David E Gerber1, David A Boothman2, Farjana J Fattah3, Ying Dong3, Hong Zhu4, Rachel A Skelton3, Laurin L Priddy3, Peggy Vo3, Jonathan E Dowell5, Venetia Sarode6, Richard Leff7, Claudia Meek7, Yang Xie4, Joan H Schiller5. 1. Department of Internal Medicine (Division of Hematology-Oncology), USA; Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA. Electronic address: david.gerber@utsouthwestern.edu. 2. Department of Pharmacology, USA; Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA. 3. Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA. 4. Department of Clinical Sciences (Biostatistics), USA; Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA. 5. Department of Internal Medicine (Division of Hematology-Oncology), USA; Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA. 6. Department of Pathology, USA. 7. Texas Tech University Health Sciences Center School of Pharmacy, USA.
Abstract
PURPOSE: Preclinical studies demonstrated anti-tumor efficacy of the combination of the histone deacetylase (HDAC) inhibitor romidepsin plus erlotinib in non-small cell lung cancer (NSCLC) models that were insensitive to erlotinib monotherapy. We therefore studied this combination in a phase 1 clinical trial in previously treated advanced NSCLC. METHODS: Romidepsin (8 or 10mg/m(2)) was administered intravenously on days 1, 8, and 15 every 28 days in combination with erlotinib (150 mg orally daily), with romidepsin monotherapy lead-in during Cycle 1. Correlative studies included peripheral blood mononuclear cell HDAC activity and histone acetylation status, and EGFR pathway activation status in skin biopsies. RESULTS: A total of 17 patients were enrolled. Median number of prior lines of therapy was 3 (range 1-5). No cases had a sensitizing EGFR mutation. The most common related adverse events were nausea, vomiting, and fatigue (each 82%), diarrhea (65%), anorexia (53%), and rash (41%). Dose-limiting nausea and vomiting occurred at the romidepsin 10 mg/m(2) level despite aggressive antiemetic prophylaxis and treatment. Among 10 evaluable patients, the best response was stable disease (n=7) and progressive disease (n=3). Median progression-free survival (PFS) was 3.3 months (range 1.4-16.5 months). Prolonged PFS (>6 months) was noted in a KRAS mutant adenocarcinoma and a squamous cell cancer previously progressed on erlotinib monotherapy. Romidepsin monotherapy inhibited HDAC activity, increased histone acetylation status, and inhibited EGFR phosphorylation. CONCLUSIONS: Romidepsin 8 mg/m(2) plus erlotinib appears well tolerated, has evidence of disease control, and exhibits effects on relevant molecular targets in an unselected advanced NSCLC population.
PURPOSE: Preclinical studies demonstrated anti-tumor efficacy of the combination of the histone deacetylase (HDAC) inhibitor romidepsin plus erlotinib in non-small cell lung cancer (NSCLC) models that were insensitive to erlotinib monotherapy. We therefore studied this combination in a phase 1 clinical trial in previously treated advanced NSCLC. METHODS:Romidepsin (8 or 10mg/m(2)) was administered intravenously on days 1, 8, and 15 every 28 days in combination with erlotinib (150 mg orally daily), with romidepsin monotherapy lead-in during Cycle 1. Correlative studies included peripheral blood mononuclear cell HDAC activity and histone acetylation status, and EGFR pathway activation status in skin biopsies. RESULTS: A total of 17 patients were enrolled. Median number of prior lines of therapy was 3 (range 1-5). No cases had a sensitizing EGFR mutation. The most common related adverse events were nausea, vomiting, and fatigue (each 82%), diarrhea (65%), anorexia (53%), and rash (41%). Dose-limiting nausea and vomiting occurred at the romidepsin 10 mg/m(2) level despite aggressive antiemetic prophylaxis and treatment. Among 10 evaluable patients, the best response was stable disease (n=7) and progressive disease (n=3). Median progression-free survival (PFS) was 3.3 months (range 1.4-16.5 months). Prolonged PFS (>6 months) was noted in a KRAS mutant adenocarcinoma and a squamous cell cancer previously progressed on erlotinib monotherapy. Romidepsin monotherapy inhibited HDAC activity, increased histone acetylation status, and inhibited EGFR phosphorylation. CONCLUSIONS:Romidepsin 8 mg/m(2) plus erlotinib appears well tolerated, has evidence of disease control, and exhibits effects on relevant molecular targets in an unselected advanced NSCLC population.
