PHASE I/IB DOSE ESCALATION AND EXPANSION OF IBRUTINIB AND BUPARLISIB IN RELAPSED/REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA, MANTLE CELL LYMPHOMA, AND FOLLICULAR LYMPHOMA

Abstract

Introduction: Based on preclinical studies that demonstrated synergism between BTK and PI3K inhibitors in B‐cell non‐Hodgkin lymphoma, we conducted a phase I/Ib investigator‐initiated study of ibrutinib (BTK inhibitor) and buparlisib (pan‐PI3K inhibitor) combination in patients (pts) with relapsed or refractory B cell lymphoma. Methods: Patients (pts) were eligible if they had relapsed/refractory diffuse large B‐cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL), ECOG = PR by CT. Results: To‐date, 25 pts enrolled (DLBCL 10, FL 5, MCL 10) with median prior systemic therapies being 4 for DLBCL (range 1‐7), 2 for FL (all had 2 prior regimens), and 1 for MCL (range 1‐2). 23 pts completed at least one cycle and were evaluable for toxicity. Pts received escalating doses of once daily ibrutinib and buparlisib in 3 dose levels (ibrutinib 420‐560 mg; buparlisib 80‐100 mg). Dose level 3 (Ibrutinib 560 mg, buparlisib 100 mg) was selected for dose expansion based on 1/6 pt with DLT. Nine patients enrolled on the dose expansion. Four of the first 7 patients enrolled on the dose expansion developed grade 2‐3 toxicities requiring dose reductions and/or interruptions, most notably rash and diarrhea. Dose expansions then proceeded at reduced dose level 2 (ibrutinib 560 mg, buparlisib 80 mg) and all patients on buparlisib 100 mg were dose reduced to 80 mg. Adverse events of all grades >=20% related to therapy include diarrhea (65%), fatigue (57%), hyperglycemia (52%), thrombocytopenia (48%), anorexia (43%), nausea (43%), hyperbilirubinemia (35%), rash (35%), depression (26%), mucositis (26%), mood swings (22%) (Figure 1A). of 23 pt, dose reduction/interruption required for ibrutinib in 11(48%) pt, buparlisib in 14 (61%) pt. All 14 pt treated beyond cycle 3 were able to tolerate subsequent cycles with dose modification as needed for toxicities. Serious adverse events (SAE) related to therapy include: colitis, orthostatic hypotension, cerebrovascular ischemia, rash, diarrhea, fall. One unexpected death from unknown cause occurred in pt on protocol. 20 pts were evaluable for response. The overall response rate (ORR) as follows: DLBCL 14%, FL 25%, MCL 100% (Figure 1B). Targeted sequencing and cell‐free DNA analysis is on‐going. (Figure Presented) Conclusions: Our preliminary results demonstrate that the combination of ibrutinib and buparlisib has a promising clinical activity, especially in pts with MCL. Initial dose expansion of ibrutinib 560 mg, burpalisib 100 mg was associated with excessive toxicity. The study is currently enrolling patients at dose level 2 (ibrutinib 560 mg, buparlisib 80 mg).