title: Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study.
abstract: BACKGROUND
  Present first-line therapy for diffuse large B-cell lymphoma, a subtype of non-Hodgkin lymphoma, is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Ibrutinib, a novel oral Bruton's tyrosine kinase inhibitor, has shown single-drug activity in relapsed or refractory B-cell malignancies. We investigated the safety and efficacy of ibrutinib in combination with R-CHOP for patients with previously untreated CD20-positive B-cell non-Hodgkin lymphoma.
  
  
  METHODS
  In this phase 1b, open-label, non-randomised study, patients were recruited across six centres in the USA and France. Eligibility was age 18 years or older and treatment-naive histopathologically confirmed CD20-positive B-cell non-Hodgkin lymphoma. In the dose-escalation phase (part 1), patients with diffuse large B-cell lymphoma, mantle-cell lymphoma, or follicular lymphoma were enrolled. The primary objective was to determine a recommended phase 2 dose of ibrutinib with a standard R-CHOP regimen, by assessing safety in all patients who received treatment. Patients received ibrutinib 280 mg, 420 mg, or 560 mg per day in combination with a standard R-CHOP regimen every 21 days. Safety of the recommended phase 2 dose was then assessed in a dose-expansion population, which consisted of patients with newly diagnosed diffuse large B-cell lymphoma (part 2). Secondary objectives included assessments of the proportion of patients who had an overall response, pharmacokinetics, and pharmacodynamics. This trial is registered with ClinicalTrials.gov, number NCT01569750.
  
  
  RESULTS
  From June 22, 2012, to March 25, 2013, 33 patients were enrolled (part 1: 17; part 2: 16) and 32 received ibrutinib plus R-CHOP treatment (one patient in the part 2 cohort withdrew). The maximum tolerated dose was not reached and the recommended phase 2 dose for ibrutinib was 560 mg per day. The most common grade 3 or greater adverse events included neutropenia (73% [24 of 33 patients]), thrombocytopenia (21% [seven patients]), and febrile neutropenia and anaemia (18% each [six patients]). The most frequently reported serious adverse events were febrile neutropenia (18% [six patients]) and hypotension (6% [two patients]). 30 (94%) of 32 patients who received one or more doses of combination treatment achieved an overall response. All 18 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose had an overall response. For those subtyped and treated at the recommended phase 2 dose, five (71%) of seven patients with the germinal centre B-cell-like subtype and two (100%) patients with the non-germinal centre B-cell-like subtype had a complete response. R-CHOP did not affect pharmacokinetics of ibrutinib, and ibrutinib did not alter the pharmacokinetics of vincristine. Pharmacodynamic data showed Bruton's tyrosine kinase was fully occupied (>90% occupancy) at the recommended phase 2 dose.
  
  
  CONCLUSIONS
  Ibrutinib is well tolerated when added to R-CHOP, and could improve responses in patients with B-cell non-Hodgkin lymphoma, but our findings need confirmation in a phase 3 trial.
  
  
  BACKGROUND
  Janssen.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Electronic address: younesa@mskcc.org.
authors.forename: Anas
authors.initials: A
authors.lastname: Younes
authors.affiliation: Hemato-oncology Department, Hôpital Saint-Louis, AP-HP, P7 University, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Thieblemont
authors.affiliation: Hematology, Centre Hospitalier Universitaire de Lille, Lille, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Morschhauser
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Flinn
authors.affiliation: Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Friedberg
authors.affiliation: Hemato-oncology Department, Hôpital Saint-Louis, AP-HP, P7 University, Paris, France.
authors.forename: Sandy
authors.initials: S
authors.lastname: Amorim
authors.affiliation: Hematology, Centre Hospitalier Universitaire de Lille, Lille, France.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Hivert
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Westin
authors.affiliation: Janssen Research and Development, Leiden, Belgium.
authors.forename: Jessica
authors.initials: J
authors.lastname: Vermeulen
authors.affiliation: Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Nibedita
authors.initials: N
authors.lastname: Bandyopadhyay
authors.affiliation: Janssen Research and Development, Beerse, Belgium.
authors.forename: Ronald
authors.initials: R
authors.lastname: de Vries
authors.affiliation: Janssen Research and Development, Springhouse, PA, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Janssen Research and Development, Beerse, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Hellemans
authors.affiliation: Janssen Research and Development, Beerse, Belgium.
authors.forename: Johan W
authors.initials: JW
authors.lastname: Smit
authors.affiliation: Janssen Research and Development, Beerse, Belgium.
authors.forename: Nele
authors.initials: N
authors.lastname: Fourneau
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Oki
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000009:adverse effects / Q000627:therapeutic use; D018951:Antigens, CD20 / Q000187:drug effects / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000009:adverse effects / Q000627:therapeutic use; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality*; D008228:Lymphoma, Non-Hodgkin / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D065228:Non-Randomized Controlled Trials as Topic; D010880:Piperidines; D011241:Prednisone / Q000009:adverse effects / Q000627:therapeutic use; D011379:Prognosis; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D000069283:Rituximab; D012720:Severity of Illness Index; D015996:Survival Rate; D016896:Treatment Outcome; D014750:Vincristine / Q000009:adverse effects / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C571759:R-CHOP protocol; C551803:ibrutinib; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D000225:Adenine; D011241:Prednisone