Abstract B268: A Phase I Study of CUDC-101, a multitarget inhibitor of HDACs, EGFR, and HER2, in combination with chemoradiation in patients with intermediate/high risk locally advanced squamous cell carcinoma of the head and neck.
Authors: Jimeno Antonio , Galloway Thomas , Wirth Lori , Gilbert Jill , Saba Nabil , Bauman Julie , Colevas Dimitrios , Mehra Ranee , Raben David , Lai Cheng-Jung , Laliberte Robert , Voi Maurizio , Burtness Barbara 
Published: August 2014

Abstract
Purpose: This study sought to establish the maximum tolerated dose (MTD) of CUDC-101 in combination with cisplatin and radiation in patients (pts) with locally advanced untreated squamous cell carcinoma of the head and neck.
Patients and Methods: Pts were enrolled onto two cohorts of IV CUDC-101: 225 mg/m2 and 275 mg/m2. Pts received CUDC-101 alone 3 times a week for 1 week followed by 7 weeks of the same dose plus radiotherapy 70 Gy and cisplatin 100 mg/m2 on days 2, 23 and 44 of radiotherapy. Endpoints included safety/tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of CUDC-101, and clinical activity.
Results: Thirteen pts were enrolled and 12 received treatment: 4 in the 225 mg/m2 and 8 in the 275 mg/m2 cohorts; 2 pts received CUDC-101 monotherapy only.Ten pts were male and 3 were female. Mean age was 63 years. Nine pts had newly diagnosed Stage IV (A or B) disease, 3 had Stage III. Eleven pts had p16 negative disease except 1 pt who was p16 positive but with a past smoking history of &gt;10 packs/year. Four pts had oropharynx as the primary tumor site, 2 larynx, 2 hypopharynx, 2 oral cavity, 1 tongue and 1 tonsil. Dose-limiting toxicities (DLT) included acute renal failure (ARF) in one pt treated at 275 mg/m2 leading to study discontinuation. Grade 3 CUDC-101 related adverse events were decreased appetite, leukopenia, hypertension, ARF (1 pt each). CUDC-101 PK were consistent with prior CUDC-101 single-agent PK.
Tumor, skin and PBMC samples collected for PD analysis showed consistent HDAC inhibition; pEGFR staining was abrogated after therapy in the 2 pts from whom PD data are available. Data at the 12-week post-treatment disease assessment are available in 6 pts: 2 had complete response, 2 had partial response and 2 stable disease. Two pts had a post-treatment biopsy with negative pathology results.
Conclusion: The results of this study showed that CUDC-101 can be combined with chemoradiation at a dose of 275 mg/m2 with ARF being the most prominent DLT. PD results showed effective HDAC target modulation. Preliminary long-term efficacy results are encouraging.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B268.
Citation Format: Antonio Jimeno, Thomas Galloway, Lori Wirth, Jill Gilbert, Nabil Saba, Julie Bauman, Dimitrios Colevas, Ranee Mehra, David Raben, Cheng-Jung Lai, Robert Laliberte, Maurizio Voi, Barbara Burtness. A Phase I Study of CUDC-101, a multitarget inhibitor of HDACs, EGFR, and HER2, in combination with chemoradiation in patients with intermediate/high risk locally advanced squamous cell carcinoma of the head and neck. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B268.