A study to evaluate use of PCI-32765 (Ibrutinib) in Patients with Leukemia

Phase 1

Conditions: An Open-label, Single arm, Multicenter Phase 2 Study of the Bruton’s Tyrosine Kinase Inhibitor PCI-32765 (Ibrutinib) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma with 17p Deletion
MedDRA version: 18.1Level: PTClassification code 10003908Term: B-cell small lymphocytic lymphomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 18.1Level: LLTClassification code 10008976Term: Chronic lymphocytic leukemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2012-004476-19-BE

Lead Sponsor: Pharmacyclics LLC

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 111

Inclusion Criteria

• Men or women, at least 18 years of age
• Diagnosis of CLL/SLL meeting published diagnostic criteria:
- monoclonal B cells (either kappa or lambda light chain restricted) that are clonally co-expressing at least 1 B-cell marker (CD19 or CD20) and CD5
- prolymphocytes may comprise no more than 55% of blood lymphocytes
• Documentation of del (17p13.1) confirmed by central laboratory FISH analysis by peripheral blood sample
• Must have relapsed or refractory disease after receiving at least 1 prior line of systemic therapy which included at least 2 cycles of chemotherapy or immunotherapy for CLL/SLL.
• Currently has active disease meeting at least 1 of the following IWCLL criteria24 for requiring treatment:
- evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin <110 g/L) and/or thrombocytopenia (platelets <100 x 109/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. Lymphocyte doubling time 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 subjects with initial blood lymphocyte counts of
<30 x 109/L, 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 anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy (also see Exclusion Criteria, Section 4.2)
- documented constitutional symptoms, defined as 1 or more of the following diseaserelated symptoms or signs:
o unintentional weight loss >10% within 6 months prior to screening
o significant fatigue (inability to work or perform usual activities)
o fevers >100.5° F or 38.0° C for 2 or more weeks prior to screening without evidence of infection
o night sweats for more than 1 month prior to screening without evidence of infection
• 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.
• Eastern Cooperative Oncology Group performance status of 0 or 1
• Adequate hematologic function, defined as absolute neutrophil count (ANC) =0.75 x 109/L (independent of growth factor support for at least 7 days prior to screening) and platelet
count =30 x 109/L (independent of transfusion and growth factor support for at least 7 days prior to screening)
• Adequate hepatic function, defined as serum aspartate transaminase (AST) and alanine transaminase (ALT) =2.5 x upper limit of normal (ULN)
• Total bilirubin =1.5 x ULN
• Estimated creatinine clearance =30 mL/min using the Cockcroft-Gault equation
• Ability to receive all outpatient treatment, all laboratory monitoring, and all radiological evaluations at the institution that administers the study drug for the entire study
• Male subjects must use an effective barrier method of contraception during the study and for 3 months following the last dose of PCI-32765 i

Exclusion Criteria

• Known involvement of the central nervous system by lymphoma or leukemia
• History or current evidence of Richter’s transformation or prolymphocytic leukemia
• Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura, such as subjects with a declining hemoglobin level or platelet count secondary to autoimmune
destruction within the 4 weeks prior to first dose of PCI-32765 or the need for daily corticosteroids =20 mg daily to control the autoimmune disease
• Prior hematologic stem cell transplantation <6 months from study enrollment or any ongoing GVHD
• Received any chemo- or immunotherapy, radiation therapy, or investigational drug within 4 weeks prior to treatment
• Received 5 or more prior lines of systemic therapy for CLL
• Prior exposure to PCI-32765
• Prior enrollment into a PCI-32765 study (subjects who did NOT receive PCI-32765)
• Corticosteroid use >20 mg prednisone (or equivalent) within 1 week prior to first dose of PCI-32765, with the exception of inhaled steroid for asthma, topical steroid use, etc. Subjects requiring steroids at daily doses
>20 mg prednisone equivalent systemic exposure daily, or those who are administered steroids for leukemia control or white blood cell (WBC) count lowering are excluded
• Major surgery within 4 weeks prior to treatment
• History of prior malignancy, with the exception of the following:
- Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to Screening and felt to be at low risk for recurrence by
treating physician
- Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer
- Adequately treated cervical carcinoma in situ without current evidence of disease
• Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia; Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to treatment
• Inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of
the small bowel, poorly controlled inflammatory bowel disease, etc.)
• Uncontrolled systemic infection or requirement for intravenous (IV) antibiotics
• Known infection with human immunodeficiency virus
• Serologic status reflecting active hepatitis B or C infection. Subjects who are hepatitis B core antibody positive who are surface antigen negative or who are hepatitis C antibody
positive will need to have a negative polymerase chain reaction (PCR) result prior to enrollment. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive
and those who are hepatitis C PCR positive will be excluded.
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment
• Current life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator’s opinion, could compromise the subject’s safety, or put the study at risk
• Requires or has received anticoagulation treatment with warfarin or equivalent Vitamin K antagonists (eg, phenprocoumon) within 28 days of the first dose of PCI-32765
• Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor
• Woman who is breast-feeding