Background: Vorinostat (V) is a potent class I & II (HDAC 6) inhibitor of histone deacetylases. In A549 and A375 cell lines (CL’s), V intensified RT induced decrease in clonogenic survival via impaired DNA repair. In CL's V downregulated thymidylate synthase (TS), a target of pemetrexed (P). Methods: This is a phase I trial of V plus C (cisplatin) or CP (carboplatin), P and RT for ECOG PS 0-1 pts with stage IIIA/B non-squamous NSCLC. V was dose-escalated in a 3+3 design (V at dose levels (DL1-3) 100, 200 and 300mg) with CRT: C (75 mg/m2) and P (500mg/m2) Q21 days x 4 with folic acid, B12, steroids), and RT (60 Gy). DL1b included CP AUC 5, P, RT and V 100mg. V was dosed for 3 consecutive days before cycle 1, and was then taken orally once a day 3 times/week during CRT. Surgical resection after CRT was allowed. The primary endpoint was to determine the MTD. Correlative analyses include TS and HDAC expression. This study was approved & funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Merck & Co., Inc. Results: Eighteen pts (51 - 80 years) enrolled from May 2010 to September 2014. Three evaluable (Ev) pts were treated on DL 1 (V 100), with no DLT. 3 Ev pts, and 2 Non-Ev pts (1 not eligible, 1 discontinued due to P-associated rash) were treated on DL 2 (V 200). At DL2, 2 pts had a DLT of grade (G) 4 hyponatremia (HNa). Accrual resumed with 3 pts on DL1, with 2 DLTs at DL1 (HNa and heart failure). Six pts were treated on DL1b with no DLTs. G 1 & 2 toxicities: nausea, anorexia, dysphagia, dehydration, esophagitis, fatigue, pain. G 3 toxicities: nausea, hyperglycemia, anemia, leukopenia. Fourteen pts completed 4 cycles of CRT and V. Two pts stopped V due to myelosuppression. One pt developed CLL 18 months after therapy. Among all pts the best response to date is CR:2, PR:4, SD: 8 pts. Three pts underwent resection, with no viable tumor in 2 specimens. With a median follow up of 15.4 months, the median PFS/OS have not been reached. Conclusions: With the exception of G4 HNa, no unexpected toxicities were noted with V and CRT. Esophagitis was mild. Assessment of PFS/OS and correlatives are ongoing. The recommended Phase 2 dose is CP AUC 5, P 500mg/m2 and V100mg 3x/week with RT. Clinical trial information: NCT01059552