A Study of PCI-32765 (Ibrutinib) in Patients With Refractory Follicular Lymphoma

An Open-Label, Multicenter, Single-Arm, Phase 2 Study of PCI-32765 (Ibrutinib) in Subjects With Refractory Follicular Lymphoma

The purpose of this study is to evaluate the efficacy and safety of PCI-32765 (ibrutinib) administered to patients with chemoimmunotherapy-resistant follicular lymphoma (FL).

This is an open-label (identity of assigned study drug will be known) study of PCI-32765 (ibrutinib) in approximately 110 patients with chemoimmunotherapy-resistant FL whose disease has relapsed from at least 2 prior lines of therapy, including at least 1 rituximab combination chemotherapy regimen. Each patient must have resistant disease to the last therapy (defined as progression of disease [PD] during or within 12 months of the last dose of chemotherapy in a CD20 antibody combination chemotherapy regimen). The study will include the following phases: screening (up to 30 days prior to the first dose of study drug), treatment (until PD or unacceptable toxicity), and posttreatment follow-up (until death, lost to follow up, withdrawal of consent, or study end [defined as 2 years after the last patient is enrolled]). Patients will receive 560 mg of PCI-32765 by mouth once daily on a 21-day cycle. Treatment will be continuous (without interruption) and self-administered at home. The treatment phase will extend from administration of the first dose of study medication until PD or unacceptable toxicity. If a patient who had radiological evidence of PD is clinically stable or improving or exhibiting signs of tumor flare without confirmation of PD by PET or biopsy, they may continue treatment with ibrutinib upon request by the investigator and approval by the sponsor. Posttreatment follow-up will extend from the end of treatment until death, lost to follow up, withdrawal of consent, or study end. Every patient, except for those who explicitly withdraw consent from further site contact, will be followed for survival status until the study ends. In addition, data on subsequent antineoplastic therapy will also be collected. Serial pharmacokinetic samples will be collected and efficacy and safety will be monitored throughout the study. A separate assessment of pharmacokinetics is planned for patients who receive a strong or moderate CYP3A4/5 inhibitor while receiving treatment with ibrutinib. For patients who have already discontinued ibrutinib due to PD, have taken no other anticancer therapy, and now have a radiologically documented delayed response, resumption of ibrutinib is permitted on a case-by-case basis, upon request by the investigator and approval of the sponsor.

Inclusion Criteria:

• Histologic proof of Grade 1, 2, or 3a follicular lymphoma (FL) without clinical or pathological evidence of transformation
• Previously treated with at least 2 prior lines of therapy, including at least 1 rituximab combination chemotherapy regimen; last prior line of therapy includes an anti CD20 monoclonal antibody-containing chemotherapy regimen (separate lines of therapy are defined as different regimens that are either separated by disease progression, refractory disease, or relapsed disease)
• Resistant disease to the last therapy, defined as progression of disease during or within 12 months of the last dose of chemotherapy in a CD20 antibody combination chemotherapy regimen
• At least 1 measurable site of disease according to International Working Group Revised Response Criteria for Malignant Lymphoma
• Eastern Cooperative Oncology Group performance status grade 0 or 1
• Hematology and biochemical laboratory values must be within protocol-defined parameters within 7 days prior to enrollment
• Agrees to protocol-defined use of effective contraception
• Women of childbearing potential must have a negative serum or urine pregnancy test at screening

Exclusion Criteria:

• Prior nitrosoureas within 6 weeks, chemotherapy within 3 weeks, therapeutic anticancer antibodies within 4 weeks, radio- or toxin-immunoconjugates within 10 weeks, radiation therapy or other investigational agents within 3 weeks, or major surgery within 4 weeks of first dose of study drug
• Prior treatment with PCI-32765 or other Bruton's tyrosine kinase inhibitors (patients who progressed or became refractory while on treatment with PI3K inhibitors are excluded)
• Concurrent enrollment in another therapeutic investigational clinical treatment study
• Received a prior allogeneic hematopoietic stem cell transplant (prior autologous hematopoietic stem cell transplant is allowed)
• Known central nervous system lymphoma
• History of prior malignancy (except malignancy treated with curative intent and with no known active disease present for >=3 years before enrollment, adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, or adequately treated cervical carcinoma in situ without evidence of disease)
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment
• Requires anticoagulation with warfarin or equivalent vitamin K antagonists
• Requires treatment with strong cytochrome P450 (CYP)3A4/5 inhibitors
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
• Known history of Human Immunodeficiency Virus (HIV) or active infection with Hepatitis C or active infection with Hepatitis B or any uncontrolled active systemic infection requiring intravenous antibiotics
• Women who are pregnant or breastfeeding
• Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety, interfere with the absorption or metabolism of PCI-32765 capsules, or put the study outcomes at undue risk