A Multi-Center Study of Ibrutinib in Combination With Obinutuzumab Versus Chlorambucil in Combination With Obinutuzumab in Patients With Treatment naïve Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

• ClinicalTrials.gov Identifier: NCT02264574
• Recruitment Status: Completed
• First Posted: October 15, 2014
• Results First Posted: April 16, 2019
• Last Update Posted: September 21, 2020
• Sponsor: Pharmacyclics LLC.
• Information provided by (Responsible Party): Pharmacyclics LLC.

Tracking Information

• First Submitted Date: October 1, 2014
• First Posted Date: October 15, 2014
• Results First Submitted Date: March 25, 2019
• Results First Posted Date: April 16, 2019
• Last Update Posted Date: September 21, 2020
• Actual Study Start Date: October 6, 2014
• Actual Primary Completion Date: March 26, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 27, 2020)

• Primary Analysis: Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 30 [ Time Frame: Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]). ]
  PFS was 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 occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease. The primary analysis was performed after observing 94 PFS events as pre-specified in the study protocol. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 30 months (that is, the estimated percentage of participants with progression-free survival at Month 30) are presented.
• Final Analysis: PFS Based on Investigator Assessment - Kaplan Meier Landmark Estimates at Month 48 [ Time Frame: Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]). ]
  PFS was defined as time from the date randomization to the date of first investigator-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 48 months (that is, the estimated percentage of participants with progression-free survival at Month 48) are presented.

Original Primary Outcome Measures (submitted: October 9, 2014)

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

Current Secondary Outcome Measures (submitted: August 27, 2020)

