Phase I dose escalation of the oral histone deacetylase inhibitor (HDACi) resminostat in combination with FOLFIRI in colorectal cancer (CRC) patients: The SHORE trial
Sie können Bookmarks mittels Listen verwalten, loggen Sie sich dafür bitte in Ihr SLUB Benutzerkonto ein.
Medientyp:
E-Artikel
Titel:
Phase I dose escalation of the oral histone deacetylase inhibitor (HDACi) resminostat in combination with FOLFIRI in colorectal cancer (CRC) patients: The SHORE trial
Beschreibung:
<jats:p> 3625 </jats:p><jats:p> Background: Resminostat is a novel oral HDAC inhibitor with broad activity in various cancer models. In CRC models, resminostat revealed synergistic effects with 5-FU and irinotecan/SN-38, indicating its (re-)sensitization potential when applied in combination therapy. Furthermore, resminostat downregulates thymidylate synthase, involved in drug resistance to 5-FU and effectively inhibits HDAC2, one of the target enzymes believed to critically support development of CRC. The phase I/II SHORE trial investigates resminostat in combination with FOLFIRI in patients previously treated with 5-FU. Methods: Patients (pts) with advanced CRC having previously received 5-FU alone or in combination with other agents who were scheduled for FOLFIRI in second or later treatment lines were included. The phase I comprised an open-label, inter-patient, ‘3+3’ dose escalation design with increasing doses of resminostat combined with standard FOLFIRI. Pts received resminostat on 5 consecutive days, followed by a 9-day drug free period (‘5+9’ scheme, i.e. 14-day cycles). On days 3 and 4 of each cycle (C), FOLFIRI was administered. Primary objective of the Phase I part was to determine safety and tolerability, the maximum tolerated dose and pharmacokinetics of the combination. Results: 17 pts (median age 61 yrs; 12 males; 11 ECOG 0; 6 ECOG 1; median therapy line 2 [2-6]) were enrolled in 4 dose levels of resminostat 200, 400, 600 mg QD (3 pts each) and 400 mg BID (6 pts) plus FOLFIRI. Two pts discontinued in C1 and were replaced. No DLT occurred. AEs consisted mainly of GI symptoms of mild and moderate intensity (nausea, vomiting and diarrhea) leading to decreased electrolyte plasma levels in some pts. In the highest dose level tested (400 mg BID) hematological toxicity, mainly neutropenia up to grade 4, was observed leading to dose reductions in 3 pts in C3 and C7. No objective responses were reported, however some pts showed SD for prolonged time (up to 32 w). Results of the completed phase I part will be reported. Conclusions: The combination of resminostat with standard FOLFIRI was safe and well tolerated warranting continuation into the Phase II part of the study. Clinical trial information: NCT01277406. </jats:p>