Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors

Shivaani Kummar; Alice Chen; Martin Gutierrez; Thomas D. Pfister; Lihua Wang; Christophe Redon; William M. Bonner; William Yutzy; Yiping Zhang; Robert J. Kinders; Jiuping Ji; Deborah Allen; Joseph M. Covey; Julie L. Eiseman; Julianne L. Holleran; Jan H. Beumer; Larry Rubinstein; Jerry Collins; Joseph Tomaszewski; Ralph Parchment; Yves Pommier; James H. Doroshow

doi:10.1007/s00280-016-2998-6

Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors

Shivaani Kummar, Alice Chen, Martin Gutierrez, Thomas D. Pfister, Lihua Wang, Christophe Redon, William M. Bonner, William Yutzy, Yiping Zhang, Robert J. Kinders, Jiuping Ji, Deborah Allen, Joseph M. Covey, Julie L. Eiseman, Julianne L. Holleran, Jan H. Beumer, Larry Rubinstein, Jerry Collins, Joseph Tomaszewski, Ralph ParchmentYves Pommier, James H. Doroshow

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

Purpose: Indenoisoquinolines are non-camptothecin topoisomerase I (TopI) inhibitors that overcome the limitations of camptothecins: chemical instability and camptothecin resistance. Two dosing schedules of the novel indenoisoquinoline, indotecan (LMP400), were evaluated in patients with advanced solid tumors. Methods: The maximum tolerated dose (MTD), toxicities, and pharmacokinetics of two indotecan drug administration schedules (daily for 5 days or weekly) were investigated. Modulation of TopI and the phosphorylation of histone H2AX (γH2AX) were assayed in tumor biopsies; γH2AX levels were also evaluated in circulating tumor cells (CTCs) and hair follicles to assess DNA damage response. Results: An MTD of 60 mg/m²/day was established for the daily regimen, compared to 90 mg/m² for the weekly regimen. The TopI response to drug showed target engagement in a subset of tumor biopsies. Pharmacokinetics profiles demonstrated a prolonged terminal half-life and tissue accumulation compared to topotecan. Dose-dependent decreases in total CTCs were measured in seven patients. Formation of γH2AX-positive foci in CTCs (day 3) and hair follicles (4–6 h) was observed following treatment. Conclusions: We established the MTD of two dosing schedules for a novel TopI inhibitor, indotecan. Target engagement was demonstrated as Top1 downregulation and γH2AX response. No objective responses were observed on either schedule in this small patient cohort. The principal toxicity of both schedules was myelosuppression; no significant gastrointestinal problems were observed. Increased DNA damage response was observed in CTCs, hair follicles, and a subset of tumor biopsies.

Original language	English (US)
Pages (from-to)	73-81
Number of pages	9
Journal	Cancer Chemotherapy and Pharmacology
Volume	78
Issue number	1
DOIs	https://doi.org/10.1007/s00280-016-2998-6
State	Published - Jul 1 2016
Externally published	Yes

Keywords

DNA damage
DNA topoisomerase I
H2AX protein
Hair follicle
Indenoisoquinolines
NSC 743400

ASJC Scopus subject areas

Oncology
Toxicology
Pharmacology
Cancer Research
Pharmacology (medical)

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10.1007/s00280-016-2998-6

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Kummar, S., Chen, A., Gutierrez, M., Pfister, T. D., Wang, L., Redon, C., Bonner, W. M., Yutzy, W., Zhang, Y., Kinders, R. J., Ji, J., Allen, D., Covey, J. M., Eiseman, J. L., Holleran, J. L., Beumer, J. H., Rubinstein, L., Collins, J., Tomaszewski, J., ... Doroshow, J. H. (2016). Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors. Cancer Chemotherapy and Pharmacology, 78(1), 73-81. https://doi.org/10.1007/s00280-016-2998-6

Kummar, S, Chen, A, Gutierrez, M, Pfister, TD, Wang, L, Redon, C, Bonner, WM, Yutzy, W, Zhang, Y, Kinders, RJ, Ji, J, Allen, D, Covey, JM, Eiseman, JL, Holleran, JL, Beumer, JH, Rubinstein, L, Collins, J, Tomaszewski, J, Parchment, R, Pommier, Y & Doroshow, JH 2016, 'Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors', Cancer Chemotherapy and Pharmacology, vol. 78, no. 1, pp. 73-81. https://doi.org/10.1007/s00280-016-2998-6

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title = "Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors",

abstract = "Purpose: Indenoisoquinolines are non-camptothecin topoisomerase I (TopI) inhibitors that overcome the limitations of camptothecins: chemical instability and camptothecin resistance. Two dosing schedules of the novel indenoisoquinoline, indotecan (LMP400), were evaluated in patients with advanced solid tumors. Methods: The maximum tolerated dose (MTD), toxicities, and pharmacokinetics of two indotecan drug administration schedules (daily for 5 days or weekly) were investigated. Modulation of TopI and the phosphorylation of histone H2AX (γH2AX) were assayed in tumor biopsies; γH2AX levels were also evaluated in circulating tumor cells (CTCs) and hair follicles to assess DNA damage response. Results: An MTD of 60 mg/m2/day was established for the daily regimen, compared to 90 mg/m2 for the weekly regimen. The TopI response to drug showed target engagement in a subset of tumor biopsies. Pharmacokinetics profiles demonstrated a prolonged terminal half-life and tissue accumulation compared to topotecan. Dose-dependent decreases in total CTCs were measured in seven patients. Formation of γH2AX-positive foci in CTCs (day 3) and hair follicles (4–6 h) was observed following treatment. Conclusions: We established the MTD of two dosing schedules for a novel TopI inhibitor, indotecan. Target engagement was demonstrated as Top1 downregulation and γH2AX response. No objective responses were observed on either schedule in this small patient cohort. The principal toxicity of both schedules was myelosuppression; no significant gastrointestinal problems were observed. Increased DNA damage response was observed in CTCs, hair follicles, and a subset of tumor biopsies.",

