A Study Combining Ibrutinib With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With CD20-Positive B-Cell Non Hodgkin Lymphoma

• Part 1 maximum tolerated dose of ibrutinib [ Time Frame: Up to Cycle 1, Day 21 in Part 1 ] [ Designated as safety issue: Yes ]
  The Part 1 maximum tolerated dose (MTD) is the Part 2 recommended ibrutinib dose.
  
  

• The number of participants affected by a dose-limiting toxicity [ Time Frame: Up to Cycle 6, Day 21 in Part 1 ] [ Designated as safety issue: Yes ]
  
• Number of participants with potential drug-drug interactions between ibrutinib and vincristine [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: Yes ]
  
• Overall response rate [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  
• Duration of response [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  
• Progression-free survival [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  
• Mean plasma concentrations of ibrutinib [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  
• Maximum observed plasma concentration of ibrutinib [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  
• Time to reach the maximum plasma concentration of ibrutinib [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  
• Area under the plasma concentration-time curve from time 0 to 24 hours of ibrutinib [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  
• Elimination half-life associated with the terminal slope of the semilogarithmic drug concentration-time curve of ibrutinib [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  
• Elimination half-life associated with the terminal slope of the semilogarithmic drug concentration-time curve of vincristine [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  
• Partial area under the plasma concentration versus time curve of vincristine [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  
• The number of participants with pharmacodynamic markers of ibrutinib in peripheral blood mononuclear cells [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  
• The number of participants with biomarkers predictive of clinical response [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  
• The number of participants affected by an adverse event [ Time Frame: Up to 30 days after the last dose of study medication ] [ Designated as safety issue: Yes ]
  

This is an open-label (individuals will know the identity of study treatments), dose escalation study to establish the recommended dose of ibrutinib combined with standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in approximately 33 adults with CD20-positive B-cell non-Hodgkin lymphoma (NHL) for whom R-CHOP is an appropriate therapy. There will be 3 periods of the study: a pretreatment (screening) period of up to 28 days before enrollment; an open-label treatment period (up to 6 cycles of ibrutinib and R-CHOP; ending at the end-of-treatment visit); and a posttreatment follow-up period until the end of study (maximum of up to 1 year after the last patient has completed the end-of-treatment visit). There are 2 parts to the study (dose escalation [Part 1] and expansion [Part 2]). During the dose escalation period, the "3+3" design will be applied and approximately 18 patients with CD20 positive B cell NHL (diffuse large B-cell lymphoma [DLBCL], mantle cell lymphoma [MCL], and follicular lymphoma [FL]) may be enrolled. Patients will be assigned to cohorts of increasing oral daily doses of ibrutinib (280, 420, and 560 mg) administered in combination with R-CHOP. The maximum tolerated dose (MTD), assessed in Cycle 1 (dose-limiting toxicity [DLT] period), is defined as the highest dose of the combination regimen at which <=33% of patients experience DLT. Baseline and follow-up electrocardiograms will be performed throughout the study. A Study Evaluation Team will review all available data upon completion of the first cycle for all patients at each dose cohort to determine DLTs, if dose escalation is acceptable, and subsequently will determine the recommended Phase 2 dose. Once the recommended Phase 2 dose is determined, approximately 15 patients with newly diagnosed DLBCL will be entered into the expansion cohort at the dose level selected to further assess the safety, pharmacokinetics, pharmacodynamics, pharmacogenomics, and activity of the combination. Patients whose disease has not progressed at the end of Cycle 1 will continue to receive ibrutinib and R CHOP up to a maximum of 6 cycles. During the posttreatment follow-up period, long term safety, survival status, disease progression, and subsequent antilymphoma therapy will be collected. The study will end 1 year after the last patient has completed the end of treatment visit.