A phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies

Abstract

In a phase 1b study of acalabrutinib (a covalent Bruton tyrosine kinase (BTK) inhibitor) in combination with vistusertib (a dual mTORC1/2 inhibitor) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), multiple ascending doses of the combination as intermittent or continuous schedules of vistusertib were evaluated. The overall response rate was 12% (3/25). The pharmacodynamic (PD) profile for acalabrutinib showed that BTK occupancy in all patients was >95%. In contrast, PD analysis for vistusertib showed variable inhibition of phosphorylated 4EBP1 (p4EBP1) without modulation of AKT phosphorylation (pAKT). The pharmacokinetic (PK)/PD relationship of vistusertib was direct for TORC1 inhibition (p4EBP1) but did not correlate with TORC2 inhibition (pAKT). Cell-of-origin subtyping or next-generation sequencing did not identify a subset of DLBCL patients with clinical benefit; however, circulating tumor DNA dynamics correlated with radiographic response. These data suggest that vistusertib does not modulate targets sufficiently to add to the clinical activity of acalabrutinib monotherapy. Clinicaltrials.gov identifier: NCT03205046.

Keywords:

• Bruton tyrosine kinase
• mammalian target of rapamycin
• Richter transformation
• lymphoma
• genomic segmentation
• gene expression profiling

Acknowledgements

Dr. Collins acknowledges support from the Haematology and Stem Cell Theme of the NIHR Oxford Biomedical Research Centre and CRUK Experimental Cancer Medicines Centre. Editorial assistance was provided by Peloton Advantage, an OPEN Health company, Parsippany, NJ, and funded by Acerta Pharma, South San Francisco, CA, a member of the AstraZeneca Group.

Disclosure statement

Graham P. Collins: Consultant: Takeda, Roche, Pfizer, BeiGene, Incyte, Daiichi Sankyo, Gilead, Novartis, Janssen; Research Support: Bristol Myers Squibb, Merck Sharpe & Dohme, Pfizer, Amgen. Tracy N. Clevenger: Equity: AstraZeneca; Personal fees: Kartos Therapeutics. Buyue Yang: Nothing to disclose. Alex MacDonald: Employment, shareholder: AstraZeneca. David Cunningham: Research grants: 4SC, AstraZeneca, Bayer, Amgen, Celgene, Clovis, Eli Lilly, Janssen, MedImmune, Merck, Merrimack, Sanofi. Christopher P. Fox: Consultant: Acerta Pharma, AstraZeneca. Andre Goy: Steering committee, advisor, advisory board, study PI-research funding for institution: AstraZeneca; Consulting, study PI-research funding for institution: Acerta Pharma; Consulting: Xcenda, MJH Associates; Consulting and travel-related expenses: Physicians Education Resource, LLC; Advisory board, consulting, study PI-research funding for institution: Kite/Gilead; Advisory board: Janssen, PracticeUpdate Oncology; Consulting/moderator: OncLive Peer Review; Consulting, study PI-research funding for institution: Celgene; Shareholder, board member, paid for attending meetings: COTA; Study PI-research funding for institution: Bayer, Bristol Myers Squibb, Constellation, Genentech, Hackensack UMC, Hoffman-La Roche, Infinity, Janssen, Karyopharm, Morphosys, Pharmacyclics. John Gribben: Research grants: AstraZeneca, Janssen; Speakers bureau: Janssen; Advisory boards: AbbVie, AstraZeneca, Janssen. Grzegorz Nowakowski: Consultant: Celgene/BMS, Morphosys, DeNovo, Kymara, Kite, Roche/Genentech, Debiopharm, Curis. Mark Roschewski: Nothing to disclose. Julie M. Vose: Research grant, advisory board: AstraZeneca. Anusha Vallurupalli: Nothing to disclose. Kathleen A. Burke: Nothing to disclose. Jean Cheung: Personal fees: Acerta Pharma, AstraZeneca. Amelia Raymond: Nothing to disclose. Barrett Nuttall: Employment: AstraZeneca. Daniel Stetson: Nothing to disclose. Brian Dougherty: Employment: AstraZeneca. Stein Schalkwijk: Employment and shareholder: AstraZeneca. Larissa S. Carnevalli: Employment and shareholder: AstraZeneca. Brandon Willis: Employment: AstraZeneca. Lin Tao: Employment: AstraZeneca. Elizabeth Harrington: Employment, shareholder: AstraZeneca. Ahmed Hamdy: Employment: Acerta Pharma at the time of the study. Patents: pending. Shareholder: Acerta Pharma and AstraZeneca. Raquel Izumi: Employment: Acerta Pharma at the time of the study. Patents: acalabrutinib (issued). Shareholder: Acerta Pharma and AstraZeneca. J. Elizabeth Pease: Nothing to disclose. Melanie M. Frigault: Employment, shareholder, patent holder: AstraZeneca. Ian Flinn: Payment to institution for conduct of clinical trial on which Dr. Flinn served as PI: Acerta Pharma, Agios, ArQule, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Curis, F. Hoffman-la Roche Ltd, Forma Therapeutics, Forty Seven, Genentech, IGM Biosciences, Incyte, Infinity Pharmaceuticals, Karyopharm Therapeutics, Loxo, Merck, Novartis, Pfizer, Portola Pharmaceuticals, Teva, Trillium Therapeutics, Triphase Research & Development Corp., AbbVie, AstraZeneca, BeiGene, Gilead, Janssen, Juno Therapeutics, Kite Pharma, MorphoSys, Pharmacyclics, Roche, Seattle Genetics, Takeda, TG Therapeutics, Unum Therapeutics, Verastem; Consulting: AbbVie, AstraZeneca, BeiGene, Curio Science, Gilead Sciences, Great Point Partners, Iksuda Therapeutics, Janssen, Juno Therapeutics, Kite Pharma, MorphoSys, Nurix Therapeutics, Pharmacyclics, Roche, Seattle Genetics, Takeda, TG Therapeutics, Unum Therapeutics, Verastem, Yingli Pharmaceuticals.

Data availability statement

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.