Activity and safety of RAD001 (everolimus) in patients affected by biliary tract cancer progressing after prior chemotherapy: a phase II ITMO study.
BACKGROUND
Biliary tract cancer (BTC) is a highly lethal disease for which the best available therapy remains undetermined. The mammalian target of rapamycin (mTOR) pathway is up-regulated in several cancers, including BTC, and preclinical evidence indicates that mTOR inhibition may be effective in the treatment of BTC. We sought to evaluate the activity and tolerability of the mTOR inhibitor RAD001-everolimus-in patients with BTC progressing after prior chemotherapy.


METHODS
This was an open-label, single-arm, phase II study (EUDRACT 2008-007152-94) conducted in eight sites in Italy. Patients with locally advanced, metastatic or recurrent BTC progressing despite previous chemotherapy received a daily oral dose of everolimus 10 mg administered continuously in 28-day cycles. The two primary end points were disease control rate (DCR) and objective response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival (OS) and time-to-progression (TTP).


RESULTS
Thirty-nine patients were enrolled. The DCR was 44.7%, and the ORR was 5.1%. One patient showed a partial response at 2 months and one patient showed a complete response sustained up to 8 months. The median (95% confidence interval) PFS was 3.2 (1.8-4.0) months, and the median OS was 7.7 (5.5-13.2) months. The median TTP was 2.0 (1.7-3.7) months. Most common toxicities were asthenia (43.6%), thrombocytopenia (35.9%), pyrexia (30.8%) and erythema, mainly of mild-to-moderate severity. Two patients required dose reduction due to adverse events.


CONCLUSIONS
Everolimus demonstrated a favourable toxicity profile and encouraging anti-tumour activity. Further trials are needed to establish the role of everolimus in the treatment of BTC. EUDRACT 2008-007152-94.
Day Hospital/Outpatient Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
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Buzzoni
Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan sara.pusceddu@istitutotumori.mi.it.
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Pusceddu
Medical Oncology Unit, Policlinico of Monza, Monza.
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E
Bajetta
Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
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De Braud
Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
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M
Platania
Biostatistician LB Research srl, Cantu.
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Iannacone
Medical Oncology Unit, Asl 1, Massa Carrara.
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Cantore
Medical Oncology Unit, Asl 1, Massa Carrara.
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A
Mambrini
Medical Oncology Unit, Presidio Ospedaliero Sondrio, Sondrio.
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A
Bertolini
Medical Oncology Unit, A.U.O. Maggiore della Carità, Novara.
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O
Alabiso
Medical Oncology Unit, Usl 4, Presidio Ospedaliero, Prato.
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A
Ciarlo
Medical Oncology Unit, Italian Trials in Medical Oncology (ITMO) Group, Fondazione IRCCS Istituto Nazionale Tumori, Milan.
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C
Turco
Gastro-Intestinal Surgery, Liver Transplantation and Hepatology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
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Mazzaferro
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018450:Disease Progression; D018572:Disease-Free Survival; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D011788:Quality of Life; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016019:Survival Analysis
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D003841:Deoxycytidine; D000068338:Everolimus; D020123:Sirolimus
advanced biliary tract cancer; everolimus; mTOR