A phase I/II study of ivaltinostat combined with gemcitabine and erlotinib in patients with untreated locally advanced or metastatic pancreatic adenocarcinoma

This phase I/II study evaluated the safety and efficacy of a new histone deacetylase (HDAC) inhibitor, ivaltinostat, in combination with gemcitabine and erlotinib for advanced pancreatic ductal adenocarcinoma (PDAC). Patients diagnosed with unresectable, histologically confirmed PDAC who had not undergone previous therapy were eligible. Phase I had a 3 + 3 dose escalation design to determine the maximum tolerable dose (MTD) of ivaltinostat (intravenously on days 1, 8 and 15) with gemcitabine (1000 mg/m2 intravenously on days 1, 8 and 15) and erlotinib (100 mg/day, orally) for a 28‐day cycle. In phase II, patients received a six‐cycle treatment with the MTD of ivaltinostat determined in phase I. The primary endpoint was the objective response rate (ORR). Secondary endpoints included overall survival (OS), disease control rate (DCR) and progression‐free survival (PFS). The MTD of ivaltinostat for the phase II trial was determined to be 250 mg/m2. In phase II, 24 patients were enrolled. The median OS and PFS were 8.6 (95% confidence interval [CI]: 5.3‐11.2) and 5.3 months (95% CI: 3.7‐5.8). Of the 16 patients evaluated for response, ORR and DCR were 25.0% and 93.8% with a median OS/PFS of 10.8 (95% CI: 8.3‐16.7)/5.8 (95% CI: 4.6‐6.7) months. Correlative studies showed that mutation burden detected by cfDNA and specific blood markers such as TIMP1, pro‐MMP10, PECAM1, proMMP‐2 and IGFBP1 were associated with clinical outcomes. Although the result of a small study, a combination of ivaltinostat, gemcitabine and erlotinib appeared to be a potential treatment option for advanced PDAC. What's new? Histone deacetylase inhibitors (HDACi) are approved for use as anticancer drugs for a range of tumors. While no clinical trials have evaluated HDACi efficacy in pancreatic ductal adenocarcinoma (PDAC), the novel intravenous HDACi ivaltinostat appears to exert a synergistic anticancer effect in PDAC cells with gemcitabine/erlotinib combinations in vitro and in vivo. This phase I/II prospective single‐arm study suggests that ivaltinostat combined with gemcitabine/erlotinib may represent a potential treatment option with an acceptable safety profile for advanced pancreatic ductal adenocarcinoma. Moreover, the results point to potential blood markers that could help predict responses to ivaltinostat treatment.