Study of Ibrutinib (a Bruton's Tyrosine Kinase Inhibitor), Versus Temsirolimus in Patients With Relapsed or Refractory Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy

• Overall response rate [ Time Frame: up to 3 years after the last patient is randomized ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: up to 3 years after the last patient is randomized ] [ Designated as safety issue: No ]
• 1-year survival rate [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
• Duration of response [ Time Frame: up to 3 years after the last patient is randomized ] [ Designated as safety issue: No ]
• Time-to-next treatment [ Time Frame: up to 3 years after the last patient is randomized ] [ Designated as safety issue: No ]
• Number of participants with adverse events [ Time Frame: up to 30 days after the last dose of study medication ] [ Designated as safety issue: Yes ]
• Mean plasma concentrations of ibrutinib [ Time Frame: Cycles 1-2: predose on Day 1, postdose at 1, 2, and 4 hours; and Cycle 3: predose on Day 1 ] [ Designated as safety issue: No ]
• Maximum observed plasma concentration of ibrutinib [ Time Frame: Cycles 1-2: predose on Day 1, postdose at 1, 2, and 4 hours; and Cycle 3: predose on Day 1 ] [ Designated as safety issue: No ]
• Minimum observed plasma concentration of ibrutinib [ Time Frame: Cycles 1-2: predose on Day 1, postdose at 1, 2, and 4 hours; and Cycle 3: predose on Day 1 ] [ Designated as safety issue: No ]
• Area under the plasma concentration-time curve from time 0 to 24 hours of ibrutinib [ Time Frame: Cycles 1-2: predose on Day 1, postdose at 1, 2, and 4 hours; and Cycle 3: predose on Day 1 ] [ Designated as safety issue: No ]
• Mean change from baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) scale score [ Time Frame: up to 3 years after the last patient is randomized ] [ Designated as safety issue: No ]
• Mean change from baseline in EuroQol (EQ-5D-5L) index score [ Time Frame: up to 3 years after the last patient is randomized ] [ Designated as safety issue: No ]
• Mean change from baseline in medical resource utilization [ Time Frame: up to 30 days from last dose of study medication ] [ Designated as safety issue: No ]
• Mean change from baseline in biomarkers that alter B-cell receptor (BCR) signaling or activate alternative signaling pathways [ Time Frame: up to 30 days from last dose of study medication ] [ Designated as safety issue: No ]
• Mean change from baseline in identified resistance biomarkers from bone marrow [ Time Frame: up to 30 days from last dose of study medication ] [ Designated as safety issue: No ]

• Overall response rate [ Time Frame: up to 3 years after the last patient is randomized ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: up to 3 years after the last patient is randomized ] [ Designated as safety issue: No ]
• 1-year survival rate [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
• Duration of response [ Time Frame: up to 3 years after the last patient is randomized ] [ Designated as safety issue: No ]
• Time-to-next treatment [ Time Frame: up to 3 years after the last patient is randomized ] [ Designated as safety issue: No ]
• Number of participants with adverse events [ Time Frame: up to 30 days after the last dose of study medication ] [ Designated as safety issue: Yes ]
• Mean plasma concentrations of ibrutinib [ Time Frame: Cycles 1-3: predose on Day 1; postdose at 1, 2, and 4 hours ] [ Designated as safety issue: No ]
• Maximum observed plasma concentration of ibrutinib [ Time Frame: Cycles 1-3: predose on Day 1; postdose at 1, 2, and 4 hours ] [ Designated as safety issue: No ]
• Minimum observed plasma concentration of ibrutinib [ Time Frame: Cycles 1-3: predose on Day 1; postdose at 1, 2, and 4 hours ] [ Designated as safety issue: No ]
• Area under the plasma concentration-time curve from time 0 to 24 hours of ibrutinib [ Time Frame: Cycles 1-3: predose on Day 1; postdose at 1, 2, and 4 hours ] [ Designated as safety issue: No ]
• Mean change from baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) scale score [ Time Frame: up to 3 years after the last patient is randomized ] [ Designated as safety issue: No ]
• Mean change from baseline in EuroQol (EQ-5D-5L) index score [ Time Frame: up to 3 years after the last patient is randomized ] [ Designated as safety issue: No ]
• Mean change from baseline in medical resource utilization [ Time Frame: up to 30 days from last dose of study medication ] [ Designated as safety issue: No ]
• Mean change from baseline in biomarkers that alter B-cell receptor (BCR) signaling or activate alternative signaling pathways [ Time Frame: up to 30 days from last dose of study medication ] [ Designated as safety issue: No ]
• Mean change from baseline in identified resistance biomarkers from bone marrow [ Time Frame: up to 30 days from last dose of study medication ] [ Designated as safety issue: No ]

