Abstract
A randomized, open-label, phase II study of high-dose interleukin 2 vs high-dose interleukin 2 plus entinostat in renal cell carcinoma.
Author
person
Roberto Pili
University at Buffalo, Buffalo, NY
info_outline
Roberto Pili, David I. Quinn, Ralph J. Hauke, Timothy Kuzel, Yan Han, Nabil Adra, Theodore F. Logan
Full text
Authors
person
Roberto Pili
University at Buffalo, Buffalo, NY
info_outline
Roberto Pili, David I. Quinn, Ralph J. Hauke, Timothy Kuzel, Yan Han, Nabil Adra, Theodore F. Logan
Organizations
University at Buffalo, Buffalo, NY, USC Norris Comprehensive Cancer Center, Keck Medicine of USC, Los Angeles, CA, Nebraska Cancer Specialists - Midwest Cancer Center, Omaha, NE, Rush University Medical Center, Chicago, IL, Indiana University, Indianapolis, IN, Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN, IU Simon Comprehensive Cancer Center, Indianapolis, IN
Abstract Disclosures
Research Funding
Pharmaceutical/Biotech Company
Clinigen, Syndax
Background:
Immunosuppressive factors such as regulatory T cells (Tregs) limit the efficacy of immunotherapies such as high dose interleukin 2 (HD-IL2). We previously reported that the histone deacetylase (HDAC) inhibitor entinostat has antitumor effects in combination with HD-IL2 by decreasing Tregs function in a preclinical model of kidney cancer. Based on these preliminary data, we hypothesized that HDAC inhibition may enhance or resensitize patients (pts) with clear cell renal cell carcinoma (ccRCC) to HD-IL2. Our group has previously conducted a Phase II, single arm, clinical trial of entinostat in combination with HD-IL2 in ccRCC, which showed an objective response rate (ORR) of 37% and a median progression-free survival (mPFS) of 13.6 months as compared to historical data with single agent HD-IL2 of 20-25% and 4.2 months, respectively. Thus, we designed a multi-center, randomized, open label Phase II study with entinostat in combination with HD-IL2 in ccRCC patients.
Methods:
The primary objective was to estimate and compare PFS in pts randomized to receive either HD-IL2
plus
entinostat (Arm 1) or HD-IL2 (Arm 2) and stratified by no prior therapies
vs
prior therapies. Due to unforeseen circumstances, enrollment halted after the first 10 patients. The treatment schedule was HD-IL2 600,000 units/kg administered IV every 8 hrs on Days 1-5 and Days 15-19 (maximum 28 doses) +/- entinostat 5 mg orally given every 2 weeks starting on Day-14, continuously. The study was originally designed to detect a 100% improvement of median PFS to 8.4 months in ARM 1. A one-sided stratified log-rank test with an overall sample size of 46 subjects (23 per group) achieves 80% power at a 0.10 significance level to detect a hazard ratio of 0.5 (median PFS of 4.2 months vs 8.4 months).
Results:
10 pts (6 pts in Arm 1 and 4 pts in Arm 2) were enrolled. Among the 10 pts, only one had prior therapy (Arm 1). The most common treatment-related toxicities ( > 50%, any grade) were diarrhea, hypotension, nausea, hypomagnesemia, hypophosphatemia, pruritus, hypocalcemia and thrombocytopenia, hypophosphatemia, proteinuria, diarrhea, fatigue, and neutropenia. The most common ≥ grade 3 toxicities were hypotension (80%), hypophosphatemia (70%), and thrombocytopenia (60%). Two pts (33%: CI 4.3%-77.7%) achieved a partial response in Arm 1 and no pts in Arm 2. The median PFS was 12.4 months (CI 2.3-NE) in Arm 1 (13.3 months in pts with no prior therapies) and 2.8 months (CI 1.2-3.3) in Arm 2 (Logrank p-value 0.0167). We have collected blood samples to conduct several correlative studies including flow cytometry and gene expression analysis on peripheral blood mononuclear cells.
Conclusions:
The preliminary results from this study confirm that the combination of entinostat and HD-IL2 may be more active than HD-IL2 alone in pts with ccRCC. Clinical trial information: NCT03501381.
Clinical status
Clinical
1 clinical trial
8 organizations
2 drugs
3 targets
Clinical trial
A Phase II Randomized, Open Label Study of High Dose Interleukin 2 vs High Dose Interleukin 2 Plus Entinostat in Advanced Renal Cell CarcinomaStatus: Active (not recruiting), Estimated PCD: 2023-01-20
Organization
USC Norris Comprehensive Cancer CenterOrganization
Keck Medicine of USCOrganization
Rush University Medical CenterOrganization
IU Simon Comprehensive Cancer CenterDrug
entinostatDrug
HD-IL2Target
Interleukin-23 (IL-23)