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)

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

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.

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).