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

• ClinicalTrials.gov Identifier: NCT01855750
• Recruitment Status: Completed
• First Posted: May 16, 2013
• Results First Posted: March 19, 2019
• Last Update Posted: April 13, 2020
• Sponsor: Janssen Research & Development, LLC
• Collaborator: Pharmacyclics LLC.
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Tracking Information

• First Submitted Date: May 14, 2013
• First Posted Date: May 16, 2013
• Results First Submitted Date: February 22, 2019
• Results First Posted Date: March 19, 2019
• Last Update Posted Date: April 13, 2020
• Actual Study Start Date: September 3, 2013
• Actual Primary Completion Date: February 26, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 30, 2020)

• Event-Free Survival (EFS) - Intent-to-Treat (ITT) Population [ Time Frame: Up to 5.5 years ]
  EFS: duration from randomization date to disease progression(PD) date, relapse from complete response(CR) assessed by investigator, initiation of subsequent systemic antilymphoma therapy for either positron emission tomography(PET)-positive/ biopsy-proven residual disease upon completion of >=6 cycles of R-CHOP therapy/death, whichever occurred first. Responses were based on Revised Response Criteria for Malignant Lymphoma. PD: any new lesion or increase by 50% of previously involved sites from nadir; PD criteria: Appearance of new nodal lesion 1.5 cm in any axis, 50% increase in sum of product of diameters(SPD) of >1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. CR: disappearance of all evidence of disease; CR criteria: nodal masses PET positive prior to therapy; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.
• Event-Free Survival (EFS) - Activated B-Cell (ABC) Population [ Time Frame: Up to approximately 4.5 years ]
  EFS: duration from randomization date to PD date, relapse from CR assessed by investigator, initiation of subsequent systemic antilymphoma therapy for either PET-positive/ biopsy-proven residual disease upon completion of >=6 cycles of R-CHOP therapy/death, whichever occurred first. Responses were based on Revised Response Criteria for Malignant Lymphoma. PD: any new lesion or increase by 50% of previously involved sites from nadir; PD criteria: Appearance of new nodal lesion 1.5 cm in any axis, 50% increase in SPD of >1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. CR: disappearance of all evidence of disease; CR criteria: nodal masses PET positive prior to therapy; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.

• Original Primary Outcome Measures (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 ]

Current Secondary Outcome Measures (submitted: March 30, 2020)

• Progression-Free Survival (PFS) [ Time Frame: Up to approximately 4.5 years ]
  PFS was defined as the duration from the date of randomization to the date of progression, relapse from CR, or death, whichever occurred first. Responses were based on Revised Response Criteria for Malignant Lymphoma. Progressive Disease (PD): any new lesion or increase by 50% of previously involved sites from nadir; PD criteria: Appearance of new nodal lesion 1.5 centimeter (cm) in any axis, 50% increase in SPD of >1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. CR: disappearance of all evidence of disease; CR criteria: nodal masses PET positive prior to therapy; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.
• Percentage of Participants Who Achieved Complete Response (CR) [ Time Frame: Up to approximately 4.5 years ]
  Percentage of participants with measurable disease who achieved CR were reported. CR: disappearance of all evidence of disease. CR Criteria: Complete disappearance of all disease-related symptoms; all lymph nodes and nodal masses regressed to normal size (less than or equal to [<=]1.5 cm in greatest transverse diameter [GTD] for nodes greater than [>]1.5 cm before therapy). Previous nodes of 1.1 to 1.5 cm in long axis and greater than (>)1.0 cm in short axis before treatment decreased to <=1.0 cm in short axis after treatment. Disappearance of all splenic and hepatic nodules and other extranodal disease; a negative positron emission tomography (PET) scan. A posttreatment residual mass of any size but PET-negative; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.
• Overall Survival [ Time Frame: Up to 5.5 years ]
  Overall survival was defined as the duration from the date of randomization to the date of the participant's death. Median Overall Survival was estimated by using the Kaplan-Meier method.
• Time to Worsening in the Lymphoma Subscale of Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) [ Time Frame: Up to approximately 4.5 years ]
  Time to worsening in the Lymphoma subscale of the FACT-Lym, defined as the interval from the date of randomization to the start date of worsening of participant symptoms. Worsening was defined by a 5-point decrease from baseline. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (higher the worse). Lymphoma subscale score is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life.

Original Secondary Outcome Measures (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 Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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: 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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Lymphoma

Intervention

• 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 *: Younes A, Sehn LH, Johnson P, Zinzani PL, Hong X, Zhu J, Patti C, Belada D, Samoilova O, Suh C, Leppä S, Rai S, Turgut M, Jurczak W, Cheung MC, Gurion R, Yeh SP, Lopez-Hernandez A, Dührsen U, Thieblemont C, Chiattone CS, Balasubramanian S, Carey J, Liu G, Shreeve SM, Sun S, Zhuang SH, Vermeulen J, Staudt LM, Wilson W; PHOENIX investigators. Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2019 May 20;37(15):1285-1295. doi: 10.1200/JCO.18.02403. Epub 2019 Mar 22.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 20, 2018): 838
• Original Estimated Enrollment (submitted: May 14, 2013): 800
• Actual Study Completion Date: April 5, 2019
• Actual Primary Completion Date: February 26, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: 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, Italy, New Zealand, Portugal

Administrative Information

• NCT Number: NCT01855750
• Other Study ID Numbers: 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: Janssen Research & Development, LLC
• Collaborators: Pharmacyclics LLC.

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

• PRS Account: Janssen Research & Development, LLC
• Verification Date: March 2020