Authors: P Therasse; S G Arbuck; E A Eisenhauer; J Wanders; R S Kaplan; L Rubinstein; J Verweij; M Van Glabbeke; A T van Oosterom; M C Christian; S G Gwyther Journal: J Natl Cancer Inst Date: 2000-02-02 Impact factor: 13.506
Authors: Suzanne F Jones; Jeffrey R Infante; David R Spigel; Nancy W Peacock; Dana S Thompson; F Anthony Greco; William McCulloch; Howard A Burris Journal: Cancer Invest Date: 2012-04-26 Impact factor: 2.176
Authors: Maryam Fouladi; Wayne L Furman; Thomas Chin; Burgess B Freeman; Lorina Dudkin; Clinton F Stewart; Mark D Krailo; Roseanne Speights; Ashish M Ingle; Peter J Houghton; John Wright; Peter C Adamson; Susan M Blaney Journal: J Clin Oncol Date: 2006-08-01 Impact factor: 44.544
Authors: Jhanelle E Gray; Eric Haura; Alberto Chiappori; Tawee Tanvetyanon; Charles C Williams; Mary Pinder-Schenck; Julie A Kish; Jenny Kreahling; Richard Lush; Anthony Neuger; Leticia Tetteh; Angela Akar; Xiuhua Zhao; Michael J Schell; Gerold Bepler; Soner Altiok Journal: Clin Cancer Res Date: 2014-01-15 Impact factor: 12.531
Authors: Barbara J Gitlitz; Eric Bernstein; Edgardo S Santos; Greg A Otterson; Ginger Milne; Mary Syto; Francis Burrows; Sara Zaknoen Journal: J Thorac Oncol Date: 2014-04 Impact factor: 15.609
Authors: Yelena Y Janjigian; Egbert F Smit; Harry J M Groen; Leora Horn; Scott Gettinger; D Ross Camidge; Gregory J Riely; Bushi Wang; Yali Fu; Vikram K Chand; Vincent A Miller; William Pao Journal: Cancer Discov Date: 2014-07-29 Impact factor: 39.397
Authors: Maria Rusan; Kapsok Li; Yvonne Li; Camilla L Christensen; Brian J Abraham; Nicholas Kwiatkowski; Kevin A Buczkowski; Bruno Bockorny; Ting Chen; Shuai Li; Kevin Rhee; Haikuo Zhang; Wankun Chen; Hideki Terai; Tiffany Tavares; Alan L Leggett; Tianxia Li; Yichen Wang; Tinghu Zhang; Tae-Jung Kim; Sook-Hee Hong; Neermala Poudel-Neupane; Michael Silkes; Tenny Mudianto; Li Tan; Takeshi Shimamura; Matthew Meyerson; Adam J Bass; Hideo Watanabe; Nathanael S Gray; Richard A Young; Kwok-Kin Wong; Peter S Hammerman Journal: Cancer Discov Date: 2017-10-20 Impact factor: 39.397
Authors: Karine Pozo; Stefan Zahler; Keisuke Ishimatsu; Angela M Carter; Rahul Telange; Chunfeng Tan; Shuaijun Wang; Roswitha Pfragner; Junya Fujimoto; Elizabeth Gardner Grubbs; Masaya Takahashi; Sarah C Oltmann; James A Bibb Journal: Oncotarget Date: 2018-12-28