Safety and Efficacy of PCI-32765 in Subjects With Relapsed/Refractory Mantle Cell Lymphoma (MCL) (PCYC-1104-CA)

• To Measure the Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Participants will be followed until progression of disease or start of another anti-cancer treatment. ] [ Designated as safety issue: Yes ]
• To Measure the Number of Participants Pharmacokinetics to Assist in Determining How the Body Responds to the Study Drug [ Time Frame: Procedure to be Performed During the First Month of Receiving Study Drug. ] [ Designated as safety issue: Yes ]
• Patient Reported Outcomes [ Time Frame: Participants will be followed until progression of disease or start of another anti-cancer treatment. ] [ Designated as safety issue: No ]
  To measure the number of participants reported outcomes in determing the health related quality of life.

• To Measure the Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Participants will be followed until progression of disease or start of another anti-cancer treatment. ] [ Designated as safety issue: Yes ]
• To Measure the Number of Participants Pharmacokinetics to Assist in Determining How the Body Responds to the Study Drug [ Time Frame: Procedure to be Performed During the First Month of Receiving Study Drug. ] [ Designated as safety issue: Yes ]

The purpose of this study is to:

1. Evaluate the efficacy of PCI-32765 in relapsed/refractory subjects with MCL.
2. The secondary objective is to evaluate the safety of a fixed daily dosing regimen of PCI-32765 capsules in this population.

The primary objective of this trial is to evaluate the efficacy of PCI-32765 in relapsed/refractory subjects with MCL. The secondary objective is to evaluate the safety of a fixed daily dosing regimen of PCI-32765 capsules in this population.

• Experimental: PCI-32765 Prior Bortezomib Treatment
  PCI-32765 for patients who have failed previous bortezomib treatment
  Intervention: Drug: PCI-32765
• Experimental: PCI-32765 Bortezomib naive
  PCI-32765 for patients who have not previously been treated with Bortezomib
  Intervention: Drug: PCI-32765

• Marostica E, Sukbuntherng J, Loury D, de Jong J, de Trixhe XW, Vermeulen A, De Nicolao G, O'Brien S, Byrd JC, Advani R, McGreivy J, Poggesi I. Population pharmacokinetic model of ibrutinib, a Bruton tyrosine kinase inhibitor, in patients with B cell malignancies. Cancer Chemother Pharmacol. 2015 Jan;75(1):111-21. doi: 10.1007/s00280-014-2617-3. Epub 2014 Nov 8.
• Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, Jurczak W, Advani RH, Romaguera JE, Williams ME, Barrientos JC, Chmielowska E, Radford J, Stilgenbauer S, Dreyling M, Jedrzejczak WW, Johnson P, Spurgeon SE, Li L, Zhang L, Newberry K, Ou Z, Cheng N, Fang B, McGreivy J, Clow F, Buggy JJ, Chang BY, Beaupre DM, Kunkel LA, Blum KA. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013 Aug 8;369(6):507-16. doi: 10.1056/NEJMoa1306220. Epub 2013 Jun 19.

Inclusion Criteria:

• Men and women ≥ 18 years of age
• ECOG performance status of ≤ 2
• Pathologically confirmed MCL, with documentation of either overexpression of cyclin D1 or t(11;14), and measurable disease on cross sectional imaging that is ≥ 2 cm in the longest diameter and measurable in 2 perpendicular dimensions
• Documented failure to achieve at least partial response (PR) with, or documented disease progression disease after, the most recent treatment regimen
• At least 1, but no more than 5, prior treatment regimens for MCL (Note: Subjects having received ≥2 cycles of prior treatment with bortezomib, either as a single agent or as part of a combination therapy regimen, will be considered to be bortezomib-exposed.)
• Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty
• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations)

Major exclusion criteria:

• Prior chemotherapy within 3 weeks, nitrosoureas within 6 weeks, therapeutic anticancer antibodies within 4 weeks, radio- or toxin-immunoconjugates within 10 weeks, radiation therapy within 3 weeks, or major surgery within 2 weeks of first dose of study drug
• Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of PCI-32765 capsules, or put the study outcomes at undue risk
• 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 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction

• Any of the following laboratory abnormalities:

  1. Absolute neutrophil count (ANC) < 750 cells/mm3 (0.75 x 109/L) unless there is documented bone marrow involvement
  2. Platelet count < 50,000 cells/mm3 (50 x 109/L) independent of transfusion support unless there is documented bone marrow involvement
  3. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN)
  4. Creatinine > 2.0 x ULN