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


RESULTS
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.


CONCLUSIONS
The combination of ipilimumab plus fotemustine has clinical activity in patients with metastatic melanoma, including those with brain metastases.


BACKGROUND
Bristol-Myers Squibb.
Medical Oncology and Immunotherapy, Azienda Ospedaliera Universitaria Senese, Istituto Toscano Tumori, Siena, Italy.
Anna Maria
AM
Di Giacomo
Paolo A
PA
Ascierto
Lorenzo
L
Pilla
Mario
M
Santinami
Pier Francesco
PF
Ferrucci
Diana
D
Giannarelli
Antonella
A
Marasco
Licia
L
Rivoltini
Ester
E
Simeone
Stefania Vl
SV
Nicoletti
Ester
E
Fonsatti
Diego
D
Annesi
Paola
P
Queirolo
Alessandro
A
Testori
Ruggero
R
Ridolfi
Giorgio
G
Parmiani
Michele
M
Maio
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D018572:Disease-Free Survival; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009607:Nitrosourea Compounds / Q000008:administration & dosage*; D009943:Organophosphorus Compounds / Q000008:administration & dosage*; D012878:Skin Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology
D000911:Antibodies, Monoclonal; D000074324:Ipilimumab; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; C054368:fotemustine