CCS1477, a Novel p300/CBP Bromodomain Inhibitor, Enhances Efficacy of Azacitidine and Venetoclax in Pre-Clinical Models of Acute Myeloid Leukaemia and Lymphoma

Abstract

E1A binding protein (p300) and CREB binding protein (CBP) are two closely related histone acetyl transferases that co-activate key oncogenes such as MYC and IRF4 which are relevant in a number of haematological malignancies. Here we describe the effects of CCS1477, a new orally available inhibitor of the p300/CBP bromodomains, given alone or in combination with azactidine or venetoclax in pre-clinical models of AML and B-cell lymphoma.As a monotherapy, daily oral dosing with CCS1477 (5, 10 and 20mg/kg) caused a significant dose-dependent reduction in tumour growth in a MOLM-16 xenograft model of AML, with regressions observed at the highest and well tolerated dose of 20mg/kg/qd. The inhibition of tumour growth during drug treatment was accompanied by a significant reduction in tumour expression of MYC by qPCR. In murine retroviral transduction and transplantation models of human AML initiated by either MLL-AF10 or MLL-AF9, daily monotherapy by oral gavage with CCS1477 at 30mg/kg for 42 days, caused a highly significant prolongation of survival. All seven control treated mice died of AML within 160 days whereas only one of seven CCS1477 treated mice had died in each model by 300 days.In the MOLM-16 xenograft model, a sub-maximal dose of CCS1477 (10mg/kg) demonstrated superior tumour growth inhibition by comparison with azacitidine (0.5mg/kg i.p) and with significant combination benefit when these two agents were combined. In this same model venetoclax (50 or 100 mg/kg/qd oral) had no effect on tumour growth, indicating that MOLM-16 tumours are intrinsically resistant. CCS1477 dosed daily at 10mg/kg restored sensitivity to venetoclax as evidenced by significantly greater tumour growth inhibition when compared with CCS1477 given alone. In a venetoclax-sensitive xenograft model of AML (MV-4-11), CCS1477 (10mg/kg) and venetoclax (100mg/kg) resulted in a similar and partial reduction in tumour growth over a 21 day dosing period. When venetoclax and CCS1477 were combined there was a significant combination benefit compared to either drug given alone. The DOHH-2 xenograft model of B-cell lymphoma was also sensitive to venetoclax (50mg/kg) and with a similar impact on tumour growth compared with CCS1477 (10mg/kg). In this model the combination of CCS1477 and venetoclax was more profound and caused complete tumour stasis during the dosing period.These data support the clinical testing of CCS1477 in combination with azacitidine and/or venetoclax in AML and B-cell lymphomas. CCS1477 is currently in Phase I/II clinical trials in AML, Non-Hodgkin lymphoma (including B-cell lymphoma) and multiple myeloma. (NCT04068597). DisclosuresBrooks: CellCentric Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Knurowski: CellCentric Ltd: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Hughes: CellCentric Ltd: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Clegg: CellCentric Ltd: Current Employment, Current holder of individual stocks in a privately-held company. West: CellCentric Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Pegg: CellCentric Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Somervaille: Novartis: Consultancy, Honoraria.