Trials in Progress: 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
Authors: Benajiba Lina , Carraway Hetty E. , Hamad Nada , Stein Eytan M. , Yannakou Costas K. , Burroughs Amy , Harris Scott , Lane Hayley , Nguyen Dorothy D. , Stuart Monic , Vargas Jesse , Puissant Alexandre , Stegmaier Kimberly , DiNardo Courtney D. 
Published: November 2020

Background:
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&lt;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.
Study design:
This is a single arm, open-label, multi-center phase 1 clinical trial. The study includes two parts: 1) a Dose Escalation phase using a single-participant cohort accelerated titration schema in R/R AML or intermediate/higher-risk MDS (IPSS-R) participants and 2) a Dose Expansion phase using a 2 stage design for further assessment of disease specific cohorts and potential combination strategies at the recommended phase 2 dose (RP2D). CB-5339 will be administered orally once-daily (QD) for 4 days, followed by a 3-day treatment-free period weekly, in successive 28-day cycles until progressive disease or intolerable toxicity. Intraparticipant dose escalation will be permitted after Cycle 1. Twice-daily (BID) dosing may also be tested depending on initial PK assessments. The primary objective of this trial is to determine the safety, tolerability, and MTD and/or RP2D of CB-5339. The secondary objectives are to characterize PK properties and antitumor activity of CB-5339. Exploratory objectives will evaluate potential pharmacodynamic (PD) biomarkers and characterize the PK/PD relationship. Key inclusion criteria include participants with pathologically confirmed AML or intermediate/higher-risk MDS relapsed and/or refractory to standard therapies, ECOG ≤2, and adequate kidney and liver functions. Key exclusion criteria include pathologically confirmed acute promyelocytic leukemia, central nervous system involvement, immediately life-threatening/severe complications of AML/MDS such as uncontrolled bleeding, uncontrolled active infection, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation, SCT within 100 days of first dose, active GVHD, or post-SCT systemic immunosuppressive therapy, concomitant active malignancy requiring chemotherapy and adverse cardiac history. Up to 60 participants (20 in dose escalation and 40 in dose expansion) will be enrolled at approximately 10 sites in the U.S and Australia. Recruitment is ongoing and this trial is registered with clinicaltrials.gov: NCT04402541.

Disclosures
Benajiba: Gilead Foundation: Research Funding. Carraway:BMS: Consultancy, Other: Research support, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Takeda: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC); Abbvie: Other: Independent Advisory Committe (IRC). Hamad:Novartis: Honoraria; Abbvie: Honoraria. Stein:Biotheryx: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Seattle Genetics: Consultancy; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy; Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy. Burroughs:Chiasma: Current equity holder in publicly-traded company; Synthetic Genomics: Current equity holder in private company; Cleave Therapeutics: Current Employment, Current equity holder in private company; Crinetics Pharmaceuticals: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Harris:Cleave Therapeutics: Current Employment, Current equity holder in private company. Lane:Cleave Therapeutics: Consultancy; Regimmune Corporation: Consultancy; Star Therapeutics: Consultancy; Nanoscope Therapeutics: Consultancy; Viewpoint Therapeutics: Ended employment in the past 24 months; Valitor: Consultancy; Revolution Medicines: Consultancy. Nguyen:Cleave Therapeutics, Inc: Current Employment, Current equity holder in private company. Stuart:Cleave Therapeutics: Consultancy; Triphase Accelerator U.S Corporation: Consultancy; Revolution Medicines Inc: Consultancy; RegImmune Corp: Consultancy; IgM Biosciences: Consultancy; Portola Pharmaceuticals Inc: Consultancy; Artiva Biotherapeutics: Consultancy; Gilead Sciences Inc: Consultancy; Theravance Biopharma: Consultancy; Integral Medicines Inc: Consultancy. Vargas:Cytomx Therapeutics, Inc.: Current equity holder in publicly-traded company; Sangamo Therapeutics: Current equity holder in publicly-traded company; Cleave Therapeutics, Inc.: Current Employment, Current equity holder in private company. Stegmaier:Novartis: Research Funding; Auron Therapeutics: Consultancy. DiNardo:ImmuneOnc: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Novartis: Consultancy; Calithera: Research Funding; Syros: Honoraria.