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A Multi-Center Study of Ibrutinib in Combination With Obinutuzumab Versus Chlorambucil in Combination With Obinutuzumab in Patients With Treatment naïve CLL or SLL

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ClinicalTrials.gov Identifier: NCT02264574
Recruitment Status : Active, not recruiting
First Posted : October 15, 2014
Results First Posted : April 16, 2019
Last Update Posted : May 15, 2019
Sponsor:
Information provided by (Responsible Party):
Pharmacyclics LLC.

Brief Summary:
An open-label, multi-center randomized, phase 3 study of ibrutinib combined with obinutuzumab versus Chlorambucil in combination with obinutuzumab in subjects with treatment-naïve Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Small-Cell Lymphoma Drug: Ibrutinib Drug: Obinutuzumab Drug: Chlorambucil Phase 3

Detailed Description:
This is a phase 3, multi-center, randomized, open-label study designed to evaluate the efficacy and safety of ibrutinib in combination with obinutuzumab compared to chlorambucil in combination with obinutuzumab in subjects with treatment-naïve chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 229 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Multi-center, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib in Combination With Obinutuzumab Versus Chlorambucil in Combination With Obinutuzumab in Subjects With Treatment-naïve Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Study Start Date : October 2014
Actual Primary Completion Date : March 26, 2018
Estimated Study Completion Date : January 2020


Arm Intervention/treatment
Experimental: IBR + OB
Ibrutinib given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.
Drug: Ibrutinib
Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) administration.

Drug: Obinutuzumab
Obinutuzumab will be supplied as 1000 mg/40 mL solution in a single-use vial for intravenous (IV) administration

Experimental: CLB + OB

Chlorambucil given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity.

Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.

Drug: Obinutuzumab
Obinutuzumab will be supplied as 1000 mg/40 mL solution in a single-use vial for intravenous (IV) administration

Drug: Chlorambucil
Chlorambucil will be supplied as 2 mg film-coated tablets for oral (PO) administration




Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: The primary analysis was performed after observing 94 PFS events as pre-specified in the study protocol. The median follow-up time was 31.3 months at the time of the analysis. ]
    PFS is defined as time from the date randomization to the date of first IRC-confirmed disease progression (PD) or date of death due to any cause, whichever occurs first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of disease progression was conducted in accordance with the IWCLL 2008 criteria with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression will not be considered progressive disease. As the median PFS was not reached in the experimental (Ibr+Ob) arm at the time of the analysis, Kaplan Meier point estimates of the PFS rate at 30 months are presented.


Secondary Outcome Measures :
  1. PFS in High-risk Subpopulation [ Time Frame: Results at an overall median follow-up of 31.3 months ]
    PFS by IRC as defined in primary endpoint was analyzed within a high-risk subpopulation which defined as randomization subjects with del17p/TP53 mutation or del 11q at baseline per central lab results.As the median PFS was not reached in the experimental (Ibr+Ob) arm at time of analysis, Kaplan Meier point estimates of the PFS rate at 30 months was presented.

  2. Rate of Sustained Hemoglobin Improvement [ Time Frame: Results at an overall median follow-up time of 31.3 months. ]
    Percent of subjects with hemoglobin increase ≥ 2 g/dL over baseline continuously for ≥ 56 days without blood transfusions or growth factors.



Information from the National Library of Medicine

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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:

Disease Related:

  1. Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria.
  2. Age 65 yrs and older OR if less than 65 years, must have at least one of the following criteria:

    • Cumulative Illness Rating Score (CIRS) >6
    • Creatinine clearance estimated <70 mL/min using Cockcroft-Gault equation.
    • Del 17p by FISH or TP53 mutation by PCR or Next Generation Sequencing
  3. Active disease meeting at least 1 of the following IWCLL criteria for requiring treatment:

    • Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and thrombocytopenia
    • Massive, progressive, or symptomatic splenomegaly
    • Massive nodes (at least 10 cm longest diameter), or progressive or symptomatic lymphadenopathy.
    • Progressive lymphocytosis with an increase of more than 50 percent over a 2-month period or a lymphocyte doubling time (LDT) of <6 months. LDT 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 <3,000/µL, LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded.
    • Autoimmune hemolytic anemia and/or immune thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy.
    • Autoimmune hemolytic anemia is defined by at least one marker of hemolysis (indirect bilirubin above the upper limit of normal (ULN) not due to liver disease, increased lactate dehydrogenase (above ULN) without alternative etiology, or increased absolute reticulocytosis (above ULN) or bone marrow erythropoiesis in the absence of bleeding AND at least one marker direct or indirect autoimmune mechanism (positive direct antiglobulin for IgG or C3d, cold agglutinins).
    • Immune thrombocytopenia is defined by platelets ≤100,000/µL and increased megakaryocytes on the bone marrow exam.
    • Constitutional symptoms, defined as one or more of the following disease-related symptoms or signs, documented in the patient's record prior to randomization:
    • unintentional weight loss >10 percent within 6 months prior to screening.
    • significant fatigue (inability to work or perform usual activities).
    • fevers >100.5°F or 38.0°C for 2 or more weeks prior to screening without evidence of infection.
    • night sweats for more than 1 month prior to screening without evidence of infection.
  4. Measurable nodal disease by computed tomography (CT), defined as at least 1 lymph node >1.5 cm in the longest diameter in a site that has not been previously irradiated. An irradiated lesion may be assessed for measurable disease only if there has been documented progression in that lesion since radiotherapy has ended.

    Laboratory

  5. Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening and randomization.
  6. Adequate hepatic and renal function
  7. Men and women ≥ 18 years of age.
  8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

Exclusion Criteria:

  1. Any prior treatment of CLL or SLL
  2. Evidence of central nervous system (CNS) involvement with primary disease of CLL/SLL
  3. History of other malignancies, except:

    • Malignancy treated with curative intent and with no known active disease present for ≥3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician.
  4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura
  5. Known or suspected history of Richter's transformation.
  6. Concurrent administration of >20mg/day of prednisone within 7 days of randomization unless indicated for prophylaxis or management of allergic reactions (eg, contrast)
  7. Known hypersensitivity to one or more study drugs
  8. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
  9. Any uncontrolled active systemic infection or an infection requiring systemic treatment that was completed ≤ 7 days before randomization.
  10. Known bleeding disorders or hemophilia.
  11. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
  12. Known history of human immunodeficiency virus (HIV) or active with hepatitis B virus (HBV) or hepatitis C virus (HCV).
  13. Major surgery within 4 weeks of randomization.
  14. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk.
  15. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
  16. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
  17. Concomitant use of warfarin or other vitamin K antagonists.
  18. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
  19. Lactating or pregnant
  20. Unwilling or unable to participate in all required study evaluations and procedures.
  21. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations).

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): NCT02264574


  Show 71 Study Locations
Sponsors and Collaborators
Pharmacyclics LLC.
Investigators
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Study Director: Lori Styles Pharmacyclics LLC.
  Study Documents (Full-Text)

Documents provided by Pharmacyclics LLC.:
Study Protocol  [PDF] February 17, 2017
Statistical Analysis Plan  [PDF] February 28, 2018


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Pharmacyclics LLC.
ClinicalTrials.gov Identifier: NCT02264574     History of Changes
Other Study ID Numbers: PCYC-1130-CA
First Posted: October 15, 2014    Key Record Dates
Results First Posted: April 16, 2019
Last Update Posted: May 15, 2019
Last Verified: March 2019

Additional relevant MeSH terms:
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Lymphoma
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
Chlorambucil
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action