Safety, pharmacokinetics, and activity of EZN-2208, a novel conjugate of polyethylene glycol and SN38, in patients with advanced malignancies

Razelle Kurzrock, Sanjay Goel, Jennifer Wheler, David Hong, Siqing Fu, Keyvan Rezai, Sonia K. Morgan-Linnell, Saik Urien, Sridhar Mani, Imran Chaudhary, Mohammed H. Ghalib, Aby Buchbinder, François Lokiec, Mary Mulcahy

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: EZN-2208 is a water-soluble, polyethylene glycol drug conjugate of SN38, which is the active moiety of irinotecan. In this study, the authors evaluated the tolerability, pharmacokinetics (PK), and activity of EZN-2208 in adult patients with advanced solid tumors. METHODS: Patients in sequential cohorts (3 + 3 design) received intravenous EZN-2208 at doses between 1.25 mg/m2 and 25 mg/m2 once every 21 days. RESULTS: Thirty-nine patients received EZN-2208. The median number of prior therapies was 2 (range, 0-10 prior therapies). Seventeen patients received prior irinotecan. Two maximum tolerated doses (MTDs) were defined: EZN-2208 with (16.5 mg/m 2) and without (10 mg/m2) granulocyte-colony-stimulating factor (G-CSF). The dose-limiting toxicity (DLT) was febrile neutropenia. Two of 19 patients who were heterozygous for a polymorphism in the uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) gene (UGT1A1*28) developed DLTs (dose, 25 mg/m2 with G-CSF), and 2 patients who were homozygous for UGT1A1*28 were treated without DLTs (dose, 5 mg/m2). PK analysis indicated a mean terminal half-life of 19.4 ± 3.4 hours. Sixteen patients (41%) achieved stable disease, including 6 of 39 patients (15%) who had stable disease that lasted ≥4 months. One patient with cholangiocarcinoma (no prior irinotecan) achieved a short-lived 32% tumor regression. Among 6 patients who had stable disease that lasted for ≥4 months, 3 had received prior irinotecan, and 1 had KRAS-positive colorectal cancer. CONCLUSIONS: EZN-2208 was well tolerated and produced stable disease that lasted for ≥4 months/unconfirmed partial responses in 7 of 39 heavily pretreated patients (18%) with advanced solid tumors, including those who had failed prior irinotecan therapy.

Original languageEnglish (US)
Pages (from-to)6144
Number of pages1
JournalCancer
Volume118
Issue number24
DOIs
StatePublished - Dec 15 2012

Fingerprint

irinotecan
Pharmacokinetics
Safety
Neoplasms
Glucuronosyltransferase
Uridine Diphosphate
Granulocyte Colony-Stimulating Factor
Peptides
EZN-2208
Febrile Neutropenia
Maximum Tolerated Dose
Cholangiocarcinoma
Granulocyte-Macrophage Colony-Stimulating Factor
Half-Life
Colorectal Neoplasms
Therapeutics

Keywords

  • camptothecins
  • EZN-2208
  • phase 1
  • SN38
  • topoisomerase I

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Safety, pharmacokinetics, and activity of EZN-2208, a novel conjugate of polyethylene glycol and SN38, in patients with advanced malignancies. / Kurzrock, Razelle; Goel, Sanjay; Wheler, Jennifer; Hong, David; Fu, Siqing; Rezai, Keyvan; Morgan-Linnell, Sonia K.; Urien, Saik; Mani, Sridhar; Chaudhary, Imran; Ghalib, Mohammed H.; Buchbinder, Aby; Lokiec, François; Mulcahy, Mary.

In: Cancer, Vol. 118, No. 24, 15.12.2012, p. 6144.

