Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: A randomised phase 2 study

Ahmad Awada, Agustin A. Garcia, Stephen Chan, Guy H M Jerusalem, Robert E. Coleman, Manon T. Huizing, Aminder Mehdi, Sue M. O'Reilly, John T. Hamm, Peter J. Barrett-Lee, Veronique Cocquyt, Kostandinos Sideras, David E. Young, Carol Zhao, Yen Lin Chia, Ute Hoch, Alison L. Hannah, Edith A. Perez

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Abstract

Background: New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials. Methods: In this randomised, two-stage, open-label phase 2 trial, we recruited patients aged 18 years or older who had received taxane therapy and undergone two or fewer previous chemotherapy regimens for metastatic breast cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from 18 sites in three countries. Eligible patients were randomly assigned (1:1) to etirinotecan pegol 145 mg/m2 every 14 days or every 21 days. The primary endpoint was the proportion of patients with a confirmed objective response as defined by Response Evaluation Criteria in Solid Tumors version 1.0, analysed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT00802945. Findings: 70 patients (35 in each group) were randomly assigned to treatment between Feb 17, 2009 and April 13, 2010. Of the 70 patients, 20 (29%; 95% CI 18·4-40·6) achieved an objective response (two [3%] had a complete response and 18 [26%] had a partial response). Ten patients on the 14-day schedule achieved an objective response (29%; 95% CI 14·6-46·3; eight partial responses, two complete responses) as did ten on the 21-day schedule (29%; 95% CI 14·6-46·3; all partial responses). The most common grade 3 or worse adverse events were delayed diarrhoea (seven [20%] of 35 patients on the 14-day schedule vs eight [23%] of 35 patients on the 21-day schedule), fatigue (five [14%] vs three [9%]), neutropenia (four [11%] vs four [11%]), and dehydration (three [9%] vs four [11%]); 14 [20%] patients discontinued treatment because of drug-related toxicity. There were two possible drug-related deaths (acute renal failure and septic shock) in the 14-day group; other drug-related serious adverse events reported by more than one patient included ten [14%] patients with diarrhoea (six [17%] patients on the 14-day schedule vs four [11%] on the 21-day schedule), six [9%] with dehydration (two [6%] vs four [11%]), two [3%] with nausea (two [6%] vs none), and two [3%] with vomiting (two [6%] vs none). Interpretation: On the basis of the overall clinical data, pharmacokinetics, and tolerability profile, etirinotecan pegol 145 mg/m2 every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer. Funding: Nektar Therapeutics.

Original languageEnglish (US)
Pages (from-to)1216-1225
Number of pages10
JournalThe Lancet Oncology
Volume14
Issue number12
DOIs
StatePublished - Nov 2013

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Appointments and Schedules
Breast Neoplasms
etirinotecan pegol
Dehydration
Diarrhea
Therapeutics
Pharmaceutical Preparations
Topoisomerase I Inhibitors
Safety
Septic Shock
Neutropenia
Drug-Related Side Effects and Adverse Reactions
Acute Kidney Injury
Nausea
Vomiting
Fatigue
Pharmacokinetics
Physicians
Drug Therapy

ASJC Scopus subject areas

  • Oncology

Cite this

Awada, A., Garcia, A. A., Chan, S., Jerusalem, G. H. M., Coleman, R. E., Huizing, M. T., ... Perez, E. A. (2013). Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: A randomised phase 2 study. The Lancet Oncology, 14(12), 1216-1225. https://doi.org/10.1016/S1470-2045(13)70429-7

Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer : A randomised phase 2 study. / Awada, Ahmad; Garcia, Agustin A.; Chan, Stephen; Jerusalem, Guy H M; Coleman, Robert E.; Huizing, Manon T.; Mehdi, Aminder; O'Reilly, Sue M.; Hamm, John T.; Barrett-Lee, Peter J.; Cocquyt, Veronique; Sideras, Kostandinos; Young, David E.; Zhao, Carol; Chia, Yen Lin; Hoch, Ute; Hannah, Alison L.; Perez, Edith A.

In: The Lancet Oncology, Vol. 14, No. 12, 11.2013, p. 1216-1225.

