Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research
Methods: This is a single center open label, Ph I study investigating CC-486 and Ven in R/R AML patients. In the dose escalation phase, subjects received CC-486 at one of two cohorts (200 mg PO days 1-14 and 300 mg PO days 1-14). Ven was given at the 400 mg/day PO regimen, for 28 days, after an initial intra-patient dose escalation per the standard of care. Using a 3+3 study design for these two cohorts, we aimed to determine the maximum tolerated dose (MTD) of CC-486 in combination with Ven. An expansion cohort is planned for 10 additional patients treated at the MTD. To assess whether CC-486 exerts similar effects in the leukemia stem cell population (LSCs) compared to conventional IV Aza, we retrospectively analyzed patient samples from cohort 1 with a patient sample treated with Ven/IV Aza outside of the study. We performed mass spectrometry-based metabolomics analyses in LSCs isolated from patient samples as well as single-cell RNA sequencing.
Results: A total of 9 patients were accrued for this Ph I study (Figure 1A). The average age at the time of enrolment was 66, and median prior treatment regimens was 1 (range 1-3). Five patients had received Ven/Aza in prior treatments. There were no dose-limiting toxicity (DLT) events and the MTD was determined to be 300mg. The most common hematologic toxicities were Gr 3-4 neutropenia (n = 8, 89%), Gr 3-4 anemia (n = 7, 78%), and Gr 3-4 thrombocytopenia (n = 5, 56%). The most common non-hematologic toxicities were Gr 1-2 nausea (n = 5, 56%), fatigue (n = 2, 22%), and diarrhea (n = 2, 22%). Febrile neutropenia was also seen in two subjects (Gr 1-2 n = 1, 11%, Gr 3-4 n= 1, 11%). Best responses were complete remission (CR) (n = 2, 22%) partial remission (PR) (n = 1, 11%), and stable disease (SD) (n= 3, 33%). Three patients proceeded to an allogeneic stem cell transplant. Overall survival was 288 days, 95% CI: (39 days, 424 days). To determine whether CC-486/Ven exerts similar effects on the LSC population compared to conventional IV Aza/Ven, LSCs were isolated from the bone marrow of a responder and non-responder, and these were compared to LSCs from a patient who underwent treatment and responded to conventional IV Aza/Ven. Given subjects who achieved a CR in the study cleared their blasts by day 4 rendering no leukemia cells for analyses, samples used were from Subject 1 (stable disease with unchanged blasts), and Subject 2 (stable disease with significant blast reduction). Metabolomics assays performed in LSCs at day 4 and day 28 suggested mitochondrial dysfunction, decreased electron transport chain complex II activity and decreased glutathione levels in Subject 2 and conventional IV Aza/Ven but not on Subject 1. These findings are consistent with Pollyea et al. 2018 suggesting CC-486/Ven targets LSCs by perturbing complex II activity and OXPHOS in LSCs. Further, scRNA seq performed in Subject 1 and 2 showed gene expression patterns similar to those seen in patients who respond to Aza/Ven vs not, including a significant shift of BCL-2 to MCL-1 expression in the cell population harboring LSCs (Figure 1B).
Conclusion: CC-486 and Ven is an all-oral regimen currently being investigated for the treatment of R/R AML. Our Ph I dose escalation demonstrated a favorable safety profile for this regimen with a MTD of 300mg CC-486. Responses were seen in both dose cohorts including 2 CRs and 1 PR, and patients have been successfully bridged to hematopoietic stem cell transplant. Analyses performed in patient samples from this study suggested a similar effect in LSCs in CC-486/Ven compared to conventional IV Aza/Ven.
Disclosures: McMahon: Syros Pharmaceuticals: Research Funding; Syndax Pharmaceuticals: Research Funding; Arcellx: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees. Schwartz: Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy. Smith: AML JV: Consultancy; OncoVerity: Current Employment, Current holder of stock options in a privately-held company. Jordan: AML JV: Consultancy. Pollyea: AbbVie, Bristol Myers Squibb, Syros, Novartis, Beigene, Bergen Bio, Arcellx, Jazz, Genentech, Immunogen, AstraZeneca, Kura, Ryvu, Magenta, Qihan, Zentalis, Medivir, Hibercell, LINK, Daiichi Sankyo, Aptevo, Rigel, Sumitomo, Adicet, Seres, Gilead, OncoVerit: Consultancy; Teva, Karyopharm, Bristol Myers Squibb, and AbbVie.: Research Funding.