Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): An open-label, single-arm phase 2 trial

Anna Maria Di Giacomo, Paolo A. Ascierto, Lorenzo Pilla, Mario Santinami, Pier Francesco Ferrucci, Diana Giannarelli, Antonella Marasco, Licia Rivoltini, Ester Simeone, Stefania V L Nicoletti, Ester Fonsatti, Diego Annesi, Paola Queirolo, Alessandro Testori, Ruggero Ridolfi, Giorgio Parmiani, Michele Maio

Research output: Contribution to journalArticle

Abstract

Background: Ipilimumab improves survival of patients with metastatic melanoma, many of whom develop brain metastases. Chemotherapy-induced release of tumour antigens might amplify ipilimumab's antitumour activity. We aimed to investigate the efficacy and safety of ipilimumab plus fotemustine in patients with metastatic melanoma with or without asymptomatic brain metastases. Methods: In our open-label, single-arm phase 2 trial, we enrolled patients 18 years or older with measurable, locally advanced, unresectable stage III or stage IV melanoma between July 6, 2010, and April 14, 2011. Eligible patients had a life expectancy of 16 weeks or more and an Eastern Cooperative Oncology Group performance status of 1 or less, and could have received a maximum of one previous line of chemotherapy. Participants received induction treatment of 10 mg/kg intravenous ipilimumab every 3 weeks to a total of four doses, and 100 mg/m 2 intravenous fotemustine weekly for 3 weeks and then every 3 weeks from week 9 to week 24. Patients with a confirmed clinical response were eligible for maintenance treatment from week 24, with ipilimumab every 12 weeks and fotemustine every 3 weeks. The primary endpoint was the proportion of patients with immune-related disease control as established with immune-related response criteria. Analyses were done per protocol. This trial is registered with EudraCT, number 2010-019356-50, and with ClinicalTrials.gov, number NCT01654692. Findings: 86 patients were eligible for treatment, of whom 20 had asymptomatic brain metastases at baseline. 40 patients in the study population achieved disease control (46·5%, 95% CI 35·7-57·6), as did ten with brain metastases (50·0%, 27·2-72·8). 47 patients (55%) had grade 3 or 4 treatment-related adverse events, of which the most common was myelotoxicity (thrombocytopenia in 21 [24%] patients and neutropenia in 16 [19%]). The most common grade 3 or 4 immune-related adverse events were hepatic: 21 patients (24%) had grade 3 or 4 increases in concentrations of alanine aminotransferase or aspartate aminotransferase. Interpretation: The combination of ipilimumab plus fotemustine has clinical activity in patients with metastatic melanoma, including those with brain metastases. Funding: Bristol-Myers Squibb.

Original languageEnglish
Pages (from-to)879-886
Number of pages8
JournalThe Lancet Oncology
Volume13
Issue number9
DOIs
Publication statusPublished - Sep 2012

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fotemustine
Melanoma
Neoplasm Metastasis
Brain
ipilimumab
Drug Therapy

ASJC Scopus subject areas

  • Oncology

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Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1) : An open-label, single-arm phase 2 trial. / Di Giacomo, Anna Maria; Ascierto, Paolo A.; Pilla, Lorenzo; Santinami, Mario; Ferrucci, Pier Francesco; Giannarelli, Diana; Marasco, Antonella; Rivoltini, Licia; Simeone, Ester; Nicoletti, Stefania V L; Fonsatti, Ester; Annesi, Diego; Queirolo, Paola; Testori, Alessandro; Ridolfi, Ruggero; Parmiani, Giorgio; Maio, Michele.

In: The Lancet Oncology, Vol. 13, No. 9, 09.2012, p. 879-886.

Research output: Contribution to journalArticle

Di Giacomo, Anna Maria ; Ascierto, Paolo A. ; Pilla, Lorenzo ; Santinami, Mario ; Ferrucci, Pier Francesco ; Giannarelli, Diana ; Marasco, Antonella ; Rivoltini, Licia ; Simeone, Ester ; Nicoletti, Stefania V L ; Fonsatti, Ester ; Annesi, Diego ; Queirolo, Paola ; Testori, Alessandro ; Ridolfi, Ruggero ; Parmiani, Giorgio ; Maio, Michele. / Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1) : An open-label, single-arm phase 2 trial. In: The Lancet Oncology. 2012 ; Vol. 13, No. 9. pp. 879-886.
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T1 - Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1)

T2 - An open-label, single-arm phase 2 trial

AU - Di Giacomo, Anna Maria

AU - Ascierto, Paolo A.

