A Study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma

Tracking Information
First Submitted Date ICMJE	May 14, 2013
First Posted Date ICMJE	May 16, 2013
Last Update Posted Date	June 1, 2018
Actual Study Start Date ICMJE	September 3, 2013
Actual Primary Completion Date	February 26, 2018 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: May 14, 2013)	Event-free survival [ Time Frame: Up to disease progression, relapse from complete response, initiation of subsequent systemic antilymphoma therapy after completion of at least 6 cycles of R-CHOP therapy, or death, whichever occurs first, up to Year 7 ]
Original Primary Outcome Measures ICMJE	Same as current
Change History	Complete list of historical versions of study NCT01855750 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: November 14, 2017)	Progression-free survival [ Time Frame: Up to disease progression, relapse from complete response, or death, whichever occurs first, up to Year 7 ]; Complete response rate [ Time Frame: Up to completion of chemotherapy treatment, up to Year 7 ]; Overall survival [ Time Frame: Up to the date of the participants death, up to Year 7 ]; Time to worsening symptoms in the Lym subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) [ Time Frame: Up to the start date of the worsening of patient symptoms, up to Year 7 ]; Oral plasma clearance of ibrutinib [ Time Frame: Predose Day 1 of Cycles 1, 2, and 3, and postdose 1 h, 2 h, and 4 h of Cycles 1 and 2 ]; Oral volume of distribution at steady state of ibrutinib [ Time Frame: Predose Day 1 of Cycles 1, 2, and 3, and postdose 1 h, 2 h, and 4 h of Cycles 1 and 2 ]; Area under the plasma concentration-time curve of ibrutinib [ Time Frame: Predose Day 1 of Cycles 1, 2, and 3, and postdose 1 h, 2 h, and 4 h of Cycles 1 and 2 ]; Minimum observed plasma concentration of ibrutinib [ Time Frame: Predose Day 1 of Cycles 1, 2, and 3, and postdose 1 h, 2 h, and 4 h of Cycles 1 and 2 ]; Number of participants affected by an adverse event [ Time Frame: Up to 30 days after the last dose of study medication ]
Original Secondary Outcome Measures ICMJE; (submitted: May 14, 2013)	Progression-free survival [ Time Frame: Up to disease progression, relapse from complete response, or death, whichever occurs first, up to Year 7 ]; Overall survival [ Time Frame: Up to the date of the participants death, up to Year 7 ]; Complete response rate [ Time Frame: Up to completion of chemotherapy treatment, up to Year 7 ]; Time to worsening symptoms in the Lym subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) [ Time Frame: Up to the start date of the worsening of patient symptoms, up to Year 7 ]; Oral plasma clearance of ibrutinib [ Time Frame: Predose Day 1 of Cycles 1, 2, and 3, and postdose 1 h, 2 h, and 4 h of Cycles 1 and 2 ]; Oral volume of distribution at steady state of ibrutinib [ Time Frame: Predose Day 1 of Cycles 1, 2, and 3, and postdose 1 h, 2 h, and 4 h of Cycles 1 and 2 ]; Area under the plasma concentration-time curve of ibrutinib [ Time Frame: Predose Day 1 of Cycles 1, 2, and 3, and postdose 1 h, 2 h, and 4 h of Cycles 1 and 2 ]; Minimum observed plasma concentration of ibrutinib [ Time Frame: Predose Day 1 of Cycles 1, 2, and 3, and postdose 1 h, 2 h, and 4 h of Cycles 1 and 2 ]; Number of participants affected by an adverse event [ Time Frame: Up to 30 days after the last dose of study medication ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	A Study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma
Official Title ICMJE	A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Subjects With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma
Brief Summary	The purpose of this study is to evaluate if ibrutinib administered in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) improves the clinical outcome in newly diagnosed patients with non-germinal center B-cell subtype (GCB) of diffuse large B-cell lymphoma (DLBCL) selected by immunohistochemistry (IHC) or newly diagnosed patients with activated B cell-like (ABC) subtype of DLBCL identified by gene expression profiling (GEP) or both populations.
Detailed Description	This is a randomized (individuals assigned to study treatment by chance), double-blind (individuals and study personnel will not know the identity of study treatments), placebo (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial)-controlled study to compare the efficacy and safety of ibrutinib in combination with R-CHOP versus R-CHOP alone in adult patients newly diagnosed non-GCB DLBCL selected by IHC or newly diagnosed patients with ABC subtype of DLBCL identified by GEP or both populations. The study will include screening, active treatment, and posttreatment follow-up phases. The study will end when 50% of participants have died or 5 years after the last participant is randomized or the sponsor terminates the study, whichever occurs first. Approximately 800 participants will be randomly assigned in a 1:1 ratio to receive either placebo+R-CHOP (treatment arm A) or ibrutinib+R-CHOP (treatment arm B). All participants will receive R-CHOP as background therapy for 6 or 8 cycles (21 days per cycle) prespecified according to local practice. After 4 treatment cycles, an interim response assessment will be performed to evaluate disease progression for each participant. Participants with progressive disease or relapsed disease after complete response will be discontinued from treatment. Participants who discontinue R-CHOP without disease progression will continue study drug (placebo or ibrutinib) until 6 or 8 cycles are completed, disease progression, or unacceptable toxicity, whichever occurs first. After completion of study drug, participants will undergo assessment of tumor response based on the Revised Response Criteria for Malignant Lymphoma. Participants with documented residual disease upon completion of at least 6 cycles of R-CHOP therapy are considered eligible to initiate subsequent antilymphoma therapy. Serial pharmacokinetic samples will be collected before and after dosing, and safety will be monitored throughout the study.
