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A Prospective, Multicenter, Phase-II Trial of Ibrutinib Plus Venetoclax in Patients With Creatinine Clearance >= 30 ml/Min Who Have Relapsed or Refractory Chronic Lymphocytic Leukemia (RR-CLL) With or Without TP53 Aberrations

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ClinicalTrials.gov Identifier: NCT03226301
Recruitment Status : Active, not recruiting
First Posted : July 21, 2017
Last Update Posted : August 2, 2022
Sponsor:
Collaborator:
Nordic CLL Study Group
Information provided by (Responsible Party):
Stichting Hemato-Oncologie voor Volwassenen Nederland

Study Description
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Brief Summary:
The aim of the current trial is to evaluate if combination treatment with venetoclax + ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (RR CLL) can lead to MRD negativity, which may induce long lasting remissions for MRD-negative patients randomized to stopping treatment after 15 induction cycles.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia in Relapse Chronic Lymphocytic Leukemia in Remission Drug: Ibrutinib + Venetoclax 15 cycles Drug: Ibrutinib until progression/relapse Drug: Possible reinitiation treatment: Ibrutinib + Venetoclax 12 cycles Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 230 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles. Patients not achieving MRD negativity after cycle 12 (PB) AND/OR cycle 15 (PB+BM) continue on ibrutinib maintenance (non-randomized group). Patients achieving MRD negativity after cycle 12 (PB) AND cycle 15 (PB+BM) are randomized 1:2 between ibrutinib maintenance (arm A) and stopping treatment (observation, arm B).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Prospective, Multicenter, Phase-II Trial of Ibrutinib Plus Venetoclax in Patients With Creatinine Clearance >= 30 ml/Min Who Have Relapsed or Refractory Chronic Lymphocytic Leukemia (RR-CLL) With or Without TP53 Aberrations
Actual Study Start Date : June 23, 2017
Actual Primary Completion Date : June 30, 2021
Estimated Study Completion Date : June 21, 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Ibrutinib until progression/relapse

All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles.

MRDpositive patients (PB and BM) will continue on Ibrutinib maintenance (non-randomized group) until progression/relapse

 Drug: Ibrutinib + Venetoclax 15 cycles
Cycle 1 + 2: 420 mg ibrutinib, day 1-28 | Cycle 3: 420 mg ibrutinib, day 1-28 | 20 mg venetoclax, day 1-7 | 50 mg venetoclax, day 8-14 | 100 mg venetoclax, day 15-21 | 200 mg venetoclax, day 22-28 | Cycle 4-15: 420 mg ibrutinib, day 1-28 + 400mg venetoclax, day 1-28

Drug: Ibrutinib until progression/relapse
420mg ibrutinib daily until progression/relapse
Experimental: Arm A

All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles.

MRD negative patients (PB and BM) will be randomized to Arm A or Arm B. Arm A: Ibrutinib until progression/relapse (Continuous ibrutinib treatment until toxicity or progression)

 Drug: Ibrutinib + Venetoclax 15 cycles
Cycle 1 + 2: 420 mg ibrutinib, day 1-28 | Cycle 3: 420 mg ibrutinib, day 1-28 | 20 mg venetoclax, day 1-7 | 50 mg venetoclax, day 8-14 | 100 mg venetoclax, day 15-21 | 200 mg venetoclax, day 22-28 | Cycle 4-15: 420 mg ibrutinib, day 1-28 + 400mg venetoclax, day 1-28

Drug: Ibrutinib until progression/relapse
420mg ibrutinib daily until progression/relapse
Experimental: Arm B

All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles.

MRD negative patients (PB and BM) will be randomized to Arm A or Arm B. Arm B: Observation until event.

Patients randomized to Arm B will get reinitiation of therapy during the observation period in case of:

  • progression according to IWCLL criteria or
  • MRD≥10-3 (PB) and at least one month later MRD ≥10-2 (PB).

Treatment reinitiation will consist of ibrutinib and venetoclax (with ramp up of venetoclax from cycle 1) for 12 cycles

 Drug: Ibrutinib + Venetoclax 15 cycles
Cycle 1 + 2: 420 mg ibrutinib, day 1-28 | Cycle 3: 420 mg ibrutinib, day 1-28 | 20 mg venetoclax, day 1-7 | 50 mg venetoclax, day 8-14 | 100 mg venetoclax, day 15-21 | 200 mg venetoclax, day 22-28 | Cycle 4-15: 420 mg ibrutinib, day 1-28 + 400mg venetoclax, day 1-28

Drug: Possible reinitiation treatment: Ibrutinib + Venetoclax 12 cycles
Cycle 1: 420 mg ibrutinib | 20 mg venetoclax, day 1-7 | 50 mg venetoclax, day 8-14 | 100 mg venetoclax, day 15-21 | 200 mg venetoclax, day 22-28 | cycles 2-12: 420 mg ibrutinib, day 1-28 + 400 mg venetoclax, day 1-28


