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

I. Kümler; P. Grundtvig Sørensen; J. Palshof; E. Høgdall; W. Skovrider-Ruminski; S. Theile; A. Fullerton; P. G. Nielsen; B. Vittrup Jensen; D. L. Nielsen

doi:10.1007/s00280-018-3720-7

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

I. Kümler^*, P. Grundtvig Sørensen, J. Palshof, E. Høgdall, W. Skovrider-Ruminski, S. Theile, A. Fullerton, P. G. Nielsen, B. Vittrup Jensen, D. L. Nielsen

^*Corresponding author for this work

Department of Clinical Medicine

3 Citations (Scopus)

4 Downloads (Pure)

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.

Original language	English
Journal	Cancer Chemotherapy and Pharmacology
Volume	83
Issue number	1
Pages (from-to)	169-178
Number of pages	10
ISSN	0344-5704
DOIs	https://doi.org/10.1007/s00280-018-3720-7
Publication status	Published - 2019

Keywords

Dose finding
Oral irinotecan
Phase I

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Oral administration of irinotecan in patients with solid tumors: an open-label, phase I, dose escalating study evaluating safety, tolerability and pharmacokineticsFinal published version, 913 KBLicence: CC BY

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Kümler, I., Sørensen, P. G., Palshof, J., Høgdall, E., Skovrider-Ruminski, W., Theile, S., Fullerton, A., Nielsen, P. G., Jensen, B. V., & Nielsen, D. L. (2019). Oral administration of irinotecan in patients with solid tumors: an open-label, phase I, dose escalating study evaluating safety, tolerability and pharmacokinetics. Cancer Chemotherapy and Pharmacology, 83(1), 169-178. https://doi.org/10.1007/s00280-018-3720-7

Oral administration of irinotecan in patients with solid tumors : an open-label, phase I, dose escalating study evaluating safety, tolerability and pharmacokinetics. / Kümler, I.; Sørensen, P. Grundtvig; Palshof, J. et al.

In: Cancer Chemotherapy and Pharmacology, Vol. 83, No. 1, 2019, p. 169-178.

Research output: Contribution to journal › Journal article › Research › peer-review

Kümler, I, Sørensen, PG, Palshof, J, Høgdall, E, Skovrider-Ruminski, W, Theile, S, Fullerton, A, Nielsen, PG, Jensen, BV & Nielsen, DL 2019, 'Oral administration of irinotecan in patients with solid tumors: an open-label, phase I, dose escalating study evaluating safety, tolerability and pharmacokinetics', Cancer Chemotherapy and Pharmacology, vol. 83, no. 1, pp. 169-178. https://doi.org/10.1007/s00280-018-3720-7

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title = "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. ",

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T1 - Oral administration of irinotecan in patients with solid tumors

T2 - an open-label, phase I, dose escalating study evaluating safety, tolerability and pharmacokinetics

AU - Kümler, I.

AU - Sørensen, P. Grundtvig

AU - Palshof, J.

AU - Høgdall, E.

AU - Skovrider-Ruminski, W.

AU - Theile, S.

AU - Fullerton, A.

AU - Nielsen, P. G.

AU - Jensen, B. Vittrup

AU - Nielsen, D. L.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - Dose finding

KW - Oral irinotecan

KW - Phase I

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DO - 10.1007/s00280-018-3720-7

M3 - Journal article

C2 - 30406838

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SN - 0943-9404

VL - 83

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EP - 178

JO - Cancer Chemotherapy and Pharmacology, Supplement

JF - Cancer Chemotherapy and Pharmacology, Supplement

IS - 1

ER -

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

Abstract

Keywords

UN SDGs

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