Study Type ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition ICMJE	Lymphoma
Intervention ICMJE	Drug: Ibrutinib 560 mg capsules administered by mouth once daily (21-day cycles); Drug: Placebo 4 matched capsules administered by mouth once daily (21-day cycles); Drug: Rituximab 375 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles); Drug: Cyclophosphamide 750 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles); Drug: Doxorubicin 50 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles); Drug: Vincristine 1.4 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles); Drug: Prednisone (or equivalent) 100 mg capsules administered by mouth once daily on Day 1 to Day 5 of each cycle
Study Arms	Placebo Comparator: Treatment Arm A: placebo + R-CHOP Treatment Arm A = placebo + R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) Interventions: Drug: Placebo Drug: Rituximab Drug: Cyclophosphamide Drug: Doxorubicin Drug: Vincristine Drug: Prednisone (or equivalent); Experimental: Treatment Arm B: ibrutinib + R-CHOP Treatment Arm B = ibrutinib + R-CHOP Interventions: Drug: Ibrutinib Drug: Rituximab Drug: Cyclophosphamide Drug: Doxorubicin Drug: Vincristine Drug: Prednisone (or equivalent)
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Active, not recruiting
Actual Enrollment ICMJE; (submitted: December 14, 2017)	838
Original Estimated Enrollment ICMJE; (submitted: May 14, 2013)	800
Estimated Study Completion Date	June 16, 2020
Actual Primary Completion Date	February 26, 2018 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: No prior treatment for diffuse B-cell lymphoma (DLBCL); Histologically-confirmed non-germinal center B-cell subtype DLBCL; Stage II (not candidates for local x-ray therapy), III, or IV disease by the Ann Arbor Classification; At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma; Revised International Prognostic Index score of >=1; Eastern Cooperative Oncology Group performance status grade of 0, 1, or 2; Hematology and biochemical laboratory values within protocol-defined parameters prior to random assignment and at baseline; Left ventricular ejection fraction within institutional normal limits, as determined by echocardiography or multiple uptake gated acquisition (MUGA) scan; Agrees to protocol-defined use of effective contraception (for women, these restrictions apply for 12 months after the last dose of rituximab or 1 month after the last dose of study drug, whichever is later; for men, these restrictions apply for 12 months after the last dose of rituximab or 3 months after the last dose of study drug, whichever is later); Men must agree to not donate sperm during and after the study for 12 months after the last dose of rituximab or 3 months after the last dose of study drug, whichever is later; Women of childbearing potential must have a negative serum or urine pregnancy test at screening Exclusion Criteria: Major surgery within 4 weeks of random assignment; Known central nervous system or primary mediastinal lymphoma; Prior history of indolent lymphoma; Diagnosed or treated for malignancy other than DLBCL, except: malignancy treated with curative intent and with no known active disease present for >=3 years before random assignment; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated carcinoma in situ without evidence of disease; History of stroke or intracranial hemorrhage within 6 months prior to random assignment; Requires anticoagulation with warfarin or equivalent vitamin K antagonists; Requires treatment with strong CYP3A inhibitors; Prior anthracycline use >=150 mg/m2; 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 or active hepatitis C virus or active hepatitis B virus infection 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 ibrutinib capsules, or put the study outcomes at undue risk
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Argentina, Australia, Belgium, Brazil, Canada, China, Czechia, Denmark, Finland, France, Germany, Hungary, Israel, Japan, Korea, Republic of, Mexico, Netherlands, Norway, Poland, Russian Federation, Spain, Sweden, Taiwan, Turkey, Ukraine, United Kingdom, United States
Removed Location Countries	Czech Republic, New Zealand, Portugal
Administrative Information
NCT Number ICMJE	NCT01855750
Other Study ID Numbers ICMJE	CR102118; PCI-32765DBL3001 ( Other Identifier: Janssen Research & Development, LLC ); U1111-1139-6222 ( Other Identifier: Universal Trial Number ); 2013-000959-40 ( EudraCT Number )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement	Not Provided
Responsible Party	Janssen Research & Development, LLC
Study Sponsor ICMJE	Janssen Research & Development, LLC
Collaborators ICMJE	Pharmacyclics LLC.
Investigators ICMJE	Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
PRS Account	Janssen Research & Development, LLC
Verification Date	May 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP