A Phase II, Single-Arm, Open-Label, Multicenter Study to Evaluate the Efficacy and Safety of P276-00, a Cyclin-Dependent Kinase Inhibitor, in Patients With Relapsed or Refractory Mantle Cell Lymphoma

Abstract

Overexpression of cyclin D1 is a hallmark feature of mantle cell lymphoma (MCL). Many of the oncogenic effects of cyclin D1 are mediated through cyclin dependent kinases (CDKs). P276-00 is a potent small-molecule inhibitor of CDK4-D1, CDK1-B, and CDK9-T with promising activity in pre-clinical models. In Phase I studies of P276-00 in patients with refractory solid neoplasms, it was well-tolerated with a mild trend of single-agent efficacy. A Phase II study of this agent was conducted in patients with relapsed or refractory MCL at the recommended dose of 185 mg/m2/day from days 1-5 of a 21-day cycle. Thirteen patients were enrolled on this study: 11 patients had disease progression, 1 patient was withdrawn due to an adverse event (AE), and 1 patient died. Eleven patients (84.6%) experienced a treatment-emergent AE deemed related to P276-00. Nine patients (69.2%) received at least 2 cycles of treatment, which was the pre-defined threshold to be evaluable for efficacy; treatment was discontinued early in 2 patients due to AEs (one of which was attributed to P276-00 administration) and in 2 patients due to disease progression. Two patients experienced stable disease for an estimated median duration of 60.5 days (range 58-63 days). The estimated median time to progression for the pre-defined efficacy population was 43 days (range 38-58 days). Given the results observed in this study, if continued evaluation of CDK inhibition in MCL occurs, it should be considered earlier in the disease course or as part of combination strategies for relapsed or refractory disease.

Targeting regulation of cyclin dependent kinase 9 as a novel therapeutic strategy in synovial sarcoma

“…Taken together, our studies suggest that CDK9 might be a novel therapeutic target in synovial sarcomas, perhaps most effective in combination with apoptosis‐inducing cytotoxic chemotherapy . Indeed, similar combinations are currently under investigation in clinical trials for the treatment of hematological cancers . However, similar clinical trials have not yet been reported in solid tumors, including synovial sarcomas.…”

The Emerging Role of Cyclin-Dependent Kinases (CDKs) in Pancreatic Ductal Adenocarcinoma

“…Rohitukine, a plant-derived chromone alkaloid, is the precursor of the promising anticancer clinical candidates flavopiridol (also known as alvocidib, HMR 1275, L86-8275) [ 222 , 223 , 224 ] and P276-00 [ 223 , 225 ]. However, the antitumor activity, pharmacokinetics, and CDK inhibitory potential of this parental product were not studied in detail for a long time.…”

Pharmacological cyclin dependent kinase inhibitors: Implications for colorectal cancer

“…Nerviano Medical Sciences, Nerviano, Italy Metastatic solid tumors [27,28] Cyclin E and CDK-2 Cyclin A and CDK-2 LY2835219 Cyclin D and CDK-4/6 Eli Lilly, Indianapolis, IN, United States Lung cancers [29] LEE011 Cyclin D and CDK-4/6 Novartis, Basel, Switzerland Gastrointestinal cancers [30] Breast Cancer [31] AZD5438 Cyclin D and CDK-4/6 Astra Zeneca, London, England Solid malignancies [32] Cyclin E and CDK-2 Cyclin A and CDK-2 Cyclin A and CDK-1 BAY 1000394 Cyclin D and CDK-4/6…”

“…Lastly, CDK4 overexpression is linked to a poor prognosis in colorectal cancer [26] . From the list of inhibitors currently in clinical trials, found in Table 1 [23, [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] , there have been a few that have been studied more specifically in colorectal cancer. One that has shown particular promise is PD-0332991, from Pfizer, New York, NY.…”