Acalabrutinib in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) As First Line Therapy for Patients with Diffuse Large B-Cell Lymphoma (DLBCL): The Accept Phase Ib/II Single Arm Study
Authors: Davies Andrew , Caddy Josh , Mercer Katy , Saunders Geoff N , Stanton Louise , Collins Graham P. , Cummin Thomas E C , Schuh Anna , Ardeshna Kirit M. , McMillan Andrew , Radford John A. , Lewis David John , Coleman Adam , Griffiths Gareth , Burton Cathy , Barrans Sharon , Johnson Peter 
Published: November 2020

Introduction: R-CHOP remains the standard of care for DLBCL yet many patients (pts.) either fail to respond or relapse after having achieved an initial remission. Dysregulation of B Cell receptor (BCR) signalling is well recognised in some sub-types of DLBCL. In the phase III PHOENIX study (NCT01855750), the addition of the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib (I) to R-CHOP (R-CHOP-I) did not improve the outcome of the study population with non-germinal centre like DLBCL. However, R-CHOP-I treated pts. who were aged less than 60 years had a significantly improved progression free survival (PFS) and overall survival (OS) compared to those receiving R-CHOP alone. In pts. aged over 60 years, the addition of I increased toxicity and compromised the delivery of R-CHOP. Acalabrutinib (A) is a second generation BTKi, with enhanced kinase selectivity and potential for better efficacy and tolerability over first-generation inhibitors. There is a strong rationale to combine A with R-CHOP in untreated de novo DLBCL to understand its safety profile and efficacy.
Methods: Eligible pts. were treatment naive with histologically confirmed DLBCL. All pts. received 6 cycles of R-CHOP therapy on a standard 21-day schedule, with the addition of A in cycles 2-6. A continuation phase of A only, for 2 cycles of 28 days was administered after R-CHOP. The primary objective of the phase Ib was to establish a recommended phase II dose (RP2D) of A in combination with R-CHOP (modified classical 6+6 design). Phase II assessed the overall response rate (ORR) of the combination and ascertained additional safety information. Secondary endpoints included metabolic complete response rates (mCR), PFS and OS and their relation to the COO, pharmacokinetics and pharmacodynamics. Cell of origin (COO) was determined by HTG EdgeSeq. Recruitment of pts. over the age of 65 was suspended as an urgent safety measure (USM) following the abstract release of data from PHOENIX (Nov 2018). ACCEPT reopened to all ages after a comprehensive safety review by the Independent Data Monitoring Committee (Sep 2019). The trial was endorsed by CRUK (CRUKDE/16/006).
Results: From May 2017 to Jan 2020, 38 pts. were enrolled (safety population: Pts. in receipt of any component of therapy). The median age was 64 years (range 24-80, 39% &gt;65 years old); 74% stage III/IV; 66%; raised LDH; 29% B symptoms; 32% bulk; 26% high IPI; 29% high-intermediate IPI; 16% High NCCN-IPI. Seven of the enrolled pts. were found to be ineligible (insufficient material for translational work, 2pts.; taking a proton pump inhibitor during therapy, 2 pts.; follicular histology, 1pt.; abnormal LFTs at baseline, 1pt.; age &gt;65 at time of USM, 1 pts). There were no dose-limiting toxicities and the maximum tolerated dose was not reached. The RP2D was chosen as 100mg bd acalabrutinib. The most common &gt;grade3 adverse events were neutropenia (26% of pts.), febrile neutropenia (13%) and diarrhoea (11%). The most frequently reported serious adverse event was febrile neutropenia (13% of pts.). Age did not compromise the delivery of full dose R-CHOP in combination with A. One patient in the first cohort (A 100mg od) progressed on therapy. Of the 24 eligible patients who received the RP2D (A 100mg bd) in either dose escalation or expansion, 22 responses have been reported (1 awaiting response assessment and 1 not assessed). Four pts. withdrew early from treatment (2 pts. subject withdrawal, 1 pt. investigator withdrawal and 1pt. due to toxicity) and are included in the efficacy analysis. The ORR was 95% with 82% of pts. achieving a mCR (3 pts. partial response (PR), 1pts. stable disease). One pt. with MYC/BCL2/BCL6 rearrangements and one pt. with MYC/BCL2 rearrangement achieved a mCR; neither have progressed. Ten of twelve ABC pts. (83%), 7/8 GCB pts (88%) and 1/2 unclassified pts. (50%) achieved a mCR. With a median follow-up of 15 months, the primary progressive patient from cohort 1 has died. PFS and OS at 12 months for those eligible pts. in receipt of the RP2D is 100%. Two of the RP2D pts. not achieving mCR have however received additional therapy (1 radiotherapy, 1 chemotherapy) prior to progression. R-CHOP did not affect the pharmacokinetics of A. Additional translational data will be presented.
Conclusions: Acalabrutinib is well tolerated when given in combination with R-CHOP chemotherapy and may be associated with improved efficacy that should be explored in future randomised trials.

Disclosures
Davies: Roche: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Acerta Pharma: Consultancy, Research Funding; Karyopharma: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; AstraZeneca: Research Funding; Gilead: Research Funding; ADC Therapeutics: Research Funding; Pfizer: Honoraria, Research Funding. Collins:Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; BeiGene: Consultancy; Amgen: Research Funding; MSD: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Celleron: Consultancy, Honoraria, Research Funding. Schuh:Illumina: Other: Consulting fees; Roche: Other: Consulting fees; Gilead: Other: Consulting fees; Abbvie: Other: Consulting fees. Ardeshna:University College London (UCL)/UCL Hospitals (UCLH) Biomedical Research Unit: Other: Supported by this organisation; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi, Genzyme, AstraZeneca: Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees. McMillan:F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel expenses, Speakers Bureau; Pfizer: Research Funding; Celgene: Honoraria, Other: Travel expenses, Speakers Bureau. Radford:Pfizer: Research Funding; ADCT: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Current equity holder in publicly-traded company, Other: Spouse; GlaxoSmithKline: Current equity holder in publicly-traded company, Other: Spouse; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Speakers Bureau. Burton:Leeds Teaching Hospitals NHS Trust: Current Employment; Takeda: Honoraria, Other: Travel Support; BMS: Honoraria; Celgene: Honoraria; Roche: Honoraria, Other: Travel Support. Johnson:Janssen: Consultancy; Oncimmune: Consultancy; Janssen: Consultancy; Takeda: Honoraria; Novartis: Honoraria; MorphoSys: Honoraria; Kymera: Honoraria; Kite Pharma: Honoraria; Incyte: Honoraria; Genmab: Honoraria; Celgene: Honoraria; Bristol-Myers: Honoraria; Epizyme: Consultancy, Research Funding; Epizyme: Consultancy, Research Funding; Oncimmune: Consultancy; Boehringer Ingelheim: Consultancy.

OffLabel Disclosure:
Acalabrutinib, a second generation Bruton's tyrosine kinase inhibitor is being used in combination with R-CHOP chemotherapy