Early Results from a Phase 1 Dose Escalation Study Evaluating MS-553, a Novel, Selective Pkcβ Inhibitor, in Relapsed or Refractory CLL/SLL Patients

Introduction: Resistance to covalent Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib and acalabrutinib is an emerging issue that presages a poor clinical outcome. MS-553 is a potent, highly selective, oral, non-covalent inhibitor of PKCβ, a signaling molecule immediately downstream of BTK and PLCγ2 in the B-cell receptor (BCR) pathway. As PKCβ is downstream of both BTK and PLCγ2, it has the potential to treat acquired BTK resistance mutations in either protein, a feature absent from many second-generation BTK inhibitors. We report the first results from an ongoing Phase 1, dose-escalation study in patients with CLL/SLL treated with MS-553 (NCT03492125).

Methods: The primary objective of the study is to evaluate the safety and tolerability and to determine the recommended dose (RP2D) for Phase 2 in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) treated with MS-553. Patients enrolled have relapsed after, or were refractory to, at least two prior therapies. Secondary objectives were to assess the pharmacokinetic (PK) profile, the pharmacodynamic (PD) activity, and evidence of anti-tumor activity following MS-553 treatment. Dose escalation was performed according to a conventional 3+3 design. Treatment emergent adverse events (TEAEs) were assessed per NCI CTCAE v.5.0. Tumor responses were evaluated according to IWCLL 2008 (CLL) or RECIL 2017 (SLL) guidelines.

Results: As of July 27, 2020, a total of 12 patients (median age 72;10 CLL; 2 SLL) have been treated with at least one cycle of therapy. The median number of prior therapies was 4.5 (range 2-12). Sixty-three percent were IGVH unmuted; 27% had 17p deletions. All had previously been treated with at least one BTK inhibitor. Patients have been dosed at four dose levels (100 mg BID, n=3; 200 mg BID, n=3; 250 mg BID, n=3; and 300 mg BID, n=3). Safety: To date, no dose limiting toxicity has been identified and the MTD has not been reached. For the entire safety population, TEAEs were mostly mild or moderate. The most common TEAEs regardless of grade occurring in > 4 patients were nausea (n=10), decreased platelets (n=10), diarrhea (n=7), fatigue (n=7), anemia (n=6), fever (n=6), hyperglycemia (n=6), decreased neutrophils (n=6), anorexia (n=5), weight loss (n=5), and pneumonia (n=5). The majority of the drug-related TEAEs were grade 1 or 2. Two instances of ≥ grade 3 neutropenia judged drug-related were observed. There have been no drug-related serious AEs. PK generally mirrored results seen in phase 1 studies of healthy volunteers. In dose cohort 4, trough concentrations at steady state averaged greater than 1 µM. Pharmacodynamic measures of PKCβ signaling demonstrated a dose-dependent inhibition, with potent to full inhibition of PKCβ signaling during 24 hours of exposure. Treatment-induced lymphocytosis was seen in all cohorts, including 5/6 patients at the two highest dose levels. A dose-dependent reduction in lymph node size has been demonstrated across all cohorts with 60% PR/PRLs in 5/5 evaluable patients in Cohorts 3 & 4. In Cohort 4, the two evaluable patients with partial responses demonstrated a reduction in lymph node sum of perpendicular dimension (SPD) values of 73% and 96%, respectively.

Conclusion: Although results are preliminary, MS-553 has been generally well tolerated with initial anti-tumor activity seen in this heavily pretreated population. Potent to full inhibition of PKCβ signaling over 24 hours of exposure has been demonstrated. Additional dosing of patients will be completed to further assess MS-553 efficacy in patients with acquired resistance mutations in BTK and PLCG2.