A phase I study to evaluate the safety and pharmacokinetic profiles of CB-5339 in participants with relapsed/refractory acute myeloid leukemia or relapsed/refractory intermediate or high-risk myelodysplastic syndrome.

Abstract

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are clonal hematopoietic disorders that predominantly occur in older adults. For a limited number of fit patients, induction followed by consolidation chemotherapy and/or allogeneic stem-cell transplant (SCT) leads to cure. However, many AML patients are ineligible for aggressive therapy; up to 30% have primary refractory disease and up to 50% will relapse after front-line therapy, requiring alternative approaches. For these patients, durable long-term remission rate is low, with 5-year overall survival rates lower than 10%. Therefore, there remains an urgent unmet need for novel therapies for such patients.

CB-5339 is a second generation, potent and selective, orally bioavailable small molecule inhibitor of valosin containing protein (VCP)/p97. VCP/p97 is a key cellular enzyme involved in cellular stress response pathways critical to cancer cell growth and survival such as protein homeostasis and the response to DNA damage.

Inhibition of VCP/p97 in a panel of 131 cancer cell lines representing 16 cancer types revealed AML as the most exquisitely dependent disease (p=0.004) on VCP/p97 function. Further, CB-5339 demonstrated antiproliferative potency in a panel of 16 AML cell lines (IC50:100nM - 500nM). To better characterize the effects of CB-5339 on human leukemia, viability assays were performed on a set of 30 genetically diverse primary AML patient samples. Cellular viability was impacted with a similar potency across samples, irrespective of underlying genetic abnormalities (mean IC50: 423nM). In vivo, CB-5339 treatment resulted in decreased circulating leukemic cells and significantly prolonged survival in an MLL-AF9 syngeneic AML mouse model (p=0.02). In addition, evidence of synergy was exhibited with standard of care AML therapy, a combination of an anthracycline and cytarabine. This triple combination regimen resulted in a 96% mean relative decrease in leukemic burden compared to control mice and significantly prolonged mice survival compared to each regimen alone (p<0.0001). Importantly, CB-5339 was well tolerated as evidenced by stable weight curves and absence of significant myelosuppression.

Here, we present a phase 1 study to evaluate CB-5339 in patients with relapsed/refractory (R/R) AML and intermediate or higher-risk MDS.