The purpose of this study is to evaluate the efficacy and safety of ibrutinib versus temsirolimus in patients with relapsed or refractory mantle cell lymphoma who received at least 1 prior chemotherapy regimen.

This is a randomized (individuals assigned to study treatment by chance), open-label (identity of assigned study drug will be known), study to evaluate the efficacy and safety of ibrutinib when compared with temsirolimus in patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least 1 prior rituximab-containing chemotherapy regimen. Approximately 280 eligible patients will be randomly assigned in a 1:1 ratio and stratified (grouped) by the number of prior lines of therapy (1 or 2 versus >=3) and simplified MCL International Prognostic Index criteria to receive either ibrutinib by mouth (Treatment Arm A) or temsirolimus intravenous infusion (Treatment Arm B). The study will consist of screening, treatment, and posttreatment phases. Data will be collected on disease response to the treatment, progression-free survival, overall survival, subsequent anti-MCL therapies, patient reported outcomes, and medical resource utilization. Tumor samples, blood collected at multiple time points, and a bone marrow aspirate will be evaluated to identify markers predictive of response or resistance to ibrutinib. Serial pharmacokinetic (study of what the body does to a drug) samples will be collected as detailed in the protocol. Safety will be monitored throughout the study. Disease evaluations will be performed every 9 weeks for up to 15 months from the start of study drug, and every 24 weeks thereafter, until disease progression, death, or the clinical cutoff, whichever comes first. Data will be analyzed up to 3 years after the last patient is enrolled for the final follow-up.

• Drug: Ibrutinib
  560 mg once daily continuous (without interruption) by mouth for 21-day cycles
• Drug: Temsirolimus
  175 mg once daily intravenous infusion on Days 1, 8, 15 of the first cycle followed by 75 mg on Days 1, 8, 15 of each 21-day cycle

• Experimental: Ibrutinib
  Intervention: Drug: Ibrutinib
• Experimental: Temsirolimus
  Intervention: Drug: Temsirolimus

Inclusion Criteria:

• Confirmed diagnosis of mantle cell lymphoma (MCL)
• Received at least 1 prior rituximab-containing chemotherapy regimen (separate lines of therapy are defined as single or combination therapies that are either separated by disease progression or by a > 6 month treatment-free interval)
• Documented relapse or disease progression following the last anti-MCL treatment
• At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma
• Eastern Cooperative Oncology Group performance status grade 0 or 1
• Protocol-defined hematology and biochemistry laboratory values

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 randomization
• Prior treatment with temsirolimus, other mTOR inhibitors, ibrutinib, or other Bruton's tyrosine kinase (BTK) inhibitors
• Known central nervous system lymphoma
• Received an allogeneic or autologous hematopoietic stem cell transplant <=6 months from the date of randomization and on immunosuppressive therapy or have evidence of active graft versus host disease
• Diagnosed or treated for malignancy other than MCL, except: malignancy treated with curative intent and with no known active disease present for >=3 years before randomization, adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, adequately treated cervical carcinoma in situ without evidence of disease
• History of stroke or intracranial hemorrhage within 6 months prior to randomization
• Requires anticoagulation with warfarin or equivalent vitamin K antagonist
• Requires treatment with strong CYP3A4/5 inhibitor
• 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 hepatitis C virus (HCV) or active hepatitis B virus (HBV) infection or any uncontrolled active systemic infection requiring intravenous antibiotics
• Woman who is pregnant or breast-feeding
• 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 ibrutinib capsules, or put the study outcomes at undue risk