Outcome Measures
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Primary Outcome Measures :
  1. Number of patients with progression free survival 27 months after starting treatment [ Time Frame: 27 months after last patient in trial ]
    arm B of the study


Secondary Outcome Measures :
  1. Number of patients with MRD negativity 27 months after starting treatment [ Time Frame: 27 months after last patient in trial ]
    all arms of the study

  2. Number of patients with progression free survival [ Time Frame: 7 years after last patient in ]
    all arms of the study

  3. Number of patients reinitiating treatment [ Time Frame: 7 years after last patient in ]
    arm B of the study

  4. Number of patients with treatment failure after reinitiating treatment [ Time Frame: 7 years after last patient in ]
    arm B of the study

  5. Number of patients initiating new CLL treatment [ Time Frame: 7 years after last patient in ]
    all arms of the study

  6. Number of patients with MRD negativity 12 (peripheral blood) and 15 months (peripheral blood and bone marrow) after starting treatment [ Time Frame: 15 months after last patient in trial ]
    all arms of the study

  7. Number of patients alive [ Time Frame: 7 years after last patient in ]
    all arms of the study

  8. Number of patients with complete remission, partial remission and stable disease and the duration of remission for each group [ Time Frame: 7 years after last patient in ]
    all arms of the study

  9. Number and grading of adverse events, serious adverse events and adverse events of special interest (bleeding, atrial fibrillation and tumorlysis) [ Time Frame: 7 years after last patient in ]
    all arms of the study

  10. Number of patients with improved quality of life (by EORTC QLQ-C30 and QLQ-CLL16 questionnaires) [ Time Frame: 51 months after last patient in trial ]
    all arms of the study


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Documented CLL or SLL requiring treatment according to IWCLL criteria after either being refractory to first line therapy or relapse after initial therapy.

    • Age at least 18 years.

    • Adequate bone marrow function defined as:

      • Absolute neutrophil count (ANC) >0.75 x 109/L
      • Platelet count >30,000 /μL 30 x 109/L.
      • Hemoglobin >8.0 g/dL (5 mmol/L) Unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy
    • Creatinine clearance (CrCL) ≥ 30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection.

    • Adequate liver function as indicated

      • Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN)
      • Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of nonhepatic origin)
      • Prothrombin time (PT)/International normal ratio (INR) <1.5 x ULN and PTT (activated partial thromboplastin time [aPTT]) <1.5 x ULN (unless abnormalities are related to coagulopathy or bleeding disorder).
    • 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 dose), negative testing for hepatitis C RNA within 42 days prior to registration.
    • WHO/ECOG performance status 0-3 (appendix C), stage 3 only if attributable to CLL.
    • Negative pregnancy test at study entry (for women of childbearing potential).
    • Male and female subjects of reproductive potential must agree to use both a highly effective method of birth control (e.g. implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence , or sterilized partner) and a barrier method (e.g., condoms, cervical ring, sponge, etc.) during the period of therapy and for 90 days after the last dose of study drug.
    • Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
    • Written informed consent.

Exclusion Criteria:

  • Any prior therapy with ibrutinib and/or venetoclax.
  • Transformation of CLL (Richter's transformation).
  • Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML).
  • Malignancies other than CLL currently requiring systemic therapies or not being treated in curative intention before or showing signs of progression after curative treatment.
  • Known allergy to xanthine oxidase inhibitors and/or rasburicase.
  • Known bleeding disorders (e.g., von Willebrand's disease or hemophilia).
  • Uncontrolled or active infection.
  • Patients requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see appendix K). or anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists. Please note: Patients being treated with NOACs can be included, but must be properly informed about the potential risk of bleeding under treatment with ibrutinib.
  • History of stroke or intracranial hemorrhage within 6 months prior to registration.
  • Major surgery within 28 days prior to registration.
  • Use of investigational agents which might interfere with the study drug within 28 days prior to registration.
  • Vaccination with live vaccines within 28 days prior to registration
  • Steroid therapy within 7 days prior to registration, with the exception of inhaled steroids for asthma, topical steroids, steroids up to 25 mg of prednisolone daily to control autoimmune phenomenon's, or replacement/stress corticosteroids.
  • Pregnant women and nursing mothers.
  • Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03226301


Locations
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Sponsors and Collaborators
Stichting Hemato-Oncologie voor Volwassenen Nederland
Nordic CLL Study Group
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Stichting Hemato-Oncologie voor Volwassenen Nederland
ClinicalTrials.gov Identifier: NCT03226301    
Other Study ID Numbers: HO141 CLL / VIsion trial
First Posted: July 21, 2017    Key Record Dates
Last Update Posted: August 2, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Hematologic Diseases
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
 Chronic Disease
Disease Attributes
Pathologic Processes
Venetoclax
Ibrutinib
Antineoplastic Agents
Tyrosine Kinase Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action