Skip to Content
Merck
  • Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors.

Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors.

Autophagy (2014-07-06)
Devalingam Mahalingam, Monica Mita, John Sarantopoulos, Leslie Wood, Ravi K Amaravadi, Lisa E Davis, Alain C Mita, Tyler J Curiel, Claudia M Espitia, Steffan T Nawrocki, Francis J Giles, Jennifer S Carew
ABSTRACT

We previously reported that inhibition of autophagy significantly augmented the anticancer activity of the histone deacetylase (HDAC) inhibitor vorinostat (VOR) through a cathepsin D-mediated mechanism. We thus conducted a first-in-human study to investigate the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and VOR in patients with advanced solid tumors. Of 27 patients treated in the study, 24 were considered fully evaluable for study assessments and toxicity. Patients were treated orally with escalating doses of HCQ daily (QD) (d 2 to 21 of a 21-d cycle) in combination with 400 mg VOR QD (d one to 21). Treatment-related adverse events (AE) included grade 1 to 2 nausea, diarrhea, fatigue, weight loss, anemia, and elevated creatinine. Grade 3 fatigue and/or myelosuppression were observed in a minority of patients. Fatigue and gastrointestinal AE were dose-limiting toxicities. Six-hundred milligrams HCQ and 400 mg VOR was established as the maximum tolerated dose and recommended phase II regimen. One patient with renal cell carcinoma had a confirmed durable partial response and 2 patients with colorectal cancer had prolonged stable disease. The addition of HCQ did not significantly impact the PK profile of VOR. Treatment-related increases in the expression of CDKN1A and CTSD were more pronounced in tumor biopsies than peripheral blood mononuclear cells. Based on the safety and preliminary efficacy of this combination, additional clinical studies are currently being planned to further investigate autophagy inhibition as a new approach to increase the efficacy of HDAC inhibitors.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Hematoxylin Solution, Gill No. 1
Sigma-Aldrich
3,3′-Diaminobenzidine, 97%
Sigma-Aldrich
Deuterium, 99.8 atom % D
Sigma-Aldrich
Deuterium hydride, extent of labeling: 96 mol% DH, 98 atom % D
Sigma-Aldrich
Deuterium, 99.96 atom % D
Sigma-Aldrich
Hematoxylin
Sigma-Aldrich
3,3′-Diaminobenzidine, 97% (HPLC)
Sigma-Aldrich
Hematoxylin, certified by the Biological Stain Commission
Sigma-Aldrich
Formic acid, reagent grade, ≥95%
Sigma-Aldrich
Formic acid, ACS reagent, ≥88%
Sigma-Aldrich
Formic acid, ≥95%, FCC, FG
Sigma-Aldrich
Formic acid solution, BioUltra, 1.0 M in H2O
Sigma-Aldrich
Deuterium, 99.9 atom % D
Sigma-Aldrich
Formic acid, puriss. p.a., ACS reagent, reag. Ph. Eur., ≥98%
Sigma-Aldrich
Formic acid, ACS reagent, ≥96%
Sigma-Aldrich
Formic acid, puriss., meets analytical specifications of DAC, FCC, 98.0-100%