A Study of Ibrutinib + Obinutuzumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

This research study is a Phase I clinical trial, which tests the safety of an investigational
intervention and also tries to define the best order of administration of these two drugs.
"Investigational" means that the intervention is being studied. The FDA (the U.S. Food and
Drug Administration) has approved ibrutinib and obinutuzumab individually for the treatment
of patients with Chronic Lymphomcytic Leukemia, your type of cancer. However, the FDA has not
approved the combination of these two drugs as a treatment for any disease.

Ibrutinib is a type of drug called a kinase inhibitor. It is believed to block a type of
protein called a kinase that helps leukemia cells live and grow. By blocking this, it is
possible that the study drug will kill cancer cells or stop them from growing.

Obinutuzumab is a type of drug called a monoclonal antibody. It is believed to attach to a
protein called CD20 on the outside of a Chronic Lymphomcytic Leukemia cell. By attaching to
the cell, the antibody can cause the Chronic Lymphomcytic Leukemia cell to die.

In this research study, the investigators are assessing the safety of various dosing regimens
of ibrutinib and obinutuzumab. The investigators are trying to determine whether it is better
to give one drug before the other or if they can be started at the same time.

Inclusion criteria:

- Must have a confirmed diagnosis of Chronic Lymphomcytic Leukemia or Small Lymphocytic
Lymphoma as per IW-CLL 2008 criteria and require therapy based on meeting at least one
of the following criteria:

- Evidence of progressive marrow failure with anemia (hemoglobin <11.0 g/L) and/or
thrombocytopenia (platelets <100 x 10^9/L)

- Massive (≥6 cm below the left costal margin), progressive, or symptomatic
splenomegaly

- Massive nodes (at least 10 cm longest diameter), progressive, or symptomatic
lymphadenopathy

- Progressive lymphocytosis with an increase of more than 50% over a 2-month period
or LDT of <6 months.

- Autoimmune anemia and/or thrombocytopenia that is poorly responsive to
corticosteroids

- Constitutional symptoms, defined as 1 or more of the following:

- unintentional weight loss >10% 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

- Relapsed after or refractory to at least one prior Chronic Lymphomcytic
Leukemia-directed therapy

- Age greater than or equal to 18 years

- ECOG Performance Status <2

- Heme criteria at screening, unless significant bone marrow involvement of Chronic
Lymphomcytic Leukemia confirmed on biopsy:

- Absolute Neutrophil Count (ANC) ≥500 cells/mm3 (0.5 x 10^9/L). Growth factor
allowed to achieve

- Platelet count ≥25,000 cells/mm3 (25 x 10^9/L) independent of transfusion within
7 days of screening

- Adequate hepatic function defined as: AST and ALT ≤ 4.0 x upper limit of normal (ULN),
bilirubin ≤2.0 x upper limit of normal (ULN) unless bilirubin rise is due to Gilbert's
syndrome)

- Adequate renal function defined by serum creatinine <2.0 x upper limit of normal (ULN)
unless due to biopsy proven Chronic Lymphomcytic Leukemia kidney infiltration

- Women of child-bearing potential and men must agree to use adequate contraception

- Patients who have undergone prior allo transplant are eligible provided that their
transplant day 0 is > 6 months from their first dose of study drug

Exclusion Criteria:

- History of severe allergic or anaphylactic reactions to monoclonal antibody therapy

- Prior treatment with either obinutuzumab or ibrutinib

- 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.

- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease.

- Adequately treated carcinoma in situ without evidence of disease.

- Low-risk prostate cancer on active surveillance

- Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc.,
or chronic administration of >20 mg/day of prednisone) within 28 days of the first
dose of study drug.

- Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.

- Recent infection requiring systemic treatment that was completed ≤7 days before the
first dose of study drug.

- Known bleeding disorders or hemophilia.

- History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

- Known history of HIV or active hepatitis C virus (HCV) or hepatitis B virus (HBV).

- Any uncontrolled active systemic infection.

- Major surgery within 4 weeks of first dose of study drug.

- Currently active, clinically significant cardiovascular disease, such as uncontrolled
arrhythmia or Class 3 or 4 CHF as defined by the NYHA Functional Classification; or a
history of Myocardial Infarction, unstable angina, or acute coronary syndrome within 6
months prior to randomization.

- Lactating or pregnant.

- Patients receiving any other study agents

- Patients with known Central Nervous System involvement

- Baseline QT Interval Corrected by the Fridericia Correction Formula (QTcF) >480 ms
unless Left Bundle Branch Block

- Patients who require warfarin or other vitamin K antagonists for anticoagulation

- Concurrent administration of strong inhibitors or inducers of CYP3A