• Primary Analysis: PFS in High-Risk Sub-Population (del17p/TP53 Mutation/Del 11q) Based on IRC Assessment - Kaplan Meier Landmark Estimates at Month 30 [ Time Frame: Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]). ]
  PFS was analyzed within the high-risk sub-population of participants with del17p or TP53 mutation or del 11q at baseline per central lab results. PFS was defined as time from the date randomization to the date of first IRC-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the IWCLL 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of PD was not considered progressive disease. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 30 months (that is, the estimated percentage of participants with progression-free survival at Month 30) are presented.
• Primary Analysis: Rate of Sustained Hemoglobin Improvement [ Time Frame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018). ]
  Percentage of participants with sustained hemoglobin improvement, defined as hemoglobin increase ≥ 2 g/dL over baseline continuously for ≥ 56 days without blood transfusions or growth factors.
• Primary Analysis: Rate of Minimal Residual Disease (MRD)-Negative Response [ Time Frame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018). ]
  Percentage of participants who achieved MRD-negative response, defined as < 1 CLL cell per 10,000 leukocytes as assessed by flow cytometry of a bone marrow aspirate per central laboratory. MRD samples were collected before initiation of subsequent antineoplastic treatment and MRD status was reported by central lab within 5 days after collection date. Participants with missing MRD data were considered non-responders.
• Primary Analysis: Overall Response Rate (ORR) Based on IRC Assessment [ Time Frame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018). ]
  ORR, defined as the percentage of participants achieving a best overall response of protocol-specified complete response (CR), CR with incomplete blood count recovery (CRi), nodular partial response (nPR), or partial response (PR) per IRC assessment at or prior to initiation of subsequent antineoplastic therapy. Assessment of response included physical examination, radiographic imaging, and evaluation of blood and marrow (if applicable), evaluated in accordance with the IWCLL 2008 criteria (Halleck et al). CR, CRi, nPR, and PR required confirmation with 2 consecutive assessments that were at least 56 days apart and no use of blood supportive product and/or growth factor during this period. Kaplan-Meier estimate.
• Primary Analysis: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 30 [ Time Frame: Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]). ]
  OS, defined as the time from the date of randomization to the date of death from any cause. All deaths observed as the time of the analysis were considered as events. For participants who were not known to have died at the time of the analysis, OS data were censored at the date last known alive. As the median OS was not reached in either treatment arm at the time of the analysis, Kaplan Meier landmark estimates of the OS rate (that is, the estimated percentage of participants still surviving at Month 30 [primary analysis]) are presented.
• Primary Analysis: Rate of Grade ≥ 3 or Serious Infusion-Related Reaction (IRR) Adverse Events [ Time Frame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018). ]
  Percentage of participants experiencing grade ≥ 3 (severe or life threatening) or serious IRR adverse events that started on the day of an obinutuzumab infusion and were assessed as related or possibly related to obinutuzumab. Categories included those events with the Medical Dictionary for Regulatory Activities (MedDRA) dictionary preferred term of IRR and those events which are among the customized standardized MedDRA query (SMQ) for IRR.
• Primary Analysis: Rate of Sustained Platelet Improvement [ Time Frame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018). ]
  Percentage of participants with platelet counts increase ≥ 50% over baseline continuously for ≥ 56 days without blood transfusion or growth factors.
• Primary Analysis: Rate of Clinically Meaningful Improvement in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EuroQol Five-Dimension (EQ-5D-5L) [ Time Frame: Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018). ]
  Percentage of participants with EQ-5D-5L utility score increase ≥ 0.08 points over baseline at or prior to initiation of subsequent antineoplastic therapy. The EQ-5D-5L is a standardized non-disease specific instrument for describing and valuing health-related quality of life, comprising 5 dimensions of health (mobility, self -care, usual activities, pain/discomfort, and anxiety/depression) to describe the participant's current health state. Each dimension comprises 5 levels with corresponding numeric scores, where 1 indicates no problems, and 5 indicates extreme problems. A unique EQ-5D-5L health state is defined by combining the numeric level scores for each of the 5 dimensions and the total score is normalized from -0.594 to 1.000, with higher scores representing a better health state. An increase in the EQ-5D-5L total score indicates improvement. Participants with missing EQ-5D-5L data were considered not achieving clinically meaningful improvement.
• Final Analysis: PFS in High-Risk Population (del17p/TP53 Mutation/Del 11q/Unmutated Immunoglobulin Heavy Chain Variable Region [IGHV]) Based on Investigator Assessment - Kaplan Meier Landmark Estimates at Month 48 [ Time Frame: Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]). ]
  PFS was analyzed within the high-risk population of participants with del17p or TP53 mutation or del 11q or IGHV unmutated at baseline per central lab results. PFS was defined as time from the date randomization to the date of first investigator-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the IWCLL 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of PD was not considered progressive disease. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 48 months (that is, the estimated percentage of participants with progression-free survival at Month 48) are presented.
• Final Analysis: Rate of Sustained Hemoglobin Improvement [ Time Frame: Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019). ]
  Percentage of participants with sustained hemoglobin improvement, defined as hemoglobin increase ≥ 2 g/dL over baseline continuously for ≥ 56 days without blood transfusions or growth factors.
• Final Analysis: Rate of Minimal Residual Disease (MRD)-Negative Response [ Time Frame: Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019). ]
  Percentage of participants who achieved MRD-negative response, defined as < 1 CLL cell per 10,000 leukocytes as assessed by flow cytometry of a bone marrow aspirate per central laboratory. MRD samples were collected before initiation of subsequent antineoplastic treatment and MRD status was reported by central lab within 5 days after collection date. Participants with missing MRD data were considered non-responders.
• Final Analysis: ORR Based on Investigator Assessment [ Time Frame: Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019). ]
  ORR, defined as the percentage of participants achieving a best overall response of protocol-specified CR, CRi, nPR or PR per investigator assessment at or prior to initiation of subsequent antineoplastic therapy. Assessment of response included physical examination, radiographic imaging, and evaluation of blood and marrow (if applicable), evaluated in accordance with the IWCLL 2008 criteria (Halleck et al). CR, CRi, nPR, and PR required confirmation with 2 consecutive assessments that were at least 56 days apart and no use of blood supportive product and/or growth factor during this period. Kaplan-Meier estimate.
• Final Analysis: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 48 [ Time Frame: Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]). ]
  OS, defined as the time from the date of randomization to the date of death from any cause. All deaths observed as the time of the analysis were considered as events. For participants who were not known to have died at the time of the analysis, OS data were censored at the date last known alive. As the median OS was not reached in either treatment arm at the time of the analysis, Kaplan Meier point estimates of the OS rate (that is, the estimated percentage of participants still surviving at Month 48 [final analysis]) are presented.
• Final Analysis: Rate of Sustained Platelet Improvement [ Time Frame: Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019). ]
  Percentage of participants with platelet counts increase ≥ 50% over baseline continuously for ≥ 56 days without blood transfusion or growth factors.

