Summary
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.
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The clinical trial was supported in part by an unrestricted grant from Novartis Pharmaceuticals. The funder had no role in collection and interpretation of data and writing of the report.
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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.
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Wood, A., George, S., Adra, N. et al. 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. Invest New Drugs 38, 1108–1116 (2020). https://doi.org/10.1007/s10637-019-00864-7
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DOI: https://doi.org/10.1007/s10637-019-00864-7