Research output: Contribution to journalArticle

Awada, A, Garcia, AA, Chan, S, Jerusalem, GHM, Coleman, RE, Huizing, MT, Mehdi, A, O'Reilly, SM, Hamm, JT, Barrett-Lee, PJ, Cocquyt, V, Sideras, K, Young, DE, Zhao, C, Chia, YL, Hoch, U, Hannah, AL & Perez, EA 2013, 'Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: A randomised phase 2 study', The Lancet Oncology, vol. 14, no. 12, pp. 1216-1225. https://doi.org/10.1016/S1470-2045(13)70429-7
Awada, Ahmad ; Garcia, Agustin A. ; Chan, Stephen ; Jerusalem, Guy H M ; Coleman, Robert E. ; Huizing, Manon T. ; Mehdi, Aminder ; O'Reilly, Sue M. ; Hamm, John T. ; Barrett-Lee, Peter J. ; Cocquyt, Veronique ; Sideras, Kostandinos ; Young, David E. ; Zhao, Carol ; Chia, Yen Lin ; Hoch, Ute ; Hannah, Alison L. ; Perez, Edith A. / Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer : A randomised phase 2 study. In: The Lancet Oncology. 2013 ; Vol. 14, No. 12. pp. 1216-1225.
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abstract = "Background: New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials. Methods: In this randomised, two-stage, open-label phase 2 trial, we recruited patients aged 18 years or older who had received taxane therapy and undergone two or fewer previous chemotherapy regimens for metastatic breast cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from 18 sites in three countries. Eligible patients were randomly assigned (1:1) to etirinotecan pegol 145 mg/m2 every 14 days or every 21 days. The primary endpoint was the proportion of patients with a confirmed objective response as defined by Response Evaluation Criteria in Solid Tumors version 1.0, analysed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT00802945. Findings: 70 patients (35 in each group) were randomly assigned to treatment between Feb 17, 2009 and April 13, 2010. Of the 70 patients, 20 (29{\%}; 95{\%} CI 18·4-40·6) achieved an objective response (two [3{\%}] had a complete response and 18 [26{\%}] had a partial response). Ten patients on the 14-day schedule achieved an objective response (29{\%}; 95{\%} CI 14·6-46·3; eight partial responses, two complete responses) as did ten on the 21-day schedule (29{\%}; 95{\%} CI 14·6-46·3; all partial responses). The most common grade 3 or worse adverse events were delayed diarrhoea (seven [20{\%}] of 35 patients on the 14-day schedule vs eight [23{\%}] of 35 patients on the 21-day schedule), fatigue (five [14{\%}] vs three [9{\%}]), neutropenia (four [11{\%}] vs four [11{\%}]), and dehydration (three [9{\%}] vs four [11{\%}]); 14 [20{\%}] patients discontinued treatment because of drug-related toxicity. There were two possible drug-related deaths (acute renal failure and septic shock) in the 14-day group; other drug-related serious adverse events reported by more than one patient included ten [14{\%}] patients with diarrhoea (six [17{\%}] patients on the 14-day schedule vs four [11{\%}] on the 21-day schedule), six [9{\%}] with dehydration (two [6{\%}] vs four [11{\%}]), two [3{\%}] with nausea (two [6{\%}] vs none), and two [3{\%}] with vomiting (two [6{\%}] vs none). Interpretation: On the basis of the overall clinical data, pharmacokinetics, and tolerability profile, etirinotecan pegol 145 mg/m2 every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer. Funding: Nektar Therapeutics.",
author = "Ahmad Awada and Garcia, {Agustin A.} and Stephen Chan and Jerusalem, {Guy H M} and Coleman, {Robert E.} and Huizing, {Manon T.} and Aminder Mehdi and O'Reilly, {Sue M.} and Hamm, {John T.} and Barrett-Lee, {Peter J.} and Veronique Cocquyt and Kostandinos Sideras and Young, {David E.} and Carol Zhao and Chia, {Yen Lin} and Ute Hoch and Hannah, {Alison L.} and Perez, {Edith A.}",
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TY - JOUR

T1 - Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer

T2 - A randomised phase 2 study

AU - Awada, Ahmad

AU - Garcia, Agustin A.

AU - Chan, Stephen

AU - Jerusalem, Guy H M

AU - Coleman, Robert E.

AU - Huizing, Manon T.

AU - Mehdi, Aminder

AU - O'Reilly, Sue M.

AU - Hamm, John T.

AU - Barrett-Lee, Peter J.