keywords = "DNA damage, DNA topoisomerase I, H2AX protein, Hair follicle, Indenoisoquinolines, NSC 743400",

author = "Shivaani Kummar and Alice Chen and Martin Gutierrez and Pfister, {Thomas D.} and Lihua Wang and Christophe Redon and Bonner, {William M.} and William Yutzy and Yiping Zhang and Kinders, {Robert J.} and Jiuping Ji and Deborah Allen and Covey, {Joseph M.} and Eiseman, {Julie L.} and Holleran, {Julianne L.} and Beumer, {Jan H.} and Larry Rubinstein and Jerry Collins and Joseph Tomaszewski and Ralph Parchment and Yves Pommier and Doroshow, {James H.}",

note = "Publisher Copyright: {\textcopyright} 2016, Springer-Verlag Berlin Heidelberg (outside the USA).",

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doi = "10.1007/s00280-016-2998-6",

language = "English (US)",

volume = "78",

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T1 - Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors

AU - Kummar, Shivaani

AU - Chen, Alice

AU - Gutierrez, Martin

AU - Pfister, Thomas D.

AU - Wang, Lihua

AU - Redon, Christophe

AU - Bonner, William M.

AU - Yutzy, William

AU - Zhang, Yiping

AU - Kinders, Robert J.

AU - Ji, Jiuping

AU - Allen, Deborah

AU - Covey, Joseph M.

AU - Eiseman, Julie L.

AU - Holleran, Julianne L.

AU - Beumer, Jan H.

AU - Rubinstein, Larry

AU - Collins, Jerry

AU - Tomaszewski, Joseph

AU - Parchment, Ralph

AU - Pommier, Yves

AU - Doroshow, James H.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - Purpose: Indenoisoquinolines are non-camptothecin topoisomerase I (TopI) inhibitors that overcome the limitations of camptothecins: chemical instability and camptothecin resistance. Two dosing schedules of the novel indenoisoquinoline, indotecan (LMP400), were evaluated in patients with advanced solid tumors. Methods: The maximum tolerated dose (MTD), toxicities, and pharmacokinetics of two indotecan drug administration schedules (daily for 5 days or weekly) were investigated. Modulation of TopI and the phosphorylation of histone H2AX (γH2AX) were assayed in tumor biopsies; γH2AX levels were also evaluated in circulating tumor cells (CTCs) and hair follicles to assess DNA damage response. Results: An MTD of 60 mg/m2/day was established for the daily regimen, compared to 90 mg/m2 for the weekly regimen. The TopI response to drug showed target engagement in a subset of tumor biopsies. Pharmacokinetics profiles demonstrated a prolonged terminal half-life and tissue accumulation compared to topotecan. Dose-dependent decreases in total CTCs were measured in seven patients. Formation of γH2AX-positive foci in CTCs (day 3) and hair follicles (4–6 h) was observed following treatment. Conclusions: We established the MTD of two dosing schedules for a novel TopI inhibitor, indotecan. Target engagement was demonstrated as Top1 downregulation and γH2AX response. No objective responses were observed on either schedule in this small patient cohort. The principal toxicity of both schedules was myelosuppression; no significant gastrointestinal problems were observed. Increased DNA damage response was observed in CTCs, hair follicles, and a subset of tumor biopsies.

AB - Purpose: Indenoisoquinolines are non-camptothecin topoisomerase I (TopI) inhibitors that overcome the limitations of camptothecins: chemical instability and camptothecin resistance. Two dosing schedules of the novel indenoisoquinoline, indotecan (LMP400), were evaluated in patients with advanced solid tumors. Methods: The maximum tolerated dose (MTD), toxicities, and pharmacokinetics of two indotecan drug administration schedules (daily for 5 days or weekly) were investigated. Modulation of TopI and the phosphorylation of histone H2AX (γH2AX) were assayed in tumor biopsies; γH2AX levels were also evaluated in circulating tumor cells (CTCs) and hair follicles to assess DNA damage response. Results: An MTD of 60 mg/m2/day was established for the daily regimen, compared to 90 mg/m2 for the weekly regimen. The TopI response to drug showed target engagement in a subset of tumor biopsies. Pharmacokinetics profiles demonstrated a prolonged terminal half-life and tissue accumulation compared to topotecan. Dose-dependent decreases in total CTCs were measured in seven patients. Formation of γH2AX-positive foci in CTCs (day 3) and hair follicles (4–6 h) was observed following treatment. Conclusions: We established the MTD of two dosing schedules for a novel TopI inhibitor, indotecan. Target engagement was demonstrated as Top1 downregulation and γH2AX response. No objective responses were observed on either schedule in this small patient cohort. The principal toxicity of both schedules was myelosuppression; no significant gastrointestinal problems were observed. Increased DNA damage response was observed in CTCs, hair follicles, and a subset of tumor biopsies.

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KW - H2AX protein

KW - Hair follicle

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KW - NSC 743400

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Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors

Abstract

Keywords

ASJC Scopus subject areas

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