Abstract 5545
Background
Many advanced melanoma patients are refractory and do not respond to checkpoint inhibition (CI) alone. Epigenetic modulation of tumors to enhance their immunogenicity, alter the tumor microenvironment and thus increase the chance of response to immunotherapy is one clinical approach. In an open label Phase Ib/II multi-center study (‘SENSITIZE’) we investigated the combination of the HDAC inhibitor domatinostat and pembrolizumab in patients with advanced melanoma.
Methods
Advanced stage melanoma patients who were refractory or non-responding to prior checkpoint inhibitor therapy were treated with domatinostat (orally) at increasing dose levels in 3 different dose cohorts in combination with pembrolizumab (2mg/kg) q3w intravenously in a modified “rolling six” study design to evaluate the safety and tolerability of the combination treatment. Tumor assessment was initially performed after 12 weeks. Tumor biopsies were taken for immunohistochemical and gene expression analysis, peripheral blood for PK/PD analysis.
Results
At time of data cut-off on May 8th, 2019 (study ongoing), a total of 23 patients were enrolled into the study. The safety profile indicates that domatinostat-specific adverse events add to the known safety profile of pembrolizumab, but no exacerbation of immune-related adverse events in rate and severity has been observed so far. Domatinostat alone and in combination was considered safe. First signs of efficacy have been observed, including patients one with a partial response and two with stable disease per irRECIST 1.1. Tumor biopsies at baseline showed a domatinostat-induced alteration of the tumor microenvironment including infiltration of CD8+ T cells, the presence of PD-1/ PD-L1 positive cells, and changes on gene expression levels. Furthermore, a dose-dependent PK profile has been observed.
Conclusions
Domatinostat given in combination with pembrolizumab is safe and tolerable and might increase anti-tumor activity in these CI-unresponsive melanoma patients by alteration of the immune tumor microenvironment.
Clinical trial identification
NCT03278665.
Editorial acknowledgement
Legal entity responsible for the study
4SC AG.
Funding
4SC AG.
Disclosure
P.A. Ascierto: Advisory / Consultancy, Travel / Accommodation / Expenses: 4SC. F. Hermann: Full / Part-time employment: 4SC AG. R. Bartz: Full / Part-time employment: 4SC AG. D. Schadendorf: Advisory / Consultancy, Travel / Accommodation / Expenses: 4SC. All other authors have declared no conflicts of interest.
Resources from the same session
5529 - Safety and efficacy of Ac-225-PSMA-617 in metastatic castration resistant prostate cancer (mCRPC) after failure of Lu-177-PSMA
Presenter: Robert Tauber
Session: Poster Display session 3
Resources:
Abstract
3611 - Phase II trial of SM 88 in Non-Metastatic Biochemical Recurrent Prostate Cancer.
Presenter: Benjamin Gartrell
Session: Poster Display session 3
Resources:
Abstract
2492 - A phase 1 study of Ad5 PSA/MUC-1/Brachyury Vaccine in Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC)
Presenter: Marijo Bilusic
Session: Poster Display session 3
Resources:
Abstract
3142 - Multicenter Phase I Trial of a DNA Vaccine Encoding the Androgen Receptor Ligand Binding Domain (pTVG-AR, MVI-118) in Patients with Metastatic Prostate Cancer
Presenter: Douglas McNeel
Session: Poster Display session 3
Resources:
Abstract
4327 - Impact of germline mutations in Homologous Recombination (HR) genes on the response to Radium-223 for metastatic castration resistant prostate cancer (mCRPC)
Presenter: Elena Castro
Session: Poster Display session 3
Resources:
Abstract
3600 - Serum biomarkers of bone metabolism in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with Radium-223 (Ra223): Results from a prospective multicentre study
Presenter: Nuria Romero Laorden
Session: Poster Display session 3
Resources:
Abstract
3742 - Prognostic value of tumor suppression genes (TP53, PTEN, Rb) in metastatic hormone sensitive prostate cancer
Presenter: Miguel Gonzalez Velez
Session: Poster Display session 3
Resources:
Abstract
2643 - Germline sequencing of advanced prostate cancer patients in the BARCODE2 trial
Presenter: Sarah Benafif
Session: Poster Display session 3
Resources:
Abstract
4349 - Impact of treatment sequence in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): data from the prospective PROREPAIR-B study.
Presenter: Carlo Cattrini
Session: Poster Display session 3
Resources:
Abstract
3301 - Implications of Single Nucleotide Polymorphisms (SNPs) in Androgen Related-Genes in Outcome of metastatic castration-resistant prostate cancer (mCRPC) patients treated with Abiraterone (Abi) and Enzalutamide (Enza)
Presenter: Isabel Aragon
Session: Poster Display session 3
Resources:
Abstract