Studie Ibrutinib + obinutuzumab u pacientů s relapsující nebo refrakterní chronickou lymfocytární leukémií

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