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Title: 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.
Epworth Authors: Yannakou, Costas
Other Authors: Benajiba, Lena
Caraway, Hetty
Hamad, Nada
Stein, Eytan
Burroughs, Amy
Haris, Scott
Lane, Hayley
Ngyuen, Dorothy
Stuart, Monic
Vargas, Jesse
Puissant, Alexandre
Stegmaier, Kimberly
Dinardo, Courtney
Keywords: Acute Myeloid Leukemia (AML)
Myelodysplastic Syndrome (MDS)
Allogeneic Stem-Cell Transplant (SCT)
Consolidation Chemotherapy
(VCP)/p97 Protein
CB-5339 Inhibitor
Clonal Hematopoietic Disorders
Relapsed/Refractory (R/R) AML
Phase 1 Clinical Trial
Single-Participant Cohort
Dose Expansion Phase
Twice Daily (BID)
Intraparticipant Dose Escalation
Pharmacodynamic (PD) Biomarkers
PK/PD Relationship
Epworth Centre for Immunotherapies and Snowdome Laboratories
Department of Molecular Oncology and Cancer Immunology, Epworth HealthCare
Cancer Services Clinical Institute, Epworth HealthCare, Victoria, Australia
Issue Date: Dec-2020
Citation: Blood (2020) 136 (Supplement 1): 21.
Conference Name: ASH Meeting 2020
Conference Location: Georgia World Congress Center, Atlanta, Georgia, United States
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.
DOI: 10.1182/blood-2020-140636
Type: Conference Poster
Affiliated Organisations: APHP, INSERM U944, Institute of Hematology - St Louis Hospital, PARIS, France
Taussig Cancer Institute, Cleveland Clinic, Department of Hematology and Medical Oncology, Cleveland, OH
Department of Haematology, St. Vincent's Hospital, Sydney, Australia
University of New South Wales, Sydney, Australia
Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
Department of Molecular Oncology and Cancer Immunology, Epworth HealthCare, East Melbourne, Australia
Cleave Therapeutics, Inc., San Francisco, CA
Cleave Therapeutics, Inc., San Diego, CA
Dana-Farber Cancer Institute, Boston, MA
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Type of Clinical Study or Trial: Clinical Trial
Appears in Collections:Cancer Services

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