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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
Last Update Posted : January 6, 2017
Sponsor:
Information provided by (Responsible Party):
Pharmacyclics LLC.

October 1, 2014
October 15, 2014
January 6, 2017
October 2014
October 2017   (Final data collection date for primary outcome measure)
The primary endpoint of this study is Progressive Free Survival [ Time Frame: 5 years after last subject is randomized ]
The efficacy of ibrutinib in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab based on the IRC assessment compared to chlorambucil in combination with obinutuzumab based on the Independent Review Committee (IRC) assessment of progression-free survival (PFS) in subjects with treatment-naive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)by independent central radiologists, findings from physical examinations and hematology results
The primary endpoint of this study is Progressive Free Survival [ Time Frame: Up to 3 years after last subject is randomized ]
The efficacy of ibrutinib in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab based on the IRC assessment compared to chlorambucil in combination with obinutuzumab based on the Independent Review Committee (IRC) assessment of progression-free survival (PFS) in subjects with treatment-naive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)by independent central radiologists, findings from physical examinations and hematology results
Complete list of historical versions of study NCT02264574 on ClinicalTrials.gov Archive Site
  • Overall Response Rate [ Time Frame: At disease progression, 5 years ]
    Overall response rate (ORR) is defined as the proportion of subjects who achieve a CR, CRi, nPR, or PR, over the course of the study as evaluated by the IRC using IWCLL 2008 criteria, with modification for treatment-related lymphocytosis. Subjects who do not have any postbaseline response assessment will be considered as nonresponders. A chi-square test will be used to compare the two treatment arms
  • Rate of minimal residual disease (MRD)-negative responses [ Time Frame: At disease progression, 5 years ]
    A chi-square test will be used to compare the rate of MRD-negative responses between the two treatment arms.
  • Overall Response Rate [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
    Overall response rate (ORR) is defined as the proportion of subjects who achieve a CR, CRi, nPR, or PR, over the course of the study as evaluated by the IRC using IWCLL 2008 criteria, with modification for treatment-related lymphocytosis. Subjects who do not have any postbaseline response assessment will be considered as nonresponders. A chi-square test will be used to compare the two treatment arms
  • Rate of minimal residual disease (MRD)-negative responses [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
    A chi-square test will be used to compare the rate of MRD-negative responses between the two treatment arms.
  • Overall Survival [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
    the time from date of randomization until date of death due to any cause
  • Hematological Improvement measured by hemoglobin [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
    Hematological improvement will be evaluated in all subjects and in the subset of subjects with cytopenia(s) at baseline (Hgb ≤11 g/dL, or platelets ≤100,000/μL), improvement is defined as either platelet counts >100,000/μL if baseline ≤100,000/μL or increase ≥50% over baseline; or hemoglobin >11 g/dL if baseline ≤11 g/dL or increase ≥50% over baseline. Improvement will be assessed in all subjects at Cycle 9 Day 1 response assessment. Sustained hematologic improvement is defined as hematological improvement that sustained continuously for ≥56 days without blood transfusion or growth factors. Percentage of subjects with sustained improvement will be compared using χ2 test
  • Patient-Reported outcomes [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
    For EQ-5D-5L, the scores for the five categorical dimensions will be used to compute a single utility score ranging from zero (0.0) to one (1.0) representing the general health status of the subject. The United Kingdom weights will be used to generate subject utilities from the five dimensions. The change in utility score from baseline will be analyzed by using ANCOVA model with treatment arms as the factor and the baseline scores as the covariate.
  • Number of participants with adverse events as a measure of safety and tolerability within each treatment arm. [ Time Frame: Up to 30 days following the last dose of study drug ]
Not Provided
  • Event Free Survival [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
    Event-free survival is measured by the absence of events defined by progressive disease (PD), death, and nonresponders
  • Time to next treatment [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
    Time to next treatment (TTNT) is defined as the time from randomization to institution of nonprotocol specified treatment for CLL/SLL
  • Clonal evolution [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
    The proportion of subjects with new cytogenetic abnormalities (del 11q, del 17p, or trisomy 21), or other cytogenetic abnormalities detected by FISH, cytogenetics, or mutational analysis at any time post commencement of study treatment will be determined
  • Response Based on Predictive Biomarkers of Efficacy and/or Resistance [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
    Biomarker exploratory analyses are planned to identify biomarkers that may associate with response (or resistance) to ibrutinib. These biomarkers include but are not limited to secreted protein analysis, genomic and expression analysis.
  • Impact of Ibrutinib on Obinutuzumab-related Infusion Reactions [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
    The impact of ibrutinib on obinutuzumab-related infusion reactions will be evaluated by secreted protein analysis. Plasma will be collected pre-dose ibrutinib/chlorambucil, immediately prior to infusion of obinutuzumab, and 2 and 4 hours into the obinutuzumab infusion on Day 1. The samples will be evaluated for secreted proteins related to infusion reactions, such as IL-6, TNFalpha, as well as other cytokines and chemokines.
  • Rate of Obinutuzumab Infusion Reactions [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
    The proportion of subjects experiencing i) no infusion reactions, ii) Grade 1 and/or Grade 2 infusion reactions or iii) Grade3 and/or Grade 4 infusion reactions will be evaluated for each treatment arm obinutuzumab
  • Medical Resource Utilisation [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
    Parameters collected for MRU associated with the therapy include number of hospitalizations, number of emergency department visits, number of blood product transfusions, and number of use of hematopoietic growth factors
  • Spare Pharmacokinetic Characteristics of Ibrutinib [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
    The plasma concentration data for ibrutinib will be summarized using descriptive statistics at each timepoint. Population PK analysis of plasma concentration-time data of ibrutinib will be performed using nonlinear mixed-effects modeling. Data may be combined with data from other studies to support a relevant population PK model. Available subject characteristics (eg, demographics, laboratory variables, genotypes, etc.) will be tested as potential covariates IMBRUVICA® (ibrutinib) PCYC-1130-CA Amendment 1 18 August 2014 FINAL Pharmacyclics, Inc. Proprietary and Confidential Page 90 affecting PK parameters. Details will be given in a population PK analysis plan and the results of the population PK analysis will be presented in a separate report.
  • Genetic and Molecular Prognostic Markers [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
    Genetic and molecular prognostic markers will be summarized with descriptive statistics
 
A Multi-Center Study of Ibrutinib in Combination With Obinutuzumab Versus Chlorambucil in Combination With Obinutuzumab in Patients With Treatment naïve CLL or SLL
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
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.
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).
Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Chronic Lymphocytic Leukemia
  • Small-Cell Lymphoma
  • 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
  • Drug: Chlorambucil
    Chlorambucil will be supplied as 2 mg film-coated tablets for oral (PO) administration
  • Experimental: A
    Oral ibrutinib 420 mg daily (3 capsules) continuously (until evidence of progressive disease or no longer tolerated by the patient) in combination with obinutuzumab 1000 mg intravenously over 6 cycles: Days 1+2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 1 followed by Day 1 only on Cycles 2-6..
    Interventions:
    • Drug: Ibrutinib
    • Drug: Obinutuzumab
  • Experimental: B
    Treatment will be 6 cycles. Chlorambucil will be administered orally at a dose of 0.5 mg/kg body weight, on Days 1 and 15 of each cycle. Obinutuzumab will be administered intravenously at a dose of 1000 mg, over 6 cycles: given on Days 1+2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 1 and on Day 1 only on Cycles 2-6. Treatment will be administered up to a maximum of 6 cycles or until disease progression or unacceptable toxicity, whichever occurs first.
    Interventions:
    • Drug: Obinutuzumab
    • Drug: Chlorambucil
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
212
Same as current
January 2020
October 2017   (Final data collection date for primary outcome measure)

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).
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
Australia,   Austria,   Belgium,   Canada,   Czech Republic,   France,   Israel,   Italy,   New Zealand,   Poland,   Russian Federation,   Spain,   Sweden,   Turkey,   United Kingdom,   United States
 
 
NCT02264574
PCYC-1130-CA
Yes
Not Provided
Not Provided
Pharmacyclics LLC.
Pharmacyclics LLC.
Not Provided
Not Provided
Pharmacyclics LLC.
January 2017

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