Combination With MRE(Methotrexate,Rituximab,Etoposide)-Chemotherapy for Adult Patients With Recurrent/Refractory Primary Central Nervous System Lymphoma (PCNSL)
Study Type
Interventional

2. Study Status

Record Verification Date
January 2021
Overall Recruitment Status
Recruiting
Study Start Date
January 1, 2020 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
December 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Second Affiliated Hospital, School of Medicine, Zhejiang University
Collaborators
Ruijin Hospital, The First Affiliated Hospital of Nanchang University, Fujian Medical University Union Hospital, RenJi Hospital, Shanghai Tong Ren Hospital, Shandong Provincial Hospital, Cancer Hospital of Guangxi Medical University, Sir Run Run Shaw Hospital, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Ningbo Medical Center Lihuili Hospital, Yinzhou Hospital Affiliated to Medical School of Ningbo University, Zhejiang University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
This is a open-label,multicenter, randomised, three-arm, phase II efficacy and safety study of ibrutinib in combination with MRE(methotrexate,rituximab,etoposide)-chemotherapy versus lenalidomide in combination with MRE-chemotherapy given to adult patients who have recurrent/refractory primary central nervous system lymphoma (PCNSL)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Recurrent/RefractoryPrimary Central Nervous System Lymphoma (PCNSL)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
I-MRE
Arm Type
Experimental
Arm Description
Ibrutinib 560 mg/day daily (starting dose) between days 4 and 28 of each cycle for six cycles. Then Ibrutinib is continued until disease progression, intolerable toxicity, death or up to two years. Methotrexate (standard hydration/leucovorin support) 3.5 g/m2 (0.5 g/m2 in 15 min+ 3 g/m2 in 3-hr infusion) d2. Rituximab 375 mg/m2 conventional infusion d1.Etoposide 250 mg/m2 over 3 hours on day3. Every 4 weeks for 1 cycle, 6 cycles will be prescribed as protocol.
Arm Title
L-MRE
Arm Type
Experimental
Arm Description
Oral lenalidomide 25mg/day (starting dose) between days 4 and 24 of each cycle for six cycles.Then lenalidomide is continued until disease progression, intolerable toxicity, death or up to two years. Methotrexate (standard hydration/leucovorin support) 3.5 g/m2 (0.5 g/m2 in 15 min+ 3 g/m2 in 3-hr infusion) d2. Rituximab 375 mg/m2 conventional infusion d1. Etoposide 250 mg/m2 over 3 hours on day3. Every 4 weeks for 1 cycle, 6 cycles will be prescribed as protocol.
Arm Title
MRE
Arm Type
Active Comparator
Arm Description
Methotrexate (standard hydration/leucovorin support) 3.5 g/m2 (0.5 g/m2 in 15 min+ 3 g/m2 in 3-hr infusion) d2. Rituximab 375 mg/m2 conventional infusion d1. Etoposide 250 mg/m2 over 3 hours on day3. Every 4 weeks for 1 cycle, 6 cycles will be prescribed as protocol. Patients who will not achieve SD or better after the 4th course, as well as those who will experience Progressive Disease (PD) at any time will be randomly allocated to the Experimental groups.
Intervention Type
Drug
Intervention Name(s)
Ibrutinib
Intervention Description
Ibrutinib 560 mg/day daily (starting dose) between days 4 and 28 of each cycle for six cycles. Then Ibrutinib is continued until disease progression, intolerable toxicity, death or up to two years.
Intervention Type
Drug
Intervention Name(s)
Lenalidomide
Intervention Description
Oral lenalidomide 25mg/day between days 4 and 24 of each cycle for six cycles. Then lenalidomide is continued until disease progression, intolerable toxicity, death or up to two years.
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Intervention Description
Methotrexate 3.5 g/m2 (0.5 g/m2 in 15 min + 3 g/m2 in 3-hr infusion) on day 1
Intervention Type
Drug
Intervention Name(s)
Rituximab
Intervention Description
Rituximab 375 mg/m2 conventional infusion on day 1
Intervention Type
Drug
Intervention Name(s)
Etoposide
Intervention Description
Etoposide 250 mg/m2 over 3 hours on day3
Intervention Type
Drug
Intervention Name(s)
PEGylated recombinant human granulocyte colony
Intervention Description
PEGylated recombinant human granulocyte colony 100 ug/kg subcutaneous injection on day 5.
Primary Outcome Measure Information:
Title
Progression-free survival (PFS)
Description
From date of randomization until recurrence/disease progression, unacceptable toxicity, death or discontinuation for any other reason, whichever comes first assessed up to 2 yrs
Time Frame
assessed up to 2 yrs
Secondary Outcome Measure Information:
Title
Objective response rate (ORR)
Description
To determine efficacy
Time Frame
assessed up to 2 yrs
Title
Overall survival (OS)
Description
To determine efficacy
Time Frame
assessed up to 2 yrs
Title
Number of patients with adverse events
Description
Number of participants with treatment- and non-treatment related adverse events as assessed by CTCAE
Time Frame
assessed up to 2 yrs

