Phase I study of the mTOR inhibitor everolimus in combination with the histone deacetylase inhibitor panobinostat in patients with advanced clear cell renal cell carcinoma

Abstract

Background Preclinical studies suggested synergistic anti-tumor activity when pairing mTOR inhibitors with histone deacetylase (HDAC) inhibitors. We completed a phase I, dose-finding trial for the mTOR inhibitor everolimus combined with the HDAC inhibitor panobinostat in advanced clear cell renal cell carcinoma (ccRCC) patients. We additionally investigated expression of microRNA 605 (miR-605) in serum samples obtained from trial participants. Patients and Methods Twenty-one patients completed our single institution, non-randomized, open-label, dose-escalation phase 1 trial. miR-605 levels were measured at cycle 1/day 1 (C1D1) and C2D1. Delta Ct method was utilized to evaluate miR-605 expression using U6B as an endogenous control. Results There were 3 dosing-limiting toxicities (DLTs): grade 4 thrombocytopenia (n = 1), grade 3 thrombocytopenia (n = 1), and grade 3 neutropenia (n = 1). Everolimus 5 mg PO daily and panobinostat 10 mg PO 3 times weekly (weeks 1 and 2) given in 21-day cycles was the recommended phase II dosing based on their maximum tolerated dose. The 6-month progression-free survival was 31% with a median of 4.1 months (95% confidence internal; 2.0-7.1). There was higher baseline expression of miR-605 in patients with progressive disease (PD) vs those with stable disease (SD) (p = 0.0112). PD patients' miR-605 levels decreased after the 1st cycle (p = 0.0245), whereas SD patients' miR-605 levels increased (p = 0.0179). Conclusion A safe and tolerable dosing regimen was established for combination everolimus/panobinostat therapy with myelosuppression as the major DLT. This therapeutic pairing did not appear to improve clinical outcomes in our group of patients with advanced ccRCC. There was differential expression of miR-605 that correlated with treatment response. Clinical trial information: NCT01582009.

Keywords: Kidney; MicroRNA; Neoplasm; Targeted therapy; miR-605.

Conflict of interest statement

Declarations of interest: none

Conflict of Interest

Anthony Wood declares that he has no conflict of interest. Saby George declares that he has no conflict of interest. Nabil Adra declares that he has no conflict of interest. Sreenivasulu Chintala declares that he has no conflict of interest. Nur Damayanti declares that she has no conflict of interest. Roberto Pili declares that he has no conflict of interest.

Figures

Figure 1.. Overview of Patients’ Course of Therapy

Swimmer plot depicting clinical course of enrolled patients. Each band represents 1 patient arranged by best response to therapy: PD - progressive disease; SD - stable disease; NE - not evaluable. The bands are color-coded based on the patients’ dose levels (DL) and extends for length of therapy with a symbol denoting reason for discontinuation on its right. Patients experiencing dose-limiting toxicities were noted as well.

Figure 2.. Kaplan-Meier Estimate of Progression-Free Survival

A Kaplan-Meier estimate of progression-free survival (PFS) for patients enrolled in study.

Figure 3.. Population miR-605 Expression

Graphical representation of population miR-605 expression relative to U6B at cycle 1/day 1 (C1D1) and C2D2 arranged by best response to therapy. Error bar represents 95% CI of the mean.

Figure 4.. Individual miR-605 Expression per Cycle Grouped by Treatment Response

Graphical representation of individual miR-605 expression relative to U6B at C1D1 and C2D2 arranged by best response to therapy. Each color pair represents an individual patient (Pt - patient #). Thick bar represents the mean, and thin bar with tick mark represents standard deviation.