A Phase Ia/Ib Study Of A Novel Btk Inhibitor, Dtrmwxhs-12 (Dtrm 12), And Combination Products, With Everolimus And Pomalidomide, In Pts With Cll Or Other B-Cell Lymphomas.

TPS7570 Background: Synthetic lethality (SL) relies on the chemical inhibition of two aberrant genes to selectively kill malignant cells. SL is now a clinical reality in an era of multiple targeted agents and advanced genetic testing. We investigated small molecule combinations for SL through in vitro and in vivo screening and optimization studies (Table, US patent 20160324878) and demonstrated the potential of SL through best-in-class combinations of targeted agents, immune modulation and low-dose combinations. We hypothesize that BTK and mTOR inhibition combined with an IMiD target multiple key signaling pathways, improve selective cell kill and address acquired drug-resistance. DTRM-555 is an optimized mechanism-based combination of the novel BTK inhibitor DTRM-12, with everolimus (E) and pomalidomide (P). In xenograft tumor models, DTRM-555 has shown superior efficacy over single agents at lower combined doses (1/18 of DTRM-12, 1/6 of E, and 1/6 of P). Methods: We are conducting a phase I, first-in-human multicenter trial exploring DTRM-555 in pts with CLL and B-cell NHL. Phase Ia consists of escalating DTRM-12 monotherapy doses. Phase Ib will explore doublet combination of DTRM-12 plus everolimus, and DTRM-555, the novel triplet combination. Safety is the primary study endpoint. Secondary endpoints include anti-tumor activity and pharmacokinetic studies. Eligible pts are > / = 18 years / ECOG < / = 1 with CLL or B-cell NHL with no available therapies. Treatment is administered for 21 consecutive days of a 28-day cycle, until disease progression or unacceptable toxicity. The trial commenced on 9/27/16. Phase 1a (single subject, 50/100mg respectively) has enrolled 5 pts without DLT and is currently at the 200 mg dose level. Up to 50 pts will be enrolled. Five additional sites are planned to open in the near future across the US. Clinical trial information: NCT02900716. [Table: see text]