Synthetic lethality (SL) selectively kills malignant cells through chemical inhibition of 2 aberrant genes, and it is now a clinical reality. Investigators demonstrated the potential of SL with best-in-class combinations of targeted agents, immune modulation, and low-dose combinations. They hypothesized that combining Bruton’s tyrosine kinase (BTK) and mTOR inhibition with an immunomodulatory agent would target multiple key signaling pathways, improve selective killing of malignant cells, and address acquired drug resistance.
Specifically, investigators are examining DTRM-555, which is a combination of a novel BTK inhibitor, DTRM-12, with everolimus and pomalidomide. DTRM-555 has shown superior efficacy over single agents at lower combined doses (1/18 of DTRM-12, 1/6 of everolimus, and 1/6 of pomalidomide) in xenograft tumor models. To take a closer look, investigators are conducting a phase 1, first-in-human multicenter trial exploring DTRM-555 in patients with chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma (NHL). There are 2 parts of this phase 1 study. Phase 1a consists of escalating the novel BTK inhibitor DTRM-12 monotherapy doses, and phase 1b will explore in one arm a doublet combination of BTK inhibitor DTRM-12 with everolimus, and in another arm the triplet combination DTRM-555. Treatment is administered for 21 consecutive days of a 28-day cycle until disease progression or unacceptable toxicity.
Eligibility criteria for patients with CLL or B-cell NHL were ≥18 years of age and an Eastern Cooperative Oncology Group performance status ≤1 with no available therapies. Safety is the primary study end point. Secondary end points include antitumor activity and pharmacokinetic studies. Since the start of this study on September 27, 2016, 5 patients have been enrolled in phase 1a, without dose-limiting toxicity. Patients enrolled in phase 1a are currently at a 200-mg dose. Investigators anticipate enrolling up to 18 patients in phase 1a and up to 36 patients in phase 1b.
Gill J, et al. ASCO Abstract TPS7570.