Phase I/Ib study of the efficacy and safety of buparlisib and ibrutinib therapy in MCL, FL, and DLBCL with serial cell-free DNA monitoring Journal Article
| Authors: | Stewart, C. M.; Michaud, L.; Whiting, K.; Nakajima, R.; Nichols, C.; De Frank, S.; Hamlin, P. A. Jr; Matasar, M. J.; Gerecitano, J. F.; Drullinsky, P.; Hamilton, A.; Straus, D.; Horwitz, S. M.; Kumar, A.; Moskowitz, C. H.; Moskowitz, A.; Zelenetz, A. D.; Rademaker, J.; Salles, G.; Seshan, V.; Schöder, H.; Younes, A.; Tsui, D. W. Y.; Batlevi, C. L. |
| Article Title: | Phase I/Ib study of the efficacy and safety of buparlisib and ibrutinib therapy in MCL, FL, and DLBCL with serial cell-free DNA monitoring |
| Abstract: | Purpose: Activation of Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K) represent parallel, synergistic pathways in lymphoma pathogenesis. As predominant PI3Kd inhibition is a possible mechanism of tumor escape, we proposed a clinical trial of dual BTK and pan-PI3K inhibition. Patients and Methods: We conducted a single-center phase I/Ib trial combining a BTK inhibitor (ibrutinib) and a pan-PI3K inhibitor (buparlisib) in 37 patients with relapsed/refractory (R/R) B-cell lymphoma. Buparlisib and ibrutinib were administered orally, once daily in 28-day cycles until progression or unacceptable toxicity. The clinical trial is registered with clinicaltrials.gov, NCT02756247. Results: Patients with mantle cell lymphoma (MCL) receiving the combination had a 94% overall response rate (ORR) and 33-month median progression-free survival; ORR of 31% and 20% were observed in patients with diffuse large B-cell lymphoma and follicular lymphoma, respectively. The maximum tolerated dose was ibrutinib 560 mg plus buparlisib 100 mg and the recommended phase II dose was ibrutinib 560 mg plus buparlisib 80 mg. The most common grade 3 adverse events were rash/pruritis/dermatitis (19%), diarrhea (11%), hyperglycemia (11%), and hypertension (11%). All grade mood disturbances ranging from anxiety, depression, to agitation were observed in 22% of patients. Results from serial monitoring of cell-free DNA samples corresponded to radiographic resolution of disease and tracked the emergence of mutations known to promote BTK inhibitor resistance. Conclusions: BTK and pan-PI3K inhibition in mantle cell lymphoma demonstrates a promising efficacy signal. Addition of BCL2 inhibitors to a BTK and pan-PI3K combination remain suitable for further development in mantle cell lymphoma. © 2021 American Association for Cancer Research. |
| Keywords: | adult; cancer survival; clinical article; event free survival; aged; unclassified drug; gene mutation; overall survival; fatigue; cancer growth; diarrhea; drug dose reduction; drug efficacy; drug safety; drug withdrawal; hypertension; treatment duration; follow up; monitoring; disease association; edema; progression free survival; mantle cell lymphoma; multiple cycle treatment; thrombocytopenia; myalgia; cohort analysis; gene frequency; drug dose escalation; hyperglycemia; pruritus; rash; aspartate aminotransferase; bilirubin; depression; dna; comorbidity; anxiety disorder; cognitive defect; dermatitis; maximum tolerated dose; phase 1 clinical trial; memory disorder; follicular lymphoma; mood disorder; muscle cramp; agitation; overall response rate; diffuse large b cell lymphoma; ibrutinib; buparlisib; dna sequencing; human; male; female; article; circulating tumor dna; variant allele frequency; cell free dna |
| Journal Title: | Clinical Cancer Research |
| Volume: | 28 |
| Issue: | 1 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2022-01-01 |
| Start Page: | 45 |
| End Page: | 56 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-21-2183 |
| PUBMED: | 34615723 |
| PROVIDER: | scopus |
| PMCID: | PMC8812724 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2022 -- Source: Scopus |
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