A phase 1 study of neoadjuvant chemotherapy followed by concurrent chemoradiation with gemcitabine, sorafenib, and vorinostat in pancreatic cancer.

Abstract

e16268 Background: The multi-kinase inhibitor sorafenib (S) and HDAC inhibitor vorinostat (V) demonstrated synergism against preclinincal pancreatic cancer (PaCa) models. The combination of S & V also potently radiosensitized pancreatic cancer cells and enhanced the activity of gemcitabine (G). This led to a phase 1 trial to determine the doses and schedule appropriate for phase 2 study of S & V with weekly G and intensity modulated radiotherapy (IMRT) as neoadjuvant treatment of PaCa following chemotherapy. Methods: Using a 3+3 dose-escalation design, adult patients with resectable, borderline resectable, unresectable, and lymph node positive PaCa were enrolled to 6 dose levels. Enrolled patients had completed at least 8w of neoadjuvant chemotherapy prior to IMRT. The schedule of administration was weekly 200mg/m2 G weekly during IMRT, S & V were dosed either 3x or 5x weekly during IMRT. Primary endpoint was to identify the dose and schedule for S & V with G based chemoradiation. Key secondary endpoints included antitumor activity, R0 resection rate, OS. Correlative studies to evaluate a variety of biomarkers and Nanostring expression analysis on pre- and post-therapy tumor specimens were also performed. Results: 22 patients were enrolled and 21 treated at 6 dose levels. Due to thrombocytopenia limiting drug exposure, the trial was modified to reduce G to 200mg/m2/wk and S & V to 3 d/wk instead of 5 d/wk. 13 patients were eligible for surgery, and 9 had R0 resections. Conclusions: Our findings indicate that the study regimen was well tolerated, typical toxicities of S (hand foot syndrome) were not observed with intermittent dosing. Uncomplicated cytopenias limited drug exposure, which was improved with intermittent S&V dosing. The RP2D of the combination is S (400mg po BID 3d/wk), V (200mg po qd 3d/wk), G 200mg/m2 IV weekly, with IMRT (50.4 Gy over 28 fractions, 5d/wk). Antitumor activity was observed across dose levels, with an encouraging R0 resection rate. These results warrant further investigation of combining S and V with G and IMRT as neoadjuvant treatment of PaCa following chemotherapy. Analyses of correlative studies and OS are underway. Clinical trial information: NCT02349867. [Table: see text]

Cancer epigenetics in clinical practice

“…A phase 2 trial in patients with neuroblastoma comparing 131 I-metaiodobenzylguanidine (MIBG) radiotherapy alone or in combination with vorinostat or vincristine and irinotecan, determined that MIBG plus vorinostat had the highest ORR (32%; 95% CI, 18%-51%) after the first course compared with 14% on either of the other two arms, with manageable toxicity (ClinicalTrials.gov identifier NCT02035137). 176 Also, in a phase 1 study combining vorinostat with radiotherapy as neoadjuvant treatment in pancreatic cancer after chemotherapy, the regimen was well tolerated, and antitumor activity was observed (ClinicalTrials.gov identifier NCT02349867), 177 warranting further investigation in this aggressive tumor type.…”

Correlating Basal Gene Expression across Chemical Sensitivity Data to Screen for Novel Synergistic Interactors of HDAC Inhibitors in Pancreatic Carcinoma

“…For example, the synergistic interaction between DNMT1 inhibitor and pan-HDACi was recently described on MIA PaCa2 cells [ 15 ]. Sorafenib is one of the kinase inhibitors (BRAF; FLT3; KDR;RAF1) with preclinical data on synergism with HDACi and this combination is currently under clinical investigations for usage in PDAC [ 8 , 16 ]. Another positive examples include combination of HDAC inhibitors with PI3K inhibitor [ 17 ], mTOR inhibitor [ 18 ], BET (BRD4 in Table 1 ) inhibitors [ 19 ], and combination with gemcitabine [ 10 ] ( Table 1 ).…”

Correlating basal gene expression across chemical sensitivity data to screen for novel synergistic interactors of HDAC inhibitors in pancreatic carcinoma

“…For example, the synergistic interaction between DNMT1 inhibitor and pan-HDACi was recently described on MiaPaCa2 cells. 13 Sorafenib is one of the kinase inhibitors (BRAF; FLT3; KDR;RAF1) with preclinical data on synergism with HDACi and this combination is currently under clinical investigations for usage in PDAC 8,14 . Another positive examples include combination of HDAC inhibitors with PI3K inhibitor 15 , mTOR inhibitor 16 , BET (BRD4 in Table 1) inhibitors 17 , and combination with gemcitabine 9 (Table 1).…”

“…For example, the synergistic interaction between DNMT1 inhibitor and pan-HDACi was recently described on MiaPaCa2 cells. 13 Sorafenib is one of the kinase inhibitors (BRAF; FLT3; KDR;RAF1) with preclinical data on synergism with HDACi and this combination is currently under clinical investigations for usage in PDAC 8,14 .…”