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出境医 / 临床实验 / A Prospective Multicenter Phase 2 Study of FCR/BR Alternating With Ibrutinib in Treatment-naive Patients With CLL (BDHCLL001)

A Prospective Multicenter Phase 2 Study of FCR/BR Alternating With Ibrutinib in Treatment-naive Patients With CLL (BDHCLL001)

Study Description
Brief Summary:
This is a prospective multicenter phase 2 study designed with the purpose to evaluate the response rate and safety of treatment with FCR/BR alternating with ibrutinib in treatment-naive patients with chronic lymphocytic leukemia.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Drug: FCR and Ibrutinib Drug: BR and Ibrutinib Drug: Ibrutinib and Thalidomide Phase 2

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Prospective Multicenter Phase 2 Study of FCR/BR Alternating With Ibrutinib in Treatment-naive Patients With Chronic Lymphocytic Leukemia
Actual Study Start Date : May 15, 2019
Estimated Primary Completion Date : December 15, 2022
Estimated Study Completion Date : December 30, 2027
Arms and Interventions
Arm Intervention/treatment
Experimental: FCR/BR alternating with ibrutinib
FCR/BR→ ibrutinib✖️3months→FCR/BR→ ibrutinib✖️3months→FCR/BR→Maintenance therapy
Drug: FCR and Ibrutinib

Induction treatment:

Patients <65 y and without significant comorbidities are given FCR 1or 2 courses (If patients' white blood cell count <10×10^9/L after first course, the second course can be saved). Then, patients takes ibrutinib orally for 3 months alternating with FCR in 2 cylcles.

  1. FCR: F(Fludarabine):25mg/m2·d,d1-3; C(Cyclophosphamide):CTX 250mg /m2·d,d1-3; R(Rituximab):375mg/m2 d0(first course),500mg/m2 d0(subsequent courses);
  2. Ibrutinib:420mg/d

Drug: BR and Ibrutinib

Induction treatment:

Patients ≥65y and ≤75 y or <65 y but with comorbidities, are given BR 1or 2 courses (If patients' white blood cell count drop to below10×10^9/Lafter first course, the second course can be saved). Then, patients takes ibrutinib orally for 3 months alternating with BR in 2 cylcles. 1.BR: B(Bendamustine):90mg/m2·d,d1-2; R(Rituximab):375mg/m2 d0(first course),500mg/m2 d0(subsequent courses); 2. Ibrutinib: 420mg/d


Drug: Ibrutinib and Thalidomide

Maintenance treatment:

After induction treatment, recommend ( but not mandatory) Ibrutinib or thalidomide monotherapy(according to patients preferrance) for MRD-positive patients.For MRD-negative patients, recommend ( but not mandatory) no maintenance therapy.


Outcome Measures
Primary Outcome Measures :
  1. CRR [ Time Frame: 3 months after completion of induction therapy ]
    Rate of complete remission


Secondary Outcome Measures :
  1. ORR [ Time Frame: 3 months after completion of induction therapy ]
    Overall Response Rate

  2. OS [ Time Frame: 5 years ]
    Overall survival

  3. PFS [ Time Frame: 5 years ]
    Progression-free survival

  4. MRD negative rate [ Time Frame: 3 months after completion of induction therapy ]
    the rate of undetectable tumor cells in bone marrow and/or peripheral blood by multicolor flow cytometry

  5. DoR [ Time Frame: 5 years ]
    Duration of Response

  6. Treatment-related side effects [ Time Frame: 10 months ]

Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Men or women ≥ 18 years and ≤ 75 of age.
  2. Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria.
  3. Treatment-naive patients. Those patients received short-term substandard treatment are permitted if meet all the items listed below:

    1. Untreated with combined chemotherapy such as CHOP ,COP and so on.
    2. Unteated with chemotherapy regimens including fludarabine and bendamustine.
    3. Unteated with Ibrutinib.
    4. If treated with chlorambucil or cyclophosphamide,should less than 3 weeks.
    5. If treated with interferon, should less than 6 months.
    6. No objective response are achieved (PR or CR).
  4. CLL/SLL requiring treatment as defined by at least one of the following criteria:

    1. Development of, or worsening of, anemia to Hb<100g/L (non-hemolytic) .
    2. Development of, or worsening of, thrombocytopenia to PLT<100,000/L.
    3. Massive (≥ 6 cm below left costal margin), progressive or symptomatic splenomegaly.
    4. Massive nodes (≥ 10 cm in longest diameter), or progressive or symptomatic lymphadenopathy .
    5. Progressive lymphocytosis with an increase of > 50% over a 2-month period or lymphocyte-doubling time of < 6 months. Lymphocyte-doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of < 30,000/L, LDT should not be used as a single parameter to define treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL/SLL (eg, infection, use glucocorticoid) should be excluded. f)Symptomatic or functional extranodal sites involved s (eg. Skin,kidney, lungs and so on).

    g)Constitutional symptoms, defined as any 1 or more of the following disease-related symptoms or signs: i. Unintentional weight loss of ≥ 10% within the previous 6 months ii.Significant fatigue (ie, inability to work or perform usual activities)

  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
  6. Expected to survival period for 3 months or more.

