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

• ClinicalTrials.gov Identifier: NCT03226301
• Recruitment Status: Active, not recruiting
• First Posted: July 21, 2017
• Last Update Posted: May 14, 2019
• Sponsor: Stichting Hemato-Oncologie voor Volwassenen Nederland
• Collaborator: Nordic CLL Study Group
• Information provided by (Responsible Party): Stichting Hemato-Oncologie voor Volwassenen Nederland

Tracking Information

• First Submitted Date: May 15, 2017
• First Posted Date: July 21, 2017
• Last Update Posted Date: May 14, 2019
• Actual Study Start Date: July 26, 2017
• Estimated Primary Completion Date: January 1, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 20, 2017)

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

• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT03226301 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: July 20, 2017)

• 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
• Number of patients with progression free survival [ Time Frame: 7 years after last patient in ]
  all arms of the study
• Number of patients reinitiating treatment [ Time Frame: 7 years after last patient in ]
  arm B of the study
• Number of patients with treatment failure after reinitiating treatment [ Time Frame: 7 years after last patient in ]
  arm B of the study
• Number of patients initiating new CLL treatment [ Time Frame: 7 years after last patient in ]
  all arms of the study
• 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
• Number of patients alive [ Time Frame: 7 years after last patient in ]
  all arms of the study
• 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
• 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
• 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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief 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
• 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

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

Condition

• Chronic Lymphocytic Leukemia in Relapse
• Chronic Lymphocytic Leukemia in Remission

Intervention

• 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
• 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

Study Arms

• 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

  Interventions:

  • Drug: Ibrutinib + Venetoclax 15 cycles
  • Drug: Ibrutinib 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)

  Interventions:

  • Drug: Ibrutinib + Venetoclax 15 cycles
  • Drug: Ibrutinib 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

  Interventions:

  • Drug: Ibrutinib + Venetoclax 15 cycles
  • Drug: Possible reinitiation treatment: Ibrutinib + Venetoclax 12 cycles

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: July 20, 2017): 230
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 1, 2026
• Estimated Primary Completion Date: January 1, 2026 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark

Administrative Information

• NCT Number: NCT03226301
• Other Study ID Numbers: HO141 CLL / VIsion trial
• 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

• Plan to Share IPD: No

• Responsible Party: Stichting Hemato-Oncologie voor Volwassenen Nederland
• Study Sponsor: Stichting Hemato-Oncologie voor Volwassenen Nederland
• Collaborators: Nordic CLL Study Group
• Investigators: Not Provided
• PRS Account: Stichting Hemato-Oncologie voor Volwassenen Nederland
• Verification Date: May 2019