A phase i clinical trial of the Poly(ADP-ribose) polymerase inhibitor veliparib and weekly topotecan in patients with solid tumors

Andrea E Wahner Hendrickson, Michael E. Menefee, Lynn C. Hartmann, Harry J. Long, Donald W Northfelt, Joel M Reid, Felix Boakye-Agyeman, Olumide Kayode, Karen S. Flatten, Maria I. Harrell, Elizabeth M. Swisher, Guy G. Poirer, Daniel Satele, Jake Allred, Janet L. Lensing, Alice Chen, Jiuping Ji, Yiping Zang, Charles Erlichman, Paul Haluska & 1 others Scott H Kaufmann

Research output: Contribution to journalArticle

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Abstract

Purpose: To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome. Experimental Design: Eligible patients had metastatic nonhematologic malignancies with measurable disease. Using a 3 þ 3 design, patients were treated with veliparib orally twice daily on days 1–3, 8–10, and 15–17 and topotecan intravenously on days 2, 9, and 16 every 28 days. Tumor responses were assessed by RECIST. Results: Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1–3, 8–10, and 15–17 along with topotecan 3 mg/m2 on days 2, 9, and 16 of a 28-day cycle. DLTs were grade 4 neutropenia lasting >5 days. The median number of cycles was 2 (1–26). The objective response rate was 10%, with 1 complete and 4 partial responses. Twenty-two patients (42%) had stable disease ranging from 4 to 26 cycles. Patients with germline BRCA1, BRCA2, or RAD51D mutations remained on study longer than those without homologous recombination repair (HRR) gene mutations (median 4 vs. 2 cycles). Conclusions: Weekly topotecan in combination with veliparib has a manageable safety profile and appears to warrant further investigation.

Original languageEnglish (US)
Pages (from-to)744-752
Number of pages9
JournalClinical Cancer Research
Volume24
Issue number4
DOIs
StatePublished - Feb 15 2018

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Topotecan
Clinical Trials
Neoplasms
Maximum Tolerated Dose
Mutation
Poly Adenosine Diphosphate Ribose
Recombinational DNA Repair
Neutropenia
Genes
veliparib
Poly(ADP-ribose) Polymerase Inhibitors
Blood Cells
Research Design
Pharmacokinetics
Safety
Serum

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A phase i clinical trial of the Poly(ADP-ribose) polymerase inhibitor veliparib and weekly topotecan in patients with solid tumors. / Wahner Hendrickson, Andrea E; Menefee, Michael E.; Hartmann, Lynn C.; Long, Harry J.; Northfelt, Donald W; Reid, Joel M; Boakye-Agyeman, Felix; Kayode, Olumide; Flatten, Karen S.; Harrell, Maria I.; Swisher, Elizabeth M.; Poirer, Guy G.; Satele, Daniel; Allred, Jake; Lensing, Janet L.; Chen, Alice; Ji, Jiuping; Zang, Yiping; Erlichman, Charles; Haluska, Paul; Kaufmann, Scott H.

In: Clinical Cancer Research, Vol. 24, No. 4, 15.02.2018, p. 744-752.

Research output: Contribution to journalArticle

Wahner Hendrickson, AE, Menefee, ME, Hartmann, LC, Long, HJ, Northfelt, DW, Reid, JM, Boakye-Agyeman, F, Kayode, O, Flatten, KS, Harrell, MI, Swisher, EM, Poirer, GG, Satele, D, Allred, J, Lensing, JL, Chen, A, Ji, J, Zang, Y, Erlichman, C, Haluska, P & Kaufmann, SH 2018, 'A phase i clinical trial of the Poly(ADP-ribose) polymerase inhibitor veliparib and weekly topotecan in patients with solid tumors', Clinical Cancer Research, vol. 24, no. 4, pp. 744-752. https://doi.org/10.1158/1078-0432.CCR-17-1590
Wahner Hendrickson, Andrea E ; Menefee, Michael E. ; Hartmann, Lynn C. ; Long, Harry J. ; Northfelt, Donald W ; Reid, Joel M ; Boakye-Agyeman, Felix ; Kayode, Olumide ; Flatten, Karen S. ; Harrell, Maria I. ; Swisher, Elizabeth M. ; Poirer, Guy G. ; Satele, Daniel ; Allred, Jake ; Lensing, Janet L. ; Chen, Alice ; Ji, Jiuping ; Zang, Yiping ; Erlichman, Charles ; Haluska, Paul ; Kaufmann, Scott H. / A phase i clinical trial of the Poly(ADP-ribose) polymerase inhibitor veliparib and weekly topotecan in patients with solid tumors. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 4. pp. 744-752.
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abstract = "Purpose: To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome. Experimental Design: Eligible patients had metastatic nonhematologic malignancies with measurable disease. Using a 3 {\th} 3 design, patients were treated with veliparib orally twice daily on days 1–3, 8–10, and 15–17 and topotecan intravenously on days 2, 9, and 16 every 28 days. Tumor responses were assessed by RECIST. Results: Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1–3, 8–10, and 15–17 along with topotecan 3 mg/m2 on days 2, 9, and 16 of a 28-day cycle. DLTs were grade 4 neutropenia lasting >5 days. The median number of cycles was 2 (1–26). The objective response rate was 10{\%}, with 1 complete and 4 partial responses. Twenty-two patients (42{\%}) had stable disease ranging from 4 to 26 cycles. Patients with germline BRCA1, BRCA2, or RAD51D mutations remained on study longer than those without homologous recombination repair (HRR) gene mutations (median 4 vs. 2 cycles). Conclusions: Weekly topotecan in combination with veliparib has a manageable safety profile and appears to warrant further investigation.",
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T1 - A phase i clinical trial of the Poly(ADP-ribose) polymerase inhibitor veliparib and weekly topotecan in patients with solid tumors

AU - Wahner Hendrickson, Andrea E

AU - Menefee, Michael E.

AU - Hartmann, Lynn C.

AU - Long, Harry J.

AU - Northfelt, Donald W

AU - Reid, Joel M

AU - Boakye-Agyeman, Felix

AU - Kayode, Olumide

AU - Flatten, Karen S.

AU - Harrell, Maria I.

AU - Swisher, Elizabeth M.

AU - Poirer, Guy G.

AU - Satele, Daniel

AU - Allred, Jake

AU - Lensing, Janet L.

AU - Chen, Alice

AU - Ji, Jiuping

AU - Zang, Yiping

AU - Erlichman, Charles

AU - Haluska, Paul

AU - Kaufmann, Scott H

PY - 2018/2/15

Y1 - 2018/2/15

N2 - Purpose: To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome. Experimental Design: Eligible patients had metastatic nonhematologic malignancies with measurable disease. Using a 3 þ 3 design, patients were treated with veliparib orally twice daily on days 1–3, 8–10, and 15–17 and topotecan intravenously on days 2, 9, and 16 every 28 days. Tumor responses were assessed by RECIST. Results: Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1–3, 8–10, and 15–17 along with topotecan 3 mg/m2 on days 2, 9, and 16 of a 28-day cycle. DLTs were grade 4 neutropenia lasting >5 days. The median number of cycles was 2 (1–26). The objective response rate was 10%, with 1 complete and 4 partial responses. Twenty-two patients (42%) had stable disease ranging from 4 to 26 cycles. Patients with germline BRCA1, BRCA2, or RAD51D mutations remained on study longer than those without homologous recombination repair (HRR) gene mutations (median 4 vs. 2 cycles). Conclusions: Weekly topotecan in combination with veliparib has a manageable safety profile and appears to warrant further investigation.

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