A Single-Center Phase IIa Study Evaluating the Safety and Tolerability of Umbralisib and Ibrutinib in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Introduction: Treatment for relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) remains an unmet medical need despite the recent approval of chimeric antigen receptor T-cell (CAR-T) therapeutic constructs. Many patients will be "too sick to CAR-T" or may have logistical/financial challenges that will not allow this treatment. As a result, non-chemotherapy agents with activity in rel/ref DLBCL require further development to help fill this need. Umbralisib (UMB) is dual PI3K delta/CK-1ε inhibitor that has single agent activity in rel/ref DLBCL with an ORR of 31% [Burris et al. 2018]. Ibrutinib (IBR) is a Bruton Tyrosine kinase (BTK) inhibitor with activity seen in the activated B-cell (ABC) subtype of DLBCL with an ORR of 37% in this subtype [Wilson et al. 2015]. Pre-clinical data (not shown) demonstrated synergistic activity of UMB-IBR against cell lines of both germinal center B-cell (GCB) and non-GCB subtypes of DLBCL. We report results of phase IIa study of the combination of UMB-IBR in rel/ref DLBCL.

Methods: Eligible patients (pts) had relapsed or refractory DLBCL, ANC ≥1000 cells/mm³, platelets ≥100 K/mm³, and adequate organ function. The Hans algorithm defined cell of origin. UMB was dosed at 800 mg daily in AM and IBR 560 mg daily in PM. Treatment stratification was performed on a 1:1:1 design to Cohort A (UMB), B (IBR), or C (UMB+IBR) by consent to optional biopsies, which included optional pre-treatment and day 8 biopsies to assess pre-specified correlative flow cytometric analysis of the B-cell receptor (BCR) pathway. In cohorts A/B the combination was initiated at day 8. A cycle was 28 days. Pts received UMB-IBR for up to 1-year of therapy in the absence of progression disease (PD) or excess toxicity. The primary endpoint was monitoring for cumulative toxicity events (CTEs) occurring during cycles 1-4. A CTE was defined as grade (G) 4 neutropenia or thrombocytopenia, G3 neutropenia or thrombocytopenia last longer than 7 days, G3 non-hematologic toxicity, or any G adverse event which led to a drug hold > 7 days. Consecutive stopping rules for CTEs and efficacy were employed. Secondary endpoints included overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, progression-free survival (PFS), time to response (TTR), and duration of response (DOR).

Results: Thirteen pts with rel/ref DLBCL were enrolled. Median age was 71 years (range 27-81) and 9 were male. Median number of prior therapies was 2 [range 1-7] with 8% having undergone prior autologous transplantation. Sixty-two percent were refractory to last therapy. DLBCL subtypes were GCB in 7 and non-GCB in 6 pts. The first 3 pts were enrolled to Cohort C regardless of optional biopsy consent. Cohorts A (n=1) and B (n=1) included pts that consented to optional biopsies. Cohort C (n=11) included the first 3 pts enrolled into the study and those thereafter that did not consent to optional biopsies. Two CTEs were seen: G3 rash and G3 Clostridium difficile (C. diff) diarrhea. No CTEs occurred during cycle 1. Notable serious or recurrent adverse events (SAEs or AEs) of interest occurring across all cycles regardless of attribution included elevated AST/ALT 0% G 3-4 (all G 31%), nausea 15% G 3-4 (all G 54%), and diarrhea 15% G 3-4 (all G 31%). The ORR of the UBR-IBR regimen was 23% with 2 PRs (both GCB) and 1 CR (non-GCB). The pt in CR remains on treatment at 7 months and recovered from a CTE during cycle 4 (C. diff). The median PFS was 3 months [95 % CI 0.85, 3.8]. No patient was taken off study for toxicity and there were no dose reductions necessary.

Conclusion: In this phase IIa study of rel/ref DLBCL, the non-chemotherapy regimen of UMB-IBR was well tolerated with only 2 CTEs and limited AEs. The evaluation of CTEs was limited by the rapid PD in many pts seen prior to 4 cycles of therapy. The ORR of the UMB-IBR was modest (23%) and of limited durability in this difficult to treat patient population. Based on limited activity and difficulty in obtaining biopsies for correlative analyses, this study was terminated prematurely.