Interim Results from the Phase 1a/1b Dose-Finding Study of CWP232291 (CWP291) in Relapsed or Refractory Myeloma (RRMM) Alone or in Combination with Lenalidomide and Dexamethasone

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 MM murine xenografts, and improving survival in combination vs. single agents alone in bone marrow engraftment models.

Methods: Subjects with RRMM 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. In Phase 1a, CWP291 was delivered as a single agent. In Phase 1b, which started at a dose lower than a demonstrably well-tolerated dose in Phase 1a, allowing for more rapid initiation of this phase of the study (J Clin Oncol 35:2017 Suppl Abstr TPS8058), subjects received CWP291 in combination with lenalidomide and dexamethasone.

Results: As of July 25, 2017, 21 subjects (13M, 8F), ages 44-79 (median 61 years) were enrolled; twelve in Phase 1a at doses from 198 - 446 mg/m² and 8 in Phase 1b at 198 - 263 mg/m². The median duration of treatment was 2 cycles (range 1 - 6 cycles) with 5 subjects ongoing. The most common (≥20% of subjects) drug-related adverse events (AEs) were due to GI toxicities, with diarrhea in 16 subjects (76%) and nausea in 10 subjects (48%); toxicities were grade ≤2 except grade 3 in 1 subject each. Asthenia/fatigue was seen in 10 subjects (48%) with 1 grade 3. Thrombocytopenia was reported in 6 subjects (29%), 5 of which were grade ≥3. Anemia was seen in 4 subjects (29%), and in 3 subjects were grade ≥3. Serious adverse events were recorded for 11 subjects with 18 separate events, the most frequent (9 events in 6 subjects) considered unrelated were hospitalizations for infections (pneumonia and parainfluenza virus) and only 3 events (urinary tract infection, grade 3 hypotension and grade 2 hypoxia) were considered possibly related. Three dose-limiting toxicities (DLT) occurred in Phase 1a in 2 subjects at 446 mg/m², which were hypoxia (grade 3), neutropenia (grade 4) and thrombocytopenia (grade 4). The 335 mg/m² cohort has now been initiated in which 1 DLT (grade 3 hypoxia) has been seen, and accrual is ongoing. One DLT (hypotension grade 3) was seen in Phase 1b at 198 mg/m² however no additional DLTs were seen and accrual is now ongoing at 263 mg/m². Fourteen subjects were evaluable for efficacy as per IMWG criteria. Six subjects had progressive disease (1 in Phase 1b), 4 subjects had stable disease, and responses were seen in 4 subjects (2 minor). 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 in Phase 1a. Changes in targeted genes in blood and BM, as well as PK, will be provided from expanded and escalated dosing cohorts.

Conclusions: CWP291, a novel and first in class molecule with significant preclinical activity, shows safety as a single agent as well as in combination with standard of care for patients with relapsed/refractory multiple myeloma Early evidence of efficacy in these subjects suggests that this is an active drug in this indication, and is continuing to be explored.