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A Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

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ClinicalTrials.gov Identifier: NCT03462719
Recruitment Status : Recruiting
First Posted : March 12, 2018
Last Update Posted : October 19, 2018
Sponsor:
Collaborator:
Pharmacyclics LLC.
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Brief Summary:
The purpose of this study is to assess progression‑free survival (PFS) from treatment with ibrutinib plus venetoclax (I+VEN) compared with obinutuzumab plus chlorambucil (G-Clb) as assessed by an Independent Review Committee (IRC).

Condition or disease Intervention/treatment Phase
Leukemia, Lymphocytic, Chronic, B-Cell Drug: Ibrutinib Drug: Venetoclax Drug: Chlorambucil Drug: Obinutuzumab Phase 3

Detailed Description:
The hypothesis is treatment with combination of I+VEN will result in longer PFS compared with G-Clb in participants with previously untreated chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) who meet International Workshop on CLL (iwCLL) treatment criteria. The study includes screening (30 days), treatment (from randomization until treatment discontinuation) and follow-up phase (from treatment discontinuation until death, lost to follow up, consent withdrawal, or study end, whichever occurs first). Participants without progression will continue disease evaluations until disease progression or death. Study duration is approximately 6 years. Safety includes review of adverse events and laboratory tests performed over time.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Open-label, Phase 3 Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Subjects With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL).
Actual Study Start Date : April 17, 2018
Estimated Primary Completion Date : February 2, 2021
Estimated Study Completion Date : April 30, 2024


Arm Intervention/treatment
Experimental: Treatment Arm A: Ibrutinib and Venetoclax (I+VEN)
Participants will initially receive ibrutinib (420 mg [milligrams]/day) for 3 cycles. Venetoclax dose ramp up (from 20 mg to 400 mg over 5 weeks) will begin at Cycle 4 and the combination of ibrutinib and venetoclax will be given for 12 cycles. Following the completion of I+VEN treatment, ibrutinib will be given for another 3 cycles for a total of up to 18 cycles of treatment (each cycle is equivalent to 28 days).
Drug: Ibrutinib
Participants will receive ibrutinib 420 mg orally once daily up to 18 cycles.

Drug: Venetoclax
Participants will receive venetoclax in combination with ibrutinib for a total of 12 cycles, beginning at Cycle 4. For the first 5 weeks of venetoclax treatment, the treatment dose will be ramped up from 20 mg to 400 mg.

Active Comparator: Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb)
Participants will receive chlorambucil and obinutuzumab (G-Clb) for 6 cycles. Participants will receive obinutuzumab, 1000 mg intravenously (IV) on Days 1, 8 and 15 of Cycle 1, and on Day 1 of Cycles 2 to 6 and chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight, on Days 1 and 15 of Cycles 1 to 6.
Drug: Chlorambucil
Participants will receive chlorambucil at a dose of 0.5 mg/kg body weight on Days 1 and 15 of Cycles 1 to 6.

Drug: Obinutuzumab
Participant will receive obinutuzumab 1000 mg intravenously on Days 1, 8, and 15 of Cycle 1, and Day 1 of Cycles 2 to 6.




Primary Outcome Measures :
  1. Progression-Free Survival (PFS) [ Time Frame: From date of randomization to date of disease progression (PD) or death, whichever occurs first (Up to approximately 6 years) ]
    PFS is defined as the duration from date of randomization to date of disease progression (PD) or death, whichever occurs first. PD is defined according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL 2008 Guidelines).


Secondary Outcome Measures :
  1. Percentage of Participants who are Minimal Residual Disease (MRD) Negative [ Time Frame: Up to approximately 6 years ]
    MRD negative disease status is defined as less than (<) 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes or < 0.01 % in the bone marrow. MRD will be assessed by flow cytometry.

  2. Overall Response Rate (ORR) [ Time Frame: Up to approximately 6 years ]
    ORR is defined as percentage of participants with complete response [CR], complete response with an incomplete marrow recovery (CRi), partial response (PR), and nodular PR (nPR), for at least 2 months. CR: lymph nodes none greater than (>) 1.5 centimeter (cm), no hepatomegaly and splenomegaly, bone marrow normocellular with less than (<) 30% lymphocytes and no lymphoid nodules, blood lymphocytes < 4,000 per microliter (mcL), platelet count >100,000/mcL, hemoglobin >11 gram per deciliter (g/dL), neutrophils >1500/mcL. PR is at least 50% reduction in at least 2 Group A (lymphadenopathy, hepatomegaly, splenomegaly, blood lymphocytes and marrow infiltrates) and improvement in at least 1 Group B (platelet count, hemoglobin and neutrophils). CRi: complete response with an incomplete recovery of the participant's bone marrow. nPR: response that meets criteria for CR, but bone marrow biopsy shows lymphoid nodules.