Research output: Contribution to journalArticle

Kurzrock, R, Goel, S, Wheler, J, Hong, D, Fu, S, Rezai, K, Morgan-Linnell, SK, Urien, S, Mani, S, Chaudhary, I, Ghalib, MH, Buchbinder, A, Lokiec, F & Mulcahy, M 2012, 'Safety, pharmacokinetics, and activity of EZN-2208, a novel conjugate of polyethylene glycol and SN38, in patients with advanced malignancies', Cancer, vol. 118, no. 24, pp. 6144. https://doi.org/10.1002/cncr.27647
Kurzrock, Razelle ; Goel, Sanjay ; Wheler, Jennifer ; Hong, David ; Fu, Siqing ; Rezai, Keyvan ; Morgan-Linnell, Sonia K. ; Urien, Saik ; Mani, Sridhar ; Chaudhary, Imran ; Ghalib, Mohammed H. ; Buchbinder, Aby ; Lokiec, François ; Mulcahy, Mary. / Safety, pharmacokinetics, and activity of EZN-2208, a novel conjugate of polyethylene glycol and SN38, in patients with advanced malignancies. In: Cancer. 2012 ; Vol. 118, No. 24. pp. 6144.
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abstract = "BACKGROUND: EZN-2208 is a water-soluble, polyethylene glycol drug conjugate of SN38, which is the active moiety of irinotecan. In this study, the authors evaluated the tolerability, pharmacokinetics (PK), and activity of EZN-2208 in adult patients with advanced solid tumors. METHODS: Patients in sequential cohorts (3 + 3 design) received intravenous EZN-2208 at doses between 1.25 mg/m2 and 25 mg/m2 once every 21 days. RESULTS: Thirty-nine patients received EZN-2208. The median number of prior therapies was 2 (range, 0-10 prior therapies). Seventeen patients received prior irinotecan. Two maximum tolerated doses (MTDs) were defined: EZN-2208 with (16.5 mg/m 2) and without (10 mg/m2) granulocyte-colony-stimulating factor (G-CSF). The dose-limiting toxicity (DLT) was febrile neutropenia. Two of 19 patients who were heterozygous for a polymorphism in the uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) gene (UGT1A1*28) developed DLTs (dose, 25 mg/m2 with G-CSF), and 2 patients who were homozygous for UGT1A1*28 were treated without DLTs (dose, 5 mg/m2). PK analysis indicated a mean terminal half-life of 19.4 ± 3.4 hours. Sixteen patients (41{\%}) achieved stable disease, including 6 of 39 patients (15{\%}) who had stable disease that lasted ≥4 months. One patient with cholangiocarcinoma (no prior irinotecan) achieved a short-lived 32{\%} tumor regression. Among 6 patients who had stable disease that lasted for ≥4 months, 3 had received prior irinotecan, and 1 had KRAS-positive colorectal cancer. CONCLUSIONS: EZN-2208 was well tolerated and produced stable disease that lasted for ≥4 months/unconfirmed partial responses in 7 of 39 heavily pretreated patients (18{\%}) with advanced solid tumors, including those who had failed prior irinotecan therapy.",
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AU - Goel, Sanjay

AU - Wheler, Jennifer

AU - Hong, David

AU - Fu, Siqing

AU - Rezai, Keyvan

AU - Morgan-Linnell, Sonia K.

AU - Urien, Saik

AU - Mani, Sridhar

AU - Chaudhary, Imran

AU - Ghalib, Mohammed H.

AU - Buchbinder, Aby

AU - Lokiec, François

AU - Mulcahy, Mary

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N2 - BACKGROUND: EZN-2208 is a water-soluble, polyethylene glycol drug conjugate of SN38, which is the active moiety of irinotecan. In this study, the authors evaluated the tolerability, pharmacokinetics (PK), and activity of EZN-2208 in adult patients with advanced solid tumors. METHODS: Patients in sequential cohorts (3 + 3 design) received intravenous EZN-2208 at doses between 1.25 mg/m2 and 25 mg/m2 once every 21 days. RESULTS: Thirty-nine patients received EZN-2208. The median number of prior therapies was 2 (range, 0-10 prior therapies). Seventeen patients received prior irinotecan. Two maximum tolerated doses (MTDs) were defined: EZN-2208 with (16.5 mg/m 2) and without (10 mg/m2) granulocyte-colony-stimulating factor (G-CSF). The dose-limiting toxicity (DLT) was febrile neutropenia. Two of 19 patients who were heterozygous for a polymorphism in the uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) gene (UGT1A1*28) developed DLTs (dose, 25 mg/m2 with G-CSF), and 2 patients who were homozygous for UGT1A1*28 were treated without DLTs (dose, 5 mg/m2). PK analysis indicated a mean terminal half-life of 19.4 ± 3.4 hours. Sixteen patients (41%) achieved stable disease, including 6 of 39 patients (15%) who had stable disease that lasted ≥4 months. One patient with cholangiocarcinoma (no prior irinotecan) achieved a short-lived 32% tumor regression. Among 6 patients who had stable disease that lasted for ≥4 months, 3 had received prior irinotecan, and 1 had KRAS-positive colorectal cancer. CONCLUSIONS: EZN-2208 was well tolerated and produced stable disease that lasted for ≥4 months/unconfirmed partial responses in 7 of 39 heavily pretreated patients (18%) with advanced solid tumors, including those who had failed prior irinotecan therapy.

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