Oral drug formulations have several advantages compared to intravenous formulation. Apart from patient convenience and favorable pharmaco-economics they offer the possibility of frequent drug administration at home. In this study, we present a new oral irinotecan formulation designed as an enteric coated immediate release tablet which in pre-clinical studies has shown good exposure with low variability.
A phase I, dose escalating study to assess safety, tolerability, pharmacokinetics and efficacy of an oral irinotecan formulation and to establish the maximum tolerated dose (MTD). Each treatment cycle was once-daily irinotecan for 14 days followed by one week rest.
25 patients were included across four cohorts; 3 patients were included in cohort 1 (20 mg/m²), 7 patients were included in cohort 2 (30 mg/m²), 3 patients were included in cohort 3 (25 mg/m²) and 12 patients were included in cohort 4 (21 mg/m²). Median age was 67 years, 52% were performance status (PS) 0 while 48% were PS 1. Median number of prior therapies was 3 (range1 to 6). MTD was established at 21 mg/m². No responses were observed. Nine patients (36%) had stable disease (SD), lasting median 19 weeks (range 7-45 weeks). Among these 5 patients had previously received irinotecan.No grade 3/4 hematologic toxicities were reported. Totally 6 patients experienced grade 1/2 anemia, 3 patients had grade 1/2 leucopenia and 1 patient had grade 1 trombocytopenia. Most common non-hematological grade 1 and 2 adverse events were nausea, fatigue, diarrhea, vomiting and cholinergic syndrome. Grade 3 toxicities included diarrhea, fatigue, nausea and vomiting, no grade 4 events were reported. PK data showed consistent daily exposures during treatment at days 1 and 14 and no drug accumulation. SN-38 interpatient variability was in the same range as after infusion.
Oral irinotecan was generally well tolerated; side effects were manageable and similar in type to those observed with intravenous irinotecan. Hematological toxicities were few and only grade 1/2. In this heavily pre-treated patient population oral irinotecan demonstrated activity even among patients previously treated with irinotecan.
Clinical trial identification
EudraCT: 2014-005584-32; NCT03295084.
Legal entity responsible for the study
Herlev and Gentofte Hospital, Department of Oncology, Herlev, Denmark.
Oncoral Pharma ApS, Ballerup, Denmark.
J.A. Palshof, I. Kümler, P.G. Sørensen, B.V. Jensen, D.L. Nielsen: Oncoral Pharma ApS provided study medication.