AU - Cocquyt, Veronique

AU - Sideras, Kostandinos

AU - Young, David E.

AU - Zhao, Carol

AU - Chia, Yen Lin

AU - Hoch, Ute

AU - Hannah, Alison L.

AU - Perez, Edith A.

PY - 2013/11

Y1 - 2013/11

N2 - Background: New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials. Methods: In this randomised, two-stage, open-label phase 2 trial, we recruited patients aged 18 years or older who had received taxane therapy and undergone two or fewer previous chemotherapy regimens for metastatic breast cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from 18 sites in three countries. Eligible patients were randomly assigned (1:1) to etirinotecan pegol 145 mg/m2 every 14 days or every 21 days. The primary endpoint was the proportion of patients with a confirmed objective response as defined by Response Evaluation Criteria in Solid Tumors version 1.0, analysed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT00802945. Findings: 70 patients (35 in each group) were randomly assigned to treatment between Feb 17, 2009 and April 13, 2010. Of the 70 patients, 20 (29%; 95% CI 18·4-40·6) achieved an objective response (two [3%] had a complete response and 18 [26%] had a partial response). Ten patients on the 14-day schedule achieved an objective response (29%; 95% CI 14·6-46·3; eight partial responses, two complete responses) as did ten on the 21-day schedule (29%; 95% CI 14·6-46·3; all partial responses). The most common grade 3 or worse adverse events were delayed diarrhoea (seven [20%] of 35 patients on the 14-day schedule vs eight [23%] of 35 patients on the 21-day schedule), fatigue (five [14%] vs three [9%]), neutropenia (four [11%] vs four [11%]), and dehydration (three [9%] vs four [11%]); 14 [20%] patients discontinued treatment because of drug-related toxicity. There were two possible drug-related deaths (acute renal failure and septic shock) in the 14-day group; other drug-related serious adverse events reported by more than one patient included ten [14%] patients with diarrhoea (six [17%] patients on the 14-day schedule vs four [11%] on the 21-day schedule), six [9%] with dehydration (two [6%] vs four [11%]), two [3%] with nausea (two [6%] vs none), and two [3%] with vomiting (two [6%] vs none). Interpretation: On the basis of the overall clinical data, pharmacokinetics, and tolerability profile, etirinotecan pegol 145 mg/m2 every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer. Funding: Nektar Therapeutics.

AB - Background: New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials. Methods: In this randomised, two-stage, open-label phase 2 trial, we recruited patients aged 18 years or older who had received taxane therapy and undergone two or fewer previous chemotherapy regimens for metastatic breast cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from 18 sites in three countries. Eligible patients were randomly assigned (1:1) to etirinotecan pegol 145 mg/m2 every 14 days or every 21 days. The primary endpoint was the proportion of patients with a confirmed objective response as defined by Response Evaluation Criteria in Solid Tumors version 1.0, analysed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT00802945. Findings: 70 patients (35 in each group) were randomly assigned to treatment between Feb 17, 2009 and April 13, 2010. Of the 70 patients, 20 (29%; 95% CI 18·4-40·6) achieved an objective response (two [3%] had a complete response and 18 [26%] had a partial response). Ten patients on the 14-day schedule achieved an objective response (29%; 95% CI 14·6-46·3; eight partial responses, two complete responses) as did ten on the 21-day schedule (29%; 95% CI 14·6-46·3; all partial responses). The most common grade 3 or worse adverse events were delayed diarrhoea (seven [20%] of 35 patients on the 14-day schedule vs eight [23%] of 35 patients on the 21-day schedule), fatigue (five [14%] vs three [9%]), neutropenia (four [11%] vs four [11%]), and dehydration (three [9%] vs four [11%]); 14 [20%] patients discontinued treatment because of drug-related toxicity. There were two possible drug-related deaths (acute renal failure and septic shock) in the 14-day group; other drug-related serious adverse events reported by more than one patient included ten [14%] patients with diarrhoea (six [17%] patients on the 14-day schedule vs four [11%] on the 21-day schedule), six [9%] with dehydration (two [6%] vs four [11%]), two [3%] with nausea (two [6%] vs none), and two [3%] with vomiting (two [6%] vs none). Interpretation: On the basis of the overall clinical data, pharmacokinetics, and tolerability profile, etirinotecan pegol 145 mg/m2 every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer. Funding: Nektar Therapeutics.

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