AU - Pilla, Lorenzo

AU - Santinami, Mario

AU - Ferrucci, Pier Francesco

AU - Giannarelli, Diana

AU - Marasco, Antonella

AU - Rivoltini, Licia

AU - Simeone, Ester

AU - Nicoletti, Stefania V L

AU - Fonsatti, Ester

AU - Annesi, Diego

AU - Queirolo, Paola

AU - Testori, Alessandro

AU - Ridolfi, Ruggero

AU - Parmiani, Giorgio

AU - Maio, Michele

PY - 2012/9

Y1 - 2012/9

N2 - Background: Ipilimumab improves survival of patients with metastatic melanoma, many of whom develop brain metastases. Chemotherapy-induced release of tumour antigens might amplify ipilimumab's antitumour activity. We aimed to investigate the efficacy and safety of ipilimumab plus fotemustine in patients with metastatic melanoma with or without asymptomatic brain metastases. Methods: In our open-label, single-arm phase 2 trial, we enrolled patients 18 years or older with measurable, locally advanced, unresectable stage III or stage IV melanoma between July 6, 2010, and April 14, 2011. Eligible patients had a life expectancy of 16 weeks or more and an Eastern Cooperative Oncology Group performance status of 1 or less, and could have received a maximum of one previous line of chemotherapy. Participants received induction treatment of 10 mg/kg intravenous ipilimumab every 3 weeks to a total of four doses, and 100 mg/m 2 intravenous fotemustine weekly for 3 weeks and then every 3 weeks from week 9 to week 24. Patients with a confirmed clinical response were eligible for maintenance treatment from week 24, with ipilimumab every 12 weeks and fotemustine every 3 weeks. The primary endpoint was the proportion of patients with immune-related disease control as established with immune-related response criteria. Analyses were done per protocol. This trial is registered with EudraCT, number 2010-019356-50, and with ClinicalTrials.gov, number NCT01654692. Findings: 86 patients were eligible for treatment, of whom 20 had asymptomatic brain metastases at baseline. 40 patients in the study population achieved disease control (46·5%, 95% CI 35·7-57·6), as did ten with brain metastases (50·0%, 27·2-72·8). 47 patients (55%) had grade 3 or 4 treatment-related adverse events, of which the most common was myelotoxicity (thrombocytopenia in 21 [24%] patients and neutropenia in 16 [19%]). The most common grade 3 or 4 immune-related adverse events were hepatic: 21 patients (24%) had grade 3 or 4 increases in concentrations of alanine aminotransferase or aspartate aminotransferase. Interpretation: The combination of ipilimumab plus fotemustine has clinical activity in patients with metastatic melanoma, including those with brain metastases. Funding: Bristol-Myers Squibb.

AB - Background: Ipilimumab improves survival of patients with metastatic melanoma, many of whom develop brain metastases. Chemotherapy-induced release of tumour antigens might amplify ipilimumab's antitumour activity. We aimed to investigate the efficacy and safety of ipilimumab plus fotemustine in patients with metastatic melanoma with or without asymptomatic brain metastases. Methods: In our open-label, single-arm phase 2 trial, we enrolled patients 18 years or older with measurable, locally advanced, unresectable stage III or stage IV melanoma between July 6, 2010, and April 14, 2011. Eligible patients had a life expectancy of 16 weeks or more and an Eastern Cooperative Oncology Group performance status of 1 or less, and could have received a maximum of one previous line of chemotherapy. Participants received induction treatment of 10 mg/kg intravenous ipilimumab every 3 weeks to a total of four doses, and 100 mg/m 2 intravenous fotemustine weekly for 3 weeks and then every 3 weeks from week 9 to week 24. Patients with a confirmed clinical response were eligible for maintenance treatment from week 24, with ipilimumab every 12 weeks and fotemustine every 3 weeks. The primary endpoint was the proportion of patients with immune-related disease control as established with immune-related response criteria. Analyses were done per protocol. This trial is registered with EudraCT, number 2010-019356-50, and with ClinicalTrials.gov, number NCT01654692. Findings: 86 patients were eligible for treatment, of whom 20 had asymptomatic brain metastases at baseline. 40 patients in the study population achieved disease control (46·5%, 95% CI 35·7-57·6), as did ten with brain metastases (50·0%, 27·2-72·8). 47 patients (55%) had grade 3 or 4 treatment-related adverse events, of which the most common was myelotoxicity (thrombocytopenia in 21 [24%] patients and neutropenia in 16 [19%]). The most common grade 3 or 4 immune-related adverse events were hepatic: 21 patients (24%) had grade 3 or 4 increases in concentrations of alanine aminotransferase or aspartate aminotransferase. Interpretation: The combination of ipilimumab plus fotemustine has clinical activity in patients with metastatic melanoma, including those with brain metastases. Funding: Bristol-Myers Squibb.

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