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Participants must be able to understand and be willing to sign a written informed consent document. Men and woman who are 18-75 years old on the day of consenting to the study. Histologically documented PCNSL and histologically documented systemic diffuse large B-cell lymphoma (DLBCL). Patients must have relapsed/refractory PCNSL or relapsed/refractory SCNSL All patients need to have received at least one prior CNS directed therapy. There is no restriction on the number of recurrences. Patients with parenchymal lesions must have unequivocal evidence of disease progression on imaging (MRI of the brain or head CT) 21 days prior to study registration. Participants must have an ECOG performance status of 0-3. Participants must have adequate bone marrow and organ function shown by: Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L Platelets ≥ 75 x 10^9/L and no platelet transfusion within the past 21 days prior to study registration Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 21 days prior to study registration International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3 times the upper limit of normal with direct bilirubin within the normal range in patients with well documented Gilbert Syndrome. Serum creatinine ≤ 2 times the upper limit of normal Woman of reproductive potential must agree to use highly effective methods of birth control during the period of therapy and for 30 days after the last dose of the study drug. Men who are sexually active must agree to use highly effective contraception during the period of therapy and for 3 months after the last dose. Patients must be able to tolerate MRI/CT scans. Participants must have recovered to grade 1 toxicity from prior therapy. Participants should be able to submit up to 20 unstained formalin-fixed, paraffinembedded (FFPE) slides from the initial tissue diagnosis prior to study registration for confirmation of diagnosis and correlative studies NOTE: Prior autologous stem cell transplant as well as prior radiation to the CNS does NOT prevent patients from enrollment into the trial. Exclusion Criteria: Patients with SCNSL actively receiving treatment for extra-CNS disease are excluded. Patient has received chemotherapy, monoclonal antibodies or targeted anticancer therapy ≤ 4 weeks or 5 half-lives, whichever is shorter, or 6 weeks for nitrosourea or mitomycin-C prior to starting the study drug, or the patient has not recovered from the side effects of such therapy. Patient has received external beam radiation therapy to the CNS within 21 days of the first dose of the study drug. Patient requires more than 8 mg of dexamethasone daily or the equivalent Patient has an active concurrent malignancy requiring active therapy The patient has been treated with radio- or toxin-immunoconjugates within 70 days of the first Patient is allergic to components of the study drug. Patient is using warfarin or any other Coumadin-derivative anticoagulant or vitamin K antagonists. Patients must be off warfarin-derivative anticoagulants for at least seven days prior to starting the study drug. Low molecular weight heparin is allowed. Patients with congenital bleeding diathesis are excluded. Patient is taking a drug known to be a moderate and strong inhibitor or inducers of the P450 isoenzyme CYP3A. Participants must be off P450/CYP3A inhibitors and inducers for at least two weeks prior to starting the study drug. Patient is using systemic immunosuppressant therapy, including cyclosporine A, tacrolimus, sirolimus, and other such medications, or chronic administration of > 5 mg/day or prednisone or the equivalent. Participants must be off immunosuppressant therapy for at least 28 days prior to the first dose of the study drug. Patient has significant abnormalities on screening electrocardiogram (EKG) and active and significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, hypertension, valvular disease, pericarditis, or myocardial infarction within 6 months of screening, Patient has a known bleeding diathesis (e.g. von Willebrand"s disease) or hemophilia. Patient is known to have human immunodeficiency virus (HIV) infection. Patient is known to have a history of active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) as determined by serologic tests. Patient is known to have an uncontrolled active systemic infection. Patient underwent major systemic surgery ≤ 4 weeks prior to starting the trial treatment or who has not recovered from the side effects of such surgery, or who plan to have surgery within 2 weeks of the first dose of the study drug. Patient is unable to swallow capsules or has a disease or condition significantly affecting gastrointestinal function, such as malabsorption syndrome, resection of the stomach or small bowel, or complete bowel obstruction. Patient has a life-threatening illness, medical condition, or organ system dysfunction that, in the opinion of the investigator, could compromise the subject"s safety or put the study outcomes at undue risk. Women who are pregnant or nursing (lactating), where pregnancy is defined as a state of a female after conception until the termination of gestation, confirmed by a positive serum hCG laboratory test of > 5 mIU/mL (See section on Pregnancy and Reproduction) Patient has undergone prior allogenic stem cell transplant (autologous stem cell transplant is NOT an exclusion) The patient is unwell or unable to participate in all required study evaluations and procedures Known hypersensitivity to ibrutinib, thalidomide or lenalidomide
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Xiaohong Zhang
Phone
+8657189713673
Email
zeyyxy@163.com
Facility Information:
Facility Name
Department of Hematology, the Second Affiliated Hospital, Zhejiang University School of Medicine
City
Hangzhou
State/Province
China/Zhejiang Province
ZIP/Postal Code
310009
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Xiaohong Zhang, MD
Phone
+8657189713673
Email
zeyyxy@163.com

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
This is a open-label,multicenter, randomised, three-arm, phase II efficacy and safety study of ibrutinib in combination with MRE(methotrexate,rituximab,etoposide)-chemotherapy versus lenalidomide in combination with MRE-chemotherapy given to adult patients who have recurrent/refractory primary central nervous system lymphoma (PCNSL)

Learn more about this trial

A Trial to Compare Ibrutinib Versus Lenalidomide in Combination With MRE-chemotherapy for Adult Patients With Recurrent/Refractory Primary Central Nervous System Lymphoma (PCNSL)

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