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: 18.0Level: PTClassification code 10003908Term: B-cell small lymphocytic lymphomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 18.0Level: 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-SE

Lead Sponsor: Pharmacyclics LLC

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 111

Inclusion Criteria

1. Men or women, at least 18 years of age
2. Diagnosis of CLL/SLL meeting published diagnostic criteria:22
• 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
3. Documentation of del (17p13.1) confirmed by central laboratory FISH analysis by peripheral blood sample
4. 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.
5. Currently has active disease meeting at least 1 of the following IWCLL criteria22 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
6. 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.
7. Eastern Cooperative Oncology Group performance status of 0 or 1
8. 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)
9. Adequate hepatic function, defined as serum aspartate transaminase (AST) and alanine transaminase (ALT) =2.5 x upper limit of normal (ULN)
10. Total bilirubin =1.5 x ULN
11. Estimated creatinine clearance =30 mL/min using the Cockcroft-Gault equation
12. 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
13. Male subjects must use an effective barrier method of contraception during the study and for 3 months following the las

Exclusion Criteria

1. Known involvement of the central nervous system by lymphoma or leukemia
2. History or current evidence of Richter’s transformation or prolymphocytic leukemia
3. 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
4. Prior hematologic stem cell transplantation <6 months from study enrollment or any ongoing GVHD
5. Received any chemo- or immunotherapy, radiation therapy, or investigational drug within 4 weeks prior to treatment
6. Received 5 or more prior lines of systemic therapy for CLL
7. Prior exposure to PCI-32765
8. Prior enrollment into a PCI-32765 study (subjects who did NOT receive PCI-32765)
9. 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
10. Major surgery within 4 weeks prior to treatment
11. History of prior malignancy, with the exception of the following:
12. 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
13. Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer
14. Adequately treated cervical carcinoma in situ without current evidence of disease
15. 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
16. 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.)
17. Uncontrolled systemic infection or requirement for intravenous (IV) antibiotics
18. Known infection with human immunodeficiency virus
19. 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.
20. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
21. 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
22. 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
23. Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibito