A phase Ib study of sorafenib (BAY 43-9006) in patients with Kaposi sarcoma

Thomas S. Uldrick; Priscila H. Gonçalves; Kathleen M. Wyvill; Cody J. Peer; Wendy Bernstein; Karen Aleman; Mark N. Polizzotto; David Venzon; Seth M. Steinberg; Vickie Marshall; Denise Whitby; Richard F. Little; John J. Wright; Michelle A. Rudek; William D. Figg; Robert Yarchoan

doi:10.1634/theoncologist.2016-0486

A phase Ib study of sorafenib (BAY 43-9006) in patients with Kaposi sarcoma

Thomas S. Uldrick, Priscila H. Gonçalves, Kathleen M. Wyvill, Cody J. Peer, Wendy Bernstein, Karen Aleman, Mark N. Polizzotto, David Venzon, Seth M. Steinberg, Vickie Marshall, Denise Whitby, Richard F. Little, John J. Wright, Michelle A. Rudek, William D. Figg, Robert Yarchoan

School of Medicine

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

6 Scopus citations

Abstract

Background. We conducted a phase Ib study of sorafenib, a vascular epithelial growth factor receptor (VEGFR), c-kit, and platelet derived growth factor receptor (PDGFR)-targeted treatment in Kaposi sarcoma (KS). We evaluated drug-drug interactions between sorafenib and ritonavir, an HIV medication with strong CYP3A4 inhibitory activity. Methods. Two cohorts were enrolled: HIV-related KS on ritonavir (Cohort R) and HIV-related or classical KS not receiving ritonavir (Cohort NR). Sorafenib dose level 1 in cohort R (R1) was 200 mg daily and 200 mg every 12 hours in cohort NR (NR1). Steady-state pharmacokinetics were evaluated at cycle 1, day 8. KS responses and correlative factors were assessed. Results. Ten patients (nine HIV⁺) were enrolled: R1 (eight), NR1 (two). Median CD4⁺ count (HIV⁺) was 500 cells/µL. Dose-limiting toxicities (DLTs) were grade 3 elevated lipase (R1), grade 4 thrombocytopenia (R1), and grade 3 hand-foot syndrome (NR1). Two of seven evaluable patients had a partial response (PR; 29%; 95% CI 4%-71%). Steady-state area under the curve of the dosing interval (AUC_TAU) of sorafenib was not significantly affected by ritonavir; however, a trend for decreased AUC_TAU of the CYP3A4 metabolite sorafenib-Noxide (3.8-fold decrease; p=.08) suggests other metabolites may be increased. Conclusion. Sorafenib was poorly tolerated, and anti-KS activity was modest. Strong CYP3A4 inhibitors may contribute to sorafenib toxicity, and ritonavir has previously been shown to be a CYP3A4 inhibitor. Alternate antiretroviral agents without predicted interactions should be used when possible for concurrent administration with sorafenib.

Original language	English (US)
Pages (from-to)	505-e49
Journal	Oncologist
Volume	22
Issue number	5
DOIs	https://doi.org/10.1634/theoncologist.2016-0486
State	Published - May 2017

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1634/theoncologist.2016-0486

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Uldrick, T. S., Gonçalves, P. H., Wyvill, K. M., Peer, C. J., Bernstein, W., Aleman, K., Polizzotto, M. N., Venzon, D., Steinberg, S. M., Marshall, V., Whitby, D., Little, R. F., Wright, J. J., Rudek, M. A., Figg, W. D., & Yarchoan, R. (2017). A phase Ib study of sorafenib (BAY 43-9006) in patients with Kaposi sarcoma. Oncologist, 22(5), 505-e49. https://doi.org/10.1634/theoncologist.2016-0486

Uldrick, TS, Gonçalves, PH, Wyvill, KM, Peer, CJ, Bernstein, W, Aleman, K, Polizzotto, MN, Venzon, D, Steinberg, SM, Marshall, V, Whitby, D, Little, RF, Wright, JJ, Rudek, MA, Figg, WD & Yarchoan, R 2017, 'A phase Ib study of sorafenib (BAY 43-9006) in patients with Kaposi sarcoma', Oncologist, vol. 22, no. 5, pp. 505-e49. https://doi.org/10.1634/theoncologist.2016-0486

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title = "A phase Ib study of sorafenib (BAY 43-9006) in patients with Kaposi sarcoma",

abstract = "Background. We conducted a phase Ib study of sorafenib, a vascular epithelial growth factor receptor (VEGFR), c-kit, and platelet derived growth factor receptor (PDGFR)-targeted treatment in Kaposi sarcoma (KS). We evaluated drug-drug interactions between sorafenib and ritonavir, an HIV medication with strong CYP3A4 inhibitory activity. Methods. Two cohorts were enrolled: HIV-related KS on ritonavir (Cohort R) and HIV-related or classical KS not receiving ritonavir (Cohort NR). Sorafenib dose level 1 in cohort R (R1) was 200 mg daily and 200 mg every 12 hours in cohort NR (NR1). Steady-state pharmacokinetics were evaluated at cycle 1, day 8. KS responses and correlative factors were assessed. Results. Ten patients (nine HIV+) were enrolled: R1 (eight), NR1 (two). Median CD4+ count (HIV+) was 500 cells/µL. Dose-limiting toxicities (DLTs) were grade 3 elevated lipase (R1), grade 4 thrombocytopenia (R1), and grade 3 hand-foot syndrome (NR1). Two of seven evaluable patients had a partial response (PR; 29%; 95% CI 4%-71%). Steady-state area under the curve of the dosing interval (AUCTAU) of sorafenib was not significantly affected by ritonavir; however, a trend for decreased AUCTAU of the CYP3A4 metabolite sorafenib-Noxide (3.8-fold decrease; p=.08) suggests other metabolites may be increased. Conclusion. Sorafenib was poorly tolerated, and anti-KS activity was modest. Strong CYP3A4 inhibitors may contribute to sorafenib toxicity, and ritonavir has previously been shown to be a CYP3A4 inhibitor. Alternate antiretroviral agents without predicted interactions should be used when possible for concurrent administration with sorafenib.",

author = "Uldrick, {Thomas S.} and Gon{\c c}alves, {Priscila H.} and Wyvill, {Kathleen M.} and Peer, {Cody J.} and Wendy Bernstein and Karen Aleman and Polizzotto, {Mark N.} and David Venzon and Steinberg, {Seth M.} and Vickie Marshall and Denise Whitby and Little, {Richard F.} and Wright, {John J.} and Rudek, {Michelle A.} and Figg, {William D.} and Robert Yarchoan",

note = "Funding Information: This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute and gift funds from Johns Hopkins University. Further support was provided by a Clinical Trials Agreement between Bayer Health Care Corporation and the NCI Cancer Therapy Evaluation Program and by NCI Contract No. HHSN261200800001E. We thank the patients who volunteered to participate; the medical, nursing, and support staffs of the HIV and AIDS Malignancy Branch, the Medical Oncology Service, and the NIH Clinical Center; and Adam Rupert and Randy Stevens and colleagues in Leidos, NCI-Frederick, Frederick, Maryland. Publisher Copyright: {\textcopyright} AlphaMedPress.",

year = "2017",

month = may,

doi = "10.1634/theoncologist.2016-0486",

language = "English (US)",

volume = "22",

pages = "505--e49",

journal = "Oncologist",

issn = "1083-7159",

publisher = "AlphaMed Press",

number = "5",

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TY - JOUR

T1 - A phase Ib study of sorafenib (BAY 43-9006) in patients with Kaposi sarcoma

AU - Uldrick, Thomas S.

AU - Gonçalves, Priscila H.

AU - Wyvill, Kathleen M.

AU - Peer, Cody J.

AU - Bernstein, Wendy

AU - Aleman, Karen

AU - Polizzotto, Mark N.

AU - Venzon, David

AU - Steinberg, Seth M.

AU - Marshall, Vickie

AU - Whitby, Denise

AU - Little, Richard F.

AU - Wright, John J.

AU - Rudek, Michelle A.

AU - Figg, William D.

AU - Yarchoan, Robert

N1 - Funding Information: This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute and gift funds from Johns Hopkins University. Further support was provided by a Clinical Trials Agreement between Bayer Health Care Corporation and the NCI Cancer Therapy Evaluation Program and by NCI Contract No. HHSN261200800001E. We thank the patients who volunteered to participate; the medical, nursing, and support staffs of the HIV and AIDS Malignancy Branch, the Medical Oncology Service, and the NIH Clinical Center; and Adam Rupert and Randy Stevens and colleagues in Leidos, NCI-Frederick, Frederick, Maryland. Publisher Copyright: © AlphaMedPress.

PY - 2017/5

Y1 - 2017/5

N2 - Background. We conducted a phase Ib study of sorafenib, a vascular epithelial growth factor receptor (VEGFR), c-kit, and platelet derived growth factor receptor (PDGFR)-targeted treatment in Kaposi sarcoma (KS). We evaluated drug-drug interactions between sorafenib and ritonavir, an HIV medication with strong CYP3A4 inhibitory activity. Methods. Two cohorts were enrolled: HIV-related KS on ritonavir (Cohort R) and HIV-related or classical KS not receiving ritonavir (Cohort NR). Sorafenib dose level 1 in cohort R (R1) was 200 mg daily and 200 mg every 12 hours in cohort NR (NR1). Steady-state pharmacokinetics were evaluated at cycle 1, day 8. KS responses and correlative factors were assessed. Results. Ten patients (nine HIV+) were enrolled: R1 (eight), NR1 (two). Median CD4+ count (HIV+) was 500 cells/µL. Dose-limiting toxicities (DLTs) were grade 3 elevated lipase (R1), grade 4 thrombocytopenia (R1), and grade 3 hand-foot syndrome (NR1). Two of seven evaluable patients had a partial response (PR; 29%; 95% CI 4%-71%). Steady-state area under the curve of the dosing interval (AUCTAU) of sorafenib was not significantly affected by ritonavir; however, a trend for decreased AUCTAU of the CYP3A4 metabolite sorafenib-Noxide (3.8-fold decrease; p=.08) suggests other metabolites may be increased. Conclusion. Sorafenib was poorly tolerated, and anti-KS activity was modest. Strong CYP3A4 inhibitors may contribute to sorafenib toxicity, and ritonavir has previously been shown to be a CYP3A4 inhibitor. Alternate antiretroviral agents without predicted interactions should be used when possible for concurrent administration with sorafenib.

AB - Background. We conducted a phase Ib study of sorafenib, a vascular epithelial growth factor receptor (VEGFR), c-kit, and platelet derived growth factor receptor (PDGFR)-targeted treatment in Kaposi sarcoma (KS). We evaluated drug-drug interactions between sorafenib and ritonavir, an HIV medication with strong CYP3A4 inhibitory activity. Methods. Two cohorts were enrolled: HIV-related KS on ritonavir (Cohort R) and HIV-related or classical KS not receiving ritonavir (Cohort NR). Sorafenib dose level 1 in cohort R (R1) was 200 mg daily and 200 mg every 12 hours in cohort NR (NR1). Steady-state pharmacokinetics were evaluated at cycle 1, day 8. KS responses and correlative factors were assessed. Results. Ten patients (nine HIV+) were enrolled: R1 (eight), NR1 (two). Median CD4+ count (HIV+) was 500 cells/µL. Dose-limiting toxicities (DLTs) were grade 3 elevated lipase (R1), grade 4 thrombocytopenia (R1), and grade 3 hand-foot syndrome (NR1). Two of seven evaluable patients had a partial response (PR; 29%; 95% CI 4%-71%). Steady-state area under the curve of the dosing interval (AUCTAU) of sorafenib was not significantly affected by ritonavir; however, a trend for decreased AUCTAU of the CYP3A4 metabolite sorafenib-Noxide (3.8-fold decrease; p=.08) suggests other metabolites may be increased. Conclusion. Sorafenib was poorly tolerated, and anti-KS activity was modest. Strong CYP3A4 inhibitors may contribute to sorafenib toxicity, and ritonavir has previously been shown to be a CYP3A4 inhibitor. Alternate antiretroviral agents without predicted interactions should be used when possible for concurrent administration with sorafenib.

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A phase Ib study of sorafenib (BAY 43-9006) in patients with Kaposi sarcoma

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