buparlisib and Lymphoma--Mantle-Cell

Activation of Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K) represent parallel, synergistic pathways in lymphoma pathogenesis. As predominant PI3Kδ inhibition is a possible mechanism of tumor escape, we proposed a clinical trial of dual BTK and pan-PI3K inhibition.. 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.. 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.. 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.

Topics: Adenine; Adult; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Cell-Free Nucleic Acids; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Morpholines; Phosphatidylinositol 3-Kinases; Piperidines; Pyrazoles; Pyrimidines

Activation of the phosphatidylinositol 3-kinase/mechanistic target of rapamycin pathway plays a role in the pathogenesis of non-Hodgkin lymphoma. This multicenter, open-label phase 2 study evaluated buparlisib (BKM120), a pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or refractory non-Hodgkin lymphoma. Three separate cohorts of patients (with diffuse large B-cell lymphoma, mantle cell lymphoma, or follicular lymphoma) received buparlisib 100 mg once daily until progression, intolerance, or withdrawal of consent. The primary endpoint was overall response rate based on a 6-month best overall response by cohort; secondary endpoints included progression-free survival, duration of response, overall survival, safety, and tolerability. Overall, 72 patients (26 with diffuse large B-cell lymphoma, 22 with mantle cell lymphoma, and 24 with follicular lymphoma) were treated. The overall response rates were 11.5%, 22.7%, and 25.0% in patients with diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma, respectively; two patients (one each with diffuse large B-cell lymphoma and mantle cell lymphoma) achieved a complete response. The most frequently reported (>20%) adverse events of any grade in the population in which safety was studied were hyperglycemia, fatigue, and nausea (36.1% each), depression (29.2%), diarrhea (27.8%), and anxiety (25.0%). The most common grade 3/4 adverse events included hyperglycemia (11.1%) and neutropenia (5.6%). Buparlisib showed activity in relapsed or refractory non-Hodgkin lymphoma, with disease stabilization and sustained tumor burden reduction in some patients, and acceptable toxicity. Development of mechanism-based combination regimens with buparlisib is warranted. (This study was funded by Novartis Pharmaceuticals Corporation and registered with

Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Female; Humans; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Morpholines; Phosphoinositide-3 Kinase Inhibitors; Recurrence; Remission Induction; Salvage Therapy

Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. Antitumor activity has been observed with mTOR inhibitors. However, they have shown limited clinical efficacy in relation to drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we have performed a comparative analysis of the mTOR inhibitor everolimus, the pan-PI3K inhibitor NVP-BKM120 and the dual PI3K/mTOR inhibitor NVP-BEZ235 in primary MCL cells. We found NVP-BEZ235 to be more powerful than everolimus or NVP-BKM120 in PI3K/Akt/mTOR signaling inhibition, indicating that targeting the PI3K/Akt/mTOR pathway at multiple levels is likely to be a more effective strategy for the treatment of MCL than single inhibition of these kinases. Among the three drugs, NVP-BEZ235 induced the highest change in gene expression profile. Functional validation demonstrated that NVP-BEZ235 inhibited angiogenesis, migration and tumor invasiveness in MCL cells. NVP-BEZ235 was the only drug able to block IL4 and IL6/STAT3 signaling which compromise the therapeutic effect of chemotherapy in MCL. Our findings support the use of the dual PI3K/mTOR inhibitor NVP-BEZ235 as a promising approach to interfere with the microenvironment-related processes in MCL.

Topics: Aminopyridines; Cell Line, Tumor; Cell Proliferation; Chemokine CXCL12; Everolimus; Human Umbilical Vein Endothelial Cells; Humans; Imidazoles; Interleukin-4; Interleukin-6; Lymphoma, Mantle-Cell; Morpholines; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Quinolines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transcriptome; Tumor Microenvironment