title: Phase 1 trial of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma: Alliance A051103.
abstract: Chemoimmunotherapy in follicular lymphoma is associated with significant toxicity. Targeted therapies are being investigated as potentially more efficacious and tolerable alternatives for this multiply-relapsing disease. Based on promising activity with rituximab and lenalidomide in previously untreated follicular lymphoma (overall response rate [ORR] 90%-96%) and ibrutinib in relapsed disease (ORR 30%-55%), the Alliance for Clinical Trials in Oncology conducted a phase 1 trial of rituximab, lenalidomide, and ibrutinib. Previously untreated patients with follicular lymphoma received rituximab 375 mg/m2on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 4, 6, 8, and 10; lenalidomide as per cohort dose on days 1 to 21 of 28 for 18 cycles; and ibrutinib as per cohort dose daily until progression. Dose escalation used a 3+3 design from a starting dose level (DL) of lenalidomide 15 mg and ibrutinib 420 mg (DL0) to DL2 (lenalidomide 20 mg, ibrutinib 560 mg). Twenty-two patients were enrolled; DL2 was determined to be the recommended phase II dose. Although no protocol-defined dose-limiting toxicities were reported, a high incidence of rash was observed (all grades 82%, grade 3 36%). Eleven patients (50%) required dose reduction, 7 because of rash. The ORR for the entire cohort was 95%, and the 12-month progression-free survival was 80% (95% confidence interval, 57%-92%). Five patients developed new malignancies; 3 had known risk factors before enrollment. Given the increased toxicity and required dose modifications, as well as the apparent lack of additional clinical benefit to the rituximab-lenalidomide doublet, further investigation of the regimen in this setting seems unwarranted. The study was registered with www.ClinicalTrials.gov as #NCT01829568.
authors.affiliation: Lombardi Comprehensive Cancer Center, Medstar Georgetown University Hospital, Washington, DC.
authors.forename: Chaitra S
authors.initials: CS
authors.lastname: Ujjani
authors.affiliation: Alliance Statistics and Data Center, Duke University, Durham, NC.
authors.forename: Sin-Ho
authors.initials: SH
authors.lastname: Jung
authors.affiliation: Alliance Statistics and Data Center, Duke University, Durham, NC.
authors.forename: Brandelyn
authors.initials: B
authors.lastname: Pitcher
authors.affiliation: Meyer Cancer Center, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, NY.
authors.forename: Peter
authors.initials: P
authors.lastname: Martin
authors.affiliation: UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Steven I
authors.initials: SI
authors.lastname: Park
authors.affiliation: Division of Hematology, The Ohio State University, Columbus, OH.
authors.forename: Kristie A
authors.initials: KA
authors.lastname: Blum
authors.affiliation: University of Chicago Medicine Comprehensive Cancer Center, University of Chicago, Chicago, IL.
authors.forename: Sonali M
authors.initials: SM
authors.lastname: Smith
authors.affiliation: Roswell Park Cancer Institute, State University of New York at Buffalo, Buffalo, NY.
authors.forename: Myron
authors.initials: M
authors.lastname: Czuczman
authors.affiliation: Dana-Farber/Partners CancerCare, Boston, MA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Davids
authors.affiliation: Roswell Park Cancer Institute, State University of New York at Buffalo, Buffalo, NY.
authors.forename: Ellis
authors.initials: E
authors.lastname: Levine
authors.affiliation: Norris Cotton Cancer Center, The Geisel School of Medicine at Dartmouth, Lebanon, NH.
authors.forename: Lionel D
authors.initials: LD
authors.lastname: Lewis
authors.affiliation: Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL; and.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Smith
authors.affiliation: Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Bartlett
authors.affiliation: Meyer Cancer Center, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, NY.
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.affiliation: Lombardi Comprehensive Cancer Center, Medstar Georgetown University Hospital, Washington, DC.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Cheson
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects; D000069283:Rituximab / Q000008:administration & dosage / Q000009:adverse effects; D015996:Survival Rate; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000069283:Rituximab; D013792:Thalidomide; D000077269:Lenalidomide; D000225:Adenine