Oral administration of irinotecan in patients with solid tumors: an open-label, phase I, dose escalating study evaluating safety, tolerability and pharmacokinetics

Abstract

Background Oral drug formulations have several advantages compared to intravenous formulation. Apart from patient convenience and favorable pharmacoeconomics, 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. Methods 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 1 week rest. Results 25 patients were included across four cohorts; 3 patients were included in cohort 1 (20 mg/m 2 ), 7 patients were included in cohort 2 (30 mg/m 2 ), 3 patients were included in cohort 3 (25 mg/m 2 ) and 12 patients were included in cohort 4 (21 mg/m 2 ). Median age was 67 years, 52% were performance status (PS) 0 while 48% were PS 1. Median number of prior therapies was 3 (range 1–6). MTD was established at 21 mg/m 2 . No responses were observed. Nine patients (36%) had stable disease (SD), lasting median 19 weeks (range 7–45 weeks). Among these five patients had previously received irinotecan. No grade 3/4 hematologic toxicities were reported. Totally six patients experienced grade 1/2 anemia, three patients had grade 1/2 leucopenia and 1 patient had grade 1 thrombocytopenia. 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. Conclusions 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.

A proximal-to-distal survey of healthy adult human small intestine and colon epithelium by single-cell transcriptomics

“…Interestingly, UGT1A1, the Phase II gene which inactivates SN-38 162 , has low gut epithelial expression (Table S6). This suggests irinotecan might remain active in the gut, supporting the idea that orally administered irinotecan might be effective against intestinal cancers [163][164][165] . Our easily-searchable dataset provides expression values for genes important for further studies probing intestinal metabolism of endobiotics, environmental toxicants, and pharmaceuticals.…”

A Proximal-to-Distal Survey of Healthy Adult Human Small Intestine and Colon Epithelium by Single-Cell Transcriptomics

“…This suggests that irinotecan may experience prolonged activation in the gut, advancing the idea that orally administered irinotecan might be effective against intestinal cancers. 133 , 134 , 135 Our easily searchable data set quantifies the expression of genes important for intestinal metabolism of endobiotics, environmental toxicants, and pharmaceuticals.

Figure 16 Drug targets.

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Antibody-drug conjugates (ADCs) targeting trophoblast cell surface antigen 2 (Trop-2) and precision treatment of breast cancer

“…Irinotecan as monotherapy for breast cancer have previously shown relatively low response rates between 10% and 30% ( 16 ). Newer formulations of irinotecan with prolonged exposure are in the pipeline, but until now without convincing efficacy ( 17 , 18 ).…”