Exclusion Criteria:

  1. History of malignant tumour except CLL in the past 1year(including active central nervous system (CNS) involvement with lymphoma).
  2. Transformed to large cell lymphoma manifested by clinical evidence, or progressed to prolymphocytic leukemia(PLL).
  3. Have active autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura, and require treatment.
  4. Inadequate hepatic and renal function defined as: AST and ALT >4.0 x upper limit of normal (ULN), bilirubin >2.0 x upper limit of normal (ULN), Adequate renal function defined by serum creatinine >1.5 x upper limit of normal (ULN),unrelated to lymphoma.
  5. Severe or uncontrolled infection.
  6. Central nervous system (CNS) dysfunction with clinical manifestation.
  7. Other serious medical diseases that may affect the study(eg. Uncontrolled diabetes, gastric ulcer, other severe cardiopulmonary disease),and final decided by the investigator.
  8. Ongoing and uncontrolled bleeding
  9. History of major life-threatening bleeding, especially due to irreversible cause.
  10. Requirement for continuous anticoagulation drugs.
  11. Major surgery within 30 days(excluding lymph node biopsy).
  12. Pregnant or Lactating women, or women of reproductive age refusal to take contraceptive measures.
  13. Allergy to any drug used in the study.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Zengjun Li +86 13642138692 lizengjun@ihcams.ac.cn
Contact: Tingyu Wang +86 15692201678 wangtingyu@ihcams.ac.cn

Locations
Layout table for location information
China, Tianjin
Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Recruiting
Tianjin, Tianjin, China, 30020
Contact: Zengjun Li    +86 13642138692    lizengjun@ihcams.ac.cn   
Contact: Tingyu Wang    +86 15692201678    wangtingyu@ihcams.ac.cn   
Principal Investigator: Zengjun Li         
Sub-Investigator: Tingyu Wang         
Sponsors and Collaborators
Institute of Hematology & Blood Diseases Hospital
Investigators
Layout table for investigator information
Principal Investigator: Zengjun Li Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Sciences & Peking Union Medical College
Tracking Information
First Submitted Date  ICMJE June 6, 2019
First Posted Date  ICMJE June 10, 2019
Last Update Posted Date June 10, 2019
Actual Study Start Date  ICMJE May 15, 2019
Estimated Primary Completion Date December 15, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 6, 2019)
CRR [ Time Frame: 3 months after completion of induction therapy ]
Rate of complete remission
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2019)
  • ORR [ Time Frame: 3 months after completion of induction therapy ]
    Overall Response Rate
  • OS [ Time Frame: 5 years ]
    Overall survival
  • PFS [ Time Frame: 5 years ]
    Progression-free survival
  • MRD negative rate [ Time Frame: 3 months after completion of induction therapy ]
    the rate of undetectable tumor cells in bone marrow and/or peripheral blood by multicolor flow cytometry
  • DoR [ Time Frame: 5 years ]
    Duration of Response
  • Treatment-related side effects [ Time Frame: 10 months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Prospective Multicenter Phase 2 Study of FCR/BR Alternating With Ibrutinib in Treatment-naive Patients With CLL
Official Title  ICMJE A Prospective Multicenter Phase 2 Study of FCR/BR Alternating With Ibrutinib in Treatment-naive Patients With Chronic Lymphocytic Leukemia
Brief Summary This is a prospective multicenter phase 2 study designed with the purpose to evaluate the response rate and safety of treatment with FCR/BR alternating with ibrutinib in treatment-naive patients with chronic lymphocytic leukemia.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Chronic Lymphocytic Leukemia
Intervention  ICMJE
  • Drug: FCR and Ibrutinib

    Induction treatment:

    Patients <65 y and without significant comorbidities are given FCR 1or 2 courses (If patients' white blood cell count <10×10^9/L after first course, the second course can be saved). Then, patients takes ibrutinib orally for 3 months alternating with FCR in 2 cylcles.

    1. FCR: F(Fludarabine):25mg/m2·d,d1-3; C(Cyclophosphamide):CTX 250mg /m2·d,d1-3; R(Rituximab):375mg/m2 d0(first course),500mg/m2 d0(subsequent courses);
    2. Ibrutinib:420mg/d
  • Drug: BR and Ibrutinib

    Induction treatment:

    Patients ≥65y and ≤75 y or <65 y but with comorbidities, are given BR 1or 2 courses (If patients' white blood cell count drop to below10×10^9/Lafter first course, the second course can be saved). Then, patients takes ibrutinib orally for 3 months alternating with BR in 2 cylcles. 1.BR: B(Bendamustine):90mg/m2·d,d1-2; R(Rituximab):375mg/m2 d0(first course),500mg/m2 d0(subsequent courses); 2. Ibrutinib: 420mg/d

  • Drug: Ibrutinib and Thalidomide

    Maintenance treatment:

    After induction treatment, recommend ( but not mandatory) Ibrutinib or thalidomide monotherapy(according to patients preferrance) for MRD-positive patients.For MRD-negative patients, recommend ( but not mandatory) no maintenance therapy.

Study Arms  ICMJE Experimental: FCR/BR alternating with ibrutinib
FCR/BR→ ibrutinib✖️3months→FCR/BR→ ibrutinib✖️3months→FCR/BR→Maintenance therapy
Interventions:
  • Drug: FCR and Ibrutinib
  • Drug: BR and Ibrutinib
  • Drug: Ibrutinib and Thalidomide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 6, 2019)
50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 30, 2027
Estimated Primary Completion Date December 15, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Men or women ≥ 18 years and ≤ 75 of age.
  2. Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria.
  3. Treatment-naive patients. Those patients received short-term substandard treatment are permitted if meet all the items listed below:

    1. Untreated with combined chemotherapy such as CHOP ,COP and so on.
    2. Unteated with chemotherapy regimens including fludarabine and bendamustine.
    3. Unteated with Ibrutinib.
    4. If treated with chlorambucil or cyclophosphamide,should less than 3 weeks.
    5. If treated with interferon, should less than 6 months.
    6. No objective response are achieved (PR or CR).
  4. CLL/SLL requiring treatment as defined by at least one of the following criteria:

    1. Development of, or worsening of, anemia to Hb<100g/L (non-hemolytic) .
    2. Development of, or worsening of, thrombocytopenia to PLT<100,000/L.
    3. Massive (≥ 6 cm below left costal margin), progressive or symptomatic splenomegaly.
    4. Massive nodes (≥ 10 cm in longest diameter), or progressive or symptomatic lymphadenopathy .
    5. Progressive lymphocytosis with an increase of > 50% over a 2-month period or lymphocyte-doubling time of < 6 months. Lymphocyte-doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of < 30,000/L, LDT should not be used as a single parameter to define treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL/SLL (eg, infection, use glucocorticoid) should be excluded. f)Symptomatic or functional extranodal sites involved s (eg. Skin,kidney, lungs and so on).

    g)Constitutional symptoms, defined as any 1 or more of the following disease-related symptoms or signs: i. Unintentional weight loss of ≥ 10% within the previous 6 months ii.Significant fatigue (ie, inability to work or perform usual activities)

  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
  6. Expected to survival period for 3 months or more.

Exclusion Criteria:

  1. History of malignant tumour except CLL in the past 1year(including active central nervous system (CNS) involvement with lymphoma).
  2. Transformed to large cell lymphoma manifested by clinical evidence, or progressed to prolymphocytic leukemia(PLL).
  3. Have active autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura, and require treatment.
  4. Inadequate hepatic and renal function defined as: AST and ALT >4.0 x upper limit of normal (ULN), bilirubin >2.0 x upper limit of normal (ULN), Adequate renal function defined by serum creatinine >1.5 x upper limit of normal (ULN),unrelated to lymphoma.
  5. Severe or uncontrolled infection.
  6. Central nervous system (CNS) dysfunction with clinical manifestation.
  7. Other serious medical diseases that may affect the study(eg. Uncontrolled diabetes, gastric ulcer, other severe cardiopulmonary disease),and final decided by the investigator.
  8. Ongoing and uncontrolled bleeding
  9. History of major life-threatening bleeding, especially due to irreversible cause.
  10. Requirement for continuous anticoagulation drugs.
  11. Major surgery within 30 days(excluding lymph node biopsy).
  12. Pregnant or Lactating women, or women of reproductive age refusal to take contraceptive measures.
  13. Allergy to any drug used in the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Zengjun Li +86 13642138692 lizengjun@ihcams.ac.cn
Contact: Tingyu Wang +86 15692201678 wangtingyu@ihcams.ac.cn
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03980002
Other Study ID Numbers  ICMJE IHBDH-IIT2018009
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party TingyuWang, Institute of Hematology & Blood Diseases Hospital
Study Sponsor  ICMJE Institute of Hematology & Blood Diseases Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Zengjun Li Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Sciences & Peking Union Medical College
PRS Account Institute of Hematology & Blood Diseases Hospital
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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