  3. Complete Response (CR) Rate [ Time Frame: Up to approximately 6 years ]
    CR is lymph nodes none > 1.5 cm, no hepatomegaly and splenomegaly, < 30% lymphocytes, bone marrow normocellular and no lymphoid nodules.

  4. Duration of Response (DOR) [ Time Frame: From the date of initial documentation of a response to the date of first documented evidence of progressive disease or death (up to approximately 6 years) ]
    DOR is defined as duration in days from the date of initial documentation of a response to the date of first documented evidence of progressive disease or death. Response and PD are defined according to iwCLL 2008 Guidelines.

  5. Overall Survival (OS) [ Time Frame: From the date of randomization to the date of death from any cause (up to approximately 6 years) ]
    OS is defined as the time from the date of randomization to the date of the participant's death from any cause.

  6. Time-to-Next Treatment [ Time Frame: From date of randomization to the start date of any anti-leukemic therapy subsequent to the study treatment (up to approximately 6 years) ]
    The time from date of randomization to the start date of any anti-leukemic therapy subsequent to the study treatment.

  7. Time to Worsening as Measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) [ Time Frame: From the date of randomization to the start date of worsening (up to approximately 6 years) ]
    Worsening in functional and global QoL scales is defined by clinically important negative change. Differences >= 10 points on EORTC scales are considered clinically important.

  8. Time to Worsening as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Total Score [ Time Frame: From the date of randomization to the start date of worsening (up to approximately 6 years) ]
    Worsening is defined by clinically important negative change. A difference of >= 3 points in FACIT-Fatigue score is considered clinically important.

  9. Time to Worsening as Measured by Using EuroQol 5 Dimension 5 Level questionnaire (EQ-5D 5L) [ Time Frame: From the date of randomization to the start date of worsening (up to approximately 6 years) ]
    Worsening is defined by clinically important negative change. A minimum difference of >= 0.07 points change in utility score is considered clinically important; for the VAS health rating, a minimum important difference is >= 7 points change.

  10. Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability [ Time Frame: Up to approximately 18 months ]
    An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product.

  11. Number of Participants with Abnormal Clinical Laboratory Findings [ Time Frame: Up to approximately 18 months ]
    The number of participants with abnormal clinical laboratory findings will be reported.

  12. Percentage of Participants with Sustained Hemoglobin Improvement [ Time Frame: Up to approximately 6 years ]
    The percentage of study participants with sustained hemoglobin improvement from baseline will be reported

  13. Percentage of Participants with Sustained Platelet Improvement [ Time Frame: Up to approximately 6 years ]
    Sustained platelet improvement rate is defined as the percentage of participants who achieve a sustained increase of platelet levels from baseline.

  14. Concentration at End of Dosing Interval (24h) at Steady-state (Ctrough, ss) [ Time Frame: Day 1 of Cycles 2, 3, 5 and 6 (each cycle is defined as 28 days) (up to approximately 6 years) ]
    Ctrough,ss is defined as concentration at the end of dosing interval (24h) at steady-state. Ibrutinib and venetoclax Ctrough, ss data will be evaluated.



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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:

  • Adult participants who are: (a) greater than or equal to (>=) 65 years old or, (b) 18 to 64 years old and have at least 1 of the following:

    1. Cumulative Illness Rating Scale (CIRS) score > 6
    2. Creatinine clearance (CrCl) estimated less than (<) 70 milliliter per minute (mL/min) using Cockcroft-Gault equation
  • Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that meets International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria
  • Measurable nodal disease (by computed tomography [CT]), defined as at least one lymph node > 1.5 centimeter (cm) in longest diameter
  • Eastern Cooperative Oncology Group (ECOG) Performance Status Grade less than or equal to (<=) 2
  • Active CLL/SLL requiring treatment per the iwCLL criteria

Exclusion Criteria:

  • Prior anti-leukemic therapy for CLL or SLL
  • Presence of deletion of the short arm of chromosome 17 (del17p) or known TP53 mutation detected at a threshold of >10 percent (%) variable allele frequency (VAF)
  • Major surgery within 4 weeks of first dose of study treatment
  • Known bleeding disorders (example, von Willebrand's disease or hemophilia)
  • Central nervous system (CNS) involvement or suspected Richter's syndrome

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): NCT03462719


Contacts
Contact: Study Contact 844-434-4210 JNJ.CT@sylogent.com

  Show 95 Study Locations
Sponsors and Collaborators
Janssen Research & Development, LLC
Pharmacyclics LLC.
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC

Additional Information:
Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT03462719     History of Changes
Other Study ID Numbers: CR108428
2017-004699-77 ( EudraCT Number )
54179060CLL3011 ( Other Identifier: Janssen Research & Development, LLC )
First Posted: March 12, 2018    Key Record Dates
Last Update Posted: October 19, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Obinutuzumab
Venetoclax
Chlorambucil
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action