Ongoing Phase 1a/1b Dose-Finding Study of CWP232291 (CWP291) in Relapsed or Refractory Multiple Myeloma (MM)

Background: CWP291, a novel peptidomimetic small molecule, has potent and selective inhibitory activity on a Wnt gene reporter and decreases expression of the β-catenin target genes, cyclin D1 and survivin. It has broad anti-cancer efficacy in vitro, outperforming lenalidomide and bortezomib in multiple myeloma murine xenografts and demonstrating improved survival when used in combination with lenalidomide in bone marrow engraftment models.

Methods: Subjects with relapsed or refractory MM were infused CWP291 iv over at least 30 minutes twice weekly for 3 weeks out of a 4-week cycle in a 3+3 dose-escalation, Phase 1 design.

Results: Results as of July 15, 2016 over a dose range of 198 - 446 mg/m² in 9 subjects are reported. Median duration of treatment was 3 cycles (range 1.3 - 6.5 cycles) with 3 subjects ongoing. The most common (>20% of subjects) drug-related adverse events (AEs) were due to GI toxicities, including diarrhea (77.8%), nausea (55.6%) and constipation (33.3%). Toxicity was mostly ≤grade 2, however grade 3/4 events were frequently related to myelosuppression, including neutropenia (33.3%), and anemia and thrombocytopenia (22.2% each). Serious adverse events were recorded for 5 subjects with 8 separate events: 6 events in 4 subjects considered unrelated were hospitalizations for pneumonia, and 2 events in 1 subject each considered possibly related were a urinary tract infection and grade 3 hypoxia. Dose-limiting toxicities occurred in 2 patients at 446 mg/m², which were hypoxia (grade 3) and thrombocytopenia (grade 4). Accrual at 335 mg/m² has now been initiated. Stable disease (≥3 months on therapy with no increase in M protein as per the IMWG) was seen in 4 subjects. There was also documentation of a 34.6% decrease in bone marrow plasma cells in one subject for whom a bone marrow aspirate was available. PK in the first 3 subjectsreceiving198 mg/m²showed plasma levels of the active metabolite had very little inter-patient variability, which were comparable to patients with AML receiving this same dose in another study. There was less than 4% excreted in the urine, and there was no evidence of accumulation from Day 1 to Day 18. Changes in targeted genes in blood and BM, as well as additional PK, will be provided from expanded and escalated dosing cohorts. Furthermore, preliminary observations in the Phase 1b part of this study, which combines the administration of CWP291 with lenalidomide and dexamethasone, will be reported.

Conclusions: CWP291, a novel and first in class molecule with significant preclinical activity, shows single agent safety as well as early evidence of efficacy in subjects with MM. Accrual is ongoing to establish the optimal dose level for both single agent and combination therapy.