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

A Phase Ib Study of Ibrutinib in Combination With Obinutuzumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

This research study is evaluating a combination of two drugs, ibrutinib and obinutuzumab, as a possible treatment for Chronic Lymphocytic Leukemia (CLL).

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 Lymphocytic 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 Lymphocytic Leukemia cell. By attaching to the cell, the antibody can cause the Chronic Lymphocytic 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 Lymphocytic 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 Lymphocytic 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 Lymphocytic 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 Lymphocytic 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