Alessandro Bertolini

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. PATIENTS AND 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. CONCLUSION 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.

Rationale for Treatment and Study Design of TAILOR: A Randomized Phase III Trial of Second-line Erlotinib Versus Docetaxel in the Treatment of Patients Affected by Advanced Non-Small-Cell Lung Cancer With the Absence of Epidermal Growth Factor Receptor Mutations

We present the rationale and study design of the Tarceva Italian Lung Optimization trial phase III, multicenter, open-label, randomized trial on efficacy of second-line therapies in different subgroups of non-small-cell lung cancer (NSCLC) patients identified using molecular and clinical evaluations. To date, we can assume that advanced NSCLC epidermal growth factor receptor (EGFR)-mutated patients benefit from EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, whereas their role in the treatment of patients who do not have EGFR mutations is controversial. The aim of this study is to assess whether it is possible to optimize second-line treatment in NSCLC patients with absence of EGFR mutations. Moreover, the predictive value of the K-ras mutation, EGFR protein expression, and EGFR gene copy number, as well as a smoking habit and histotype for determining a different effect of erlotinib compared with chemotherapy will be assessed in patients who do not have EGFR mutations. The primary endpoint is overall survival; the secondary endpoints are progression-free survival, response rate, quality of life, and toxicity. We have planned to collect blood samples to identify different prognosis-related polymorphisms and to assess their sensitivity and specificity in the detection of EGFR and K-ras mutations with respect to histologic samples.

Role of KRAS-LCS6 polymorphism in advanced NSCLC patients treated with erlotinib or docetaxel in second line treatment (TAILOR).

MicroRNAs were described to target mRNA and regulate the transcription of genes involved in processes de-regulated in tumorigenesis, such as proliferation, differentiation and survival. In particular, the miRNA let-7 has been suggested to regulate the expression of the KRAS gene, a common mutated gene in non-small cell lung cancer (NSCLC), through a let-7 complementary site (LCS) in 3′UTR of KRAS mRNA. We have reported the analysis performed on the role of the polymorphism located in the KRAS-LCS (rs61764370) which is involved in the disruption of the let-7 complementary site in NSCLC patients enrolled within the TAILOR trial, a randomised trial comparing erlotinib versus docetaxel in second line treatment. In our cohort of patients, KRAS-LCS6 polymorphism did not have any impact on both overall survival (OS) and progression free survival (PFS) and was not associated with any patient’s baseline characteristics included in the study. Overall, patients had a better prognosis when treated with docetaxel instead of erlotinib for both OS and PFS. Considering KRAS-LCS6 status, the TG/GG patients