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

(2013) LANCET ONCOLOGY. 14(12). p.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/m(2) 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/m(2) every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer.
Keywords
IXABEPILONE BMS-247550, ERIBULIN MESYLATE, HALICHONDRIN B ANALOG, ANTITUMOR-ACTIVITY, SOLID TUMORS, TAXANE, ANTHRACYCLINE, IRINOTECAN, TRIAL, CAPECITABINE

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Chicago
Awada, Ahmad, Agustin A Garcia, Stephen Chan, Guy HM Jerusalem, Robert E Coleman, Manon T Huizing, Aminder Mehdi, et al. 2013. “Two Schedules of Etirinotecan Pegol (NKTR-102) in Patients with Previously Treated Metastatic Breast Cancer: a Randomised Phase 2 Study.” Lancet Oncology 14 (12): 1216–1225.
APA
Awada, A., Garcia, A. A., Chan, S., Jerusalem, G. H., Coleman, R. E., Huizing, M. T., Mehdi, A., et al. (2013). Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study. LANCET ONCOLOGY, 14(12), 1216–1225.
Vancouver
1.
Awada A, Garcia AA, Chan S, Jerusalem GH, Coleman RE, Huizing MT, et al. Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study. LANCET ONCOLOGY. 2013;14(12):1216–25.
MLA
Awada, Ahmad, Agustin A Garcia, Stephen Chan, et al. “Two Schedules of Etirinotecan Pegol (NKTR-102) in Patients with Previously Treated Metastatic Breast Cancer: a Randomised Phase 2 Study.” LANCET ONCOLOGY 14.12 (2013): 1216–1225. Print.
@article{4221253,
  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/m(2) 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/m(2) every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer.},
  author       = {Awada, Ahmad and Garcia, Agustin A and Chan, Stephen and Jerusalem, Guy HM and Coleman, Robert E and Huizing, Manon T and Mehdi, Aminder and O'Reilly, Sue M and Hamm, John T and Barrett-Lee, Peter J and Cocquyt, Veronique and Sideras, Kostandinos and Young, David E and Zhao, Carol and Chia, Yen Lin and Hoch, Ute and Hannah, Alison L and Perez, Edith A},
  issn         = {1470-2045},
  journal      = {LANCET ONCOLOGY},
  keyword      = {IXABEPILONE BMS-247550,ERIBULIN MESYLATE,HALICHONDRIN B ANALOG,ANTITUMOR-ACTIVITY,SOLID TUMORS,TAXANE,ANTHRACYCLINE,IRINOTECAN,TRIAL,CAPECITABINE},
  language     = {eng},
  number       = {12},
  pages        = {1216--1225},
  title        = {Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study},
  url          = {http://dx.doi.org/10.1016/S1470-2045(13)70429-7},
  volume       = {14},
  year         = {2013},
}

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