PDE4 inhibitors are safe and active in B cell malignancies

Purpose:In this study, we aimed to validate our extensive pre-clinical data on phosphodiesterase 4 (PDE4) as actionable target in B-cell malignancies. Our specific objectives were to determine the safety, pharmacokinetics and pharmacodynamics (PI3K/AKT activity), as well as to capture any potential anti-tumor activity of the FDA-approved PDE4 inhibitor roflumilast in combination with prednisone in patients with advanced B cell malignancies. Experimental Design: Single center, exploratory phase Ib open-label, non-randomized study. Roflumilast (500 mcg PO) was given daily for 21 days with prednisone on days 8-14. Additional 21-day cycles were started if patients tolerated cycle 1 and had at least stable disease. Results:Ten patients, median age 65 years with an average of three prior therapies were enrolled. The median number of cycles administered was 4 [range: 1-13]. Treatment was generally well tolerated; the most common {greater than or equal to}Grade 2 treatment-related adverse events ({greater than or equal to}25%) were fatigue, anorexia and transient {greater than or equal to} grade 2 neutropenia (30%). Treatment with roflumilast as a single agent significantly suppressed PI3K activity in the 77% of patients evaluated; on average, patients with PI3K/AKT suppression stayed in trial for 156 days (49 - 315) vs. 91 days (28 - 139 days) for those without this biomarker response. Six of the nine evaluable patients (66%) had partial response or stable disease. The median number of days in trial was 105 days [range: 28-315]. Conclusions:Repurposing the PDE4 inhibitor roflumilast for treatment of B-cell malignancies is a safe, suppresses the activity of the oncogenic PI3K/AKT kinases, and may have clinical activity in this setting

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