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Ibrutinib Monotherapy Versus Fixed-duration Venetoclax Plus Obinutuzumab Versus Fixed-duration Ibrutinib Plus Venetoclax in Patients With Previously Untreated Chronic Lymphocytic Leukaemia (CLL) (CLL17)

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ClinicalTrials.gov Identifier: NCT04608318
Recruitment Status : Recruiting
First Posted : October 29, 2020
Last Update Posted : January 24, 2022
Sponsor:
Collaborators:
Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON)
Nordic CLL Study Group (NCLLSG)
Swiss Group for Clinical Cancer Research (SAKK)
Cancer Trials Ireland
Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA)
Grupo Español de Leucemia Linfocítica Crónica (GELLC)
The Israeli CLL Study Group (ICLLSG)
Information provided by (Responsible Party):
German CLL Study Group

Tracking Information
First Submitted Date  ICMJE October 23, 2020
First Posted Date  ICMJE October 29, 2020
Last Update Posted Date January 24, 2022
Actual Study Start Date  ICMJE March 1, 2021
Estimated Primary Completion Date March 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 23, 2020)
Investigator-assessed progression-free survival (PFS) [ Time Frame: Up to 80 month ]
Time from randomization to the first occurrence of progression or relapse (determined using standard iwCLL guidelines), or death from any cause, whichever occurs first
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 23, 2020)
  • Rates of undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM) [ Time Frame: At final restaging (RE): 18 months after start of treatment and additional BM assessment approx. 12 months after RE ]
    Undetectable MRD (uMRD) is defined as <10-4 (=1 CLL-cell per 10,000 leukocytes analyzed).The uMRD rate is defined as the proportion of patients having achieved uMRD.
  • MRD levels in PB at different time points [ Time Frame: Up to 80 month ]
    MRD is defined as the number of CLL-cells that can be detected in peripheral blood (PB) or bone marrow (BM). MRD values will be categorized into negative (<10-4) and positive (≥10-4)
  • Overall response rate (ORR) [ Time Frame: At final restaging (RE): 18 months after start of treatment ]
    Proportion of patients having achieved a complete response (CR), a CR with incomplete recovery of the bone marrow (CRi), or a partial response (PR) as best response.
  • CR/CRi rate [ Time Frame: At final restaging (RE): 18 months after start of treatment ]
    Proportion of patients having achieved a CR or CRi as best response (= number of patients with best response CR or CRi divided by the number of the intention-to-treat population (ITT) population)
  • Incidence of safety parameters such as adverse events (AE) and adverse events of particular/special interest (AEPI/AESI) [ Time Frame: Up to 80 month ]
    Type, frequency, severity and relationship to study treatment.of AEs and AEPIs/AESIs
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 Ibrutinib Monotherapy Versus Fixed-duration Venetoclax Plus Obinutuzumab Versus Fixed-duration Ibrutinib Plus Venetoclax in Patients With Previously Untreated Chronic Lymphocytic Leukaemia (CLL)
Official Title  ICMJE A Phase 3 Multicentre, Randomized, Prospective, Open-label Trial of Ibrutinib Monotherapy Versus Fixed-duration Venetoclax Plus Obinutuzumab Versus Fixed-duration Ibrutinib Plus Venetoclax in Patients With Previously Untreated Chronic Lymphocytic Leukaemia (CLL)
Brief Summary The aim of this study is to compare the efficacy of continuous ibrutinib monotherapy with fixed-duration venetoclax plus obinutuzumab and fixed-duration ibrutinib plus venetoclax by measuring progression-free survival (PFS) in patients with previously untreated CLL.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Chronic Lymphoid Leukemia
Intervention  ICMJE
  • Biological: Ibrutinib
    Cycles 1 - X: 420 mg daily, d1-28 p.o.
    Other Name: Imbruvica
  • Biological: Venetoclax

    Arm VG

    Cycle 1: 20 mg (2 tabl. at 10 mg), d22-28 p.o.

    Cycle 2: 50 mg (1 tabl. at 50 mg), d1-7; 100 mg (1 tabl. at 100 mg), d8-14; 200 mg (2 tabl. at 100 mg), d15-21; 400 mg (4 tabl. at 100 mg), d22-28 p.o.

    Cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28 p.o.

    Arm VI

    Cycle 4: 20 mg (2 tabl. at 10 mg), d1-7; 50 mg (1 tabl. at 50 mg), d8-14; 100 mg (1 tabl. at 100 mg), d15-21; 200 mg (2 tabl. at 100 mg), d22-28 p.o.

    Cycles 5-15: 400 mg (4 tabl. at 100 mg), d1-28 p.o.

    Other Name: ABT-199, Venclyxto
  • Biological: Obinutuzumab
    Cycle 1: (100 mg, d1 + 900 mg, d2) or 1000 mg, d1; 1000 mg, d8 + d15 i.v. Cycle 2 - 6: 1000 mg, d1 i.v.
    Other Name: GA101, Gazyvaro
Study Arms  ICMJE
  • Experimental: I (Ibrutinib)
    Ibrutinib p.o. will be administered until occurrence of unacceptable toxicity, progression of CLL or end of trial, whichever occurs first.
    Intervention: Biological: Ibrutinib
  • Experimental: VG (Obinutuzumab + Venetoclax)
    12 cycles (q 28d): Obinutuzumab i.v. + Venetoclax p.o. will be administered for 6 cycles, followed by 6 additional cycles of Venetoclax alone
    Interventions:
    • Biological: Venetoclax
    • Biological: Obinutuzumab
  • Experimental: VI (Venetoclax + Ibrutinib)
    15 cycles (q 28d): Ibrutinib p.o. + Venetoclax p.o. will be administered for a total of 12 cycles with a prior Ibrutinib monotherapy lead-in of 3 cycles
    Interventions:
    • Biological: Ibrutinib
    • Biological: Venetoclax
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: October 23, 2020)
897
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2027
Estimated Primary Completion Date March 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Documented CLL requiring treatment according to iwCLL criteria.
  2. Age at least 18 years.
  3. Life expectancy ≥ 6 months.
  4. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
  5. Adequate bone marrow function independent of growth factor or transfusion support within 2 weeks of screening initiation as follows, unless cytopenia is due to CLL:

    1. Absolute neutrophil count ≥ 1.0 × 109/L
    2. Platelet counts ≥ 30 × 109/L; in cases of thrombocytopenia clearly due to CLL (per the discretion of the investigator), platelet count should be ≥ 10 × 109/L
    3. Total haemoglobin ≥ 9 g/dL (without transfusion support, unless anaemia is due to CLL)
  6. GFR >30ml/min directly measured with 24hr urine collection, calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 - age) x bodyweight)/ (72 x creatinine), for women x 0, 85) or an equally accurate method.

    a. For patients with creatinine values within the normal range the calculation of the clearance is not necessary. Dehydrated patients with an estimated creatinine clearance less than 30 ml/min may be eligible if a repeat estimate after adequate hydration is > 30 ml/min.

  7. Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST/ ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome.
  8. Negative serological testing for hepatitis B (HbsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to registration for study screening (i.e. PCR only required when serology was positive).
  9. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2.

Exclusion criteria:

  1. Any prior CLL-specific therapies (except corticosteroid treatment administered due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents up to 20 mg prednisolone are permitted).
  2. Transformation of CLL (Richter transformation). When Richter transformation is suspected, PET-CT and/or biopsy should be performed to rule out transformation.
  3. Patients with a history of PML.
  4. An individual organ/ system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the study treatment or any other life-threatening illness, medical condition or organ system dysfunction that, in the investigator´s opinion, could compromise the patients' safety or interfere with the absorption or metabolism of the study drugs (e.g. inability to swallow tablets or impaired resorption in the gastrointestinal tract).
  5. Malignancies other than CLL currently requiring systemic therapies, not being treated with curative intent before (unless the malignant disease is in a stable remission due to the discretion of the treating physician or showing signs of progression after curative treatment.
  6. Uncontrolled or active infection.
  7. Patients with known infection with human immunodeficiency virus (HIV).
  8. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/ inducers (incl. up to 7 days prior to study treatment start).
  9. Anticoagulant therapy with warfarin or phenprocoumon, (alternative anticoagulation is allowed (e.g. DOACs), but patients must be properly informed about the potential risk of bleeding under treatment with ibrutinib).
  10. History of stroke or intracranial hemorrhage within 6 months prior to registration for study screening.
  11. Known bleeding disorders
  12. Child B / C liver cirrhosis
  13. Use of investigational agents which might interfere with the study drug within 28 days prior to registration for study screening.
  14. Vaccination with live vaccines 28 days prior to registration for study screening.
  15. Major surgery less than 30 days before start of study treatment.
  16. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products.
  17. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.
  18. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of study treatment; further pregnancy testing will be performed monthly).
  19. Fertile men or women of childbearing potential unless:

    1. surgically sterile or ≥ 2 years after the onset of menopause
    2. willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after the end of study treatment.
  20. Legal incapacity.
  21. Prisoners or subjects who are institutionalized by regulatory or court order.
  22. Persons who are in dependence to the sponsor or an investigator.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Othman Al-Sawaf, Dr. med. +49 221 478 88220 othman.al-sawaf@uk-koeln.de
Listed Location Countries  ICMJE Austria,   Belgium,   Denmark,   Finland,   Germany,   Ireland,   Israel,   Italy,   Netherlands,   Norway,   Spain,   Sweden,   Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04608318
Other Study ID Numbers  ICMJE CLL17
2019-003854-99 ( EudraCT Number )
Has Data Monitoring Committee Yes
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 German CLL Study Group
Study Sponsor  ICMJE German CLL Study Group
Collaborators  ICMJE
  • Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON)
  • Nordic CLL Study Group (NCLLSG)
  • Swiss Group for Clinical Cancer Research (SAKK)
  • Cancer Trials Ireland
  • Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA)
  • Grupo Español de Leucemia Linfocítica Crónica (GELLC)
  • The Israeli CLL Study Group (ICLLSG)
Investigators  ICMJE
Principal Investigator: Othman Al-Sawaf, Dr. med. German CLL Study Group
PRS Account German CLL Study Group
Verification Date January 2022

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