Original Secondary Outcome Measures (submitted: October 9, 2014)

• 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 ]

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: October 9, 2014)

• 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

Descriptive Information

• Brief Title: A Multi-Center Study of Ibrutinib in Combination With Obinutuzumab Versus Chlorambucil in Combination With Obinutuzumab in Patients With Treatment naïve Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)
• 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
• Brief Summary: The primary objective of this study is to evaluate the efficacy of ibrutinib in combination with obinutuzumab compared to chlorambucil in combination with obinutuzumab based on the Independent Review Committee (IRC) assessment of progression free survival (PFS). Efficacy will be evaluated according to 2008 International Workshop for Chronic Lymphocytic Leukemia (IWCLL) criteria with the modification for treatment-related lymphocytosis, in subjects with treatment-naive CLL or SLL.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Chronic Lymphocytic Leukemia
• Small-Cell Lymphoma

Intervention

• 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

Study Arms

• Experimental: IBR + OB
  Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) 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.
  Interventions:

  • Drug: Ibrutinib
  • Drug: Obinutuzumab
• Experimental: CLB + OB

  Chlorambucil (CLB) 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.

  Interventions:

  • Drug: Obinutuzumab
  • Drug: Chlorambucil

Publications *

• Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Samoilova O, Novak J, Ben-Yehuda D, Strugov V, Gill D, Gribben JG, Hsu E, Lih CJ, Zhou C, Clow F, James DF, Styles L, Flinn IW. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):43-56. doi: 10.1016/S1470-2045(18)30788-5. Epub 2018 Dec 3. Erratum In: Lancet Oncol. 2019 Jan;20(1):e10.
• Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Novak J, Strugov V, Gill D, Gribben JG, Kwei K, Dai S, Hsu E, Dean JP, Flinn IW. First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase III iLLUMINATE trial. Haematologica. 2022 Sep 1;107(9):2108-2120. doi: 10.3324/haematol.2021.279012.
• Burger JA, Robak T, Demirkan F, Bairey O, Moreno C, Simpson D, Munir T, Stevens DA, Dai S, Cheung LWK, Kwei K, Lal I, Hsu E, Kipps TJ, Tedeschi A. Up to 6.5 years (median 4 years) of follow-up of first-line ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and high-risk genomic features: integrated analysis of two phase 3 studies. Leuk Lymphoma. 2022 Jun;63(6):1375-1386. doi: 10.1080/10428194.2021.2020779. Epub 2022 Jan 11.
• Allan JN, Shanafelt T, Wiestner A, Moreno C, O'Brien SM, Li J, Krigsfeld G, Dean JP, Ahn IE. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022 Feb;196(4):947-953. doi: 10.1111/bjh.17984. Epub 2021 Dec 5.
• Greil R, Tedeschi A, Moreno C, Anz B, Larratt L, Simkovic M, Gill D, Gribben JG, Flinn IW, Wang Z, Cheung LWK, Nguyen AN, Zhou C, Styles L, Demirkan F. Pretreatment with ibrutinib reduces cytokine secretion and limits the risk of obinutuzumab-induced infusion-related reactions in patients with CLL: analysis from the iLLUMINATE study. Ann Hematol. 2021 Jul;100(7):1733-1742. doi: 10.1007/s00277-021-04536-6. Epub 2021 May 20.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 25, 2019): 229
• Original Estimated Enrollment (submitted: October 9, 2014): 212
• Actual Study Completion Date: September 3, 2019
• Actual Primary Completion Date: March 26, 2018 (Final data collection date for primary outcome measure)

Eligibility 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 fluorescence in situ hybridization (FISH) or TP53 mutation by polymerase chain reaction (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 <30,000/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 immunoglobulin G [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).

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: Australia, Austria, Belgium, Canada, Czechia, France, Israel, Italy, New Zealand, Poland, Russian Federation, Spain, Sweden, Turkey, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT02264574
• Other Study ID Numbers: PCYC-1130-CA
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Requests for access to individual participant data from clinical studies conducted by Pharmacyclics LLC, an AbbVie Company, can be submitted through Yale Open Data Access (YODA) Project site at the following link.
• URL: http://yoda.yale.edu

• Current Responsible Party: Pharmacyclics LLC.
• Original Responsible Party: Same as current
• Current Study Sponsor: Pharmacyclics LLC.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Lori Styles; Pharmacyclics LLC.

• PRS Account: Pharmacyclics LLC.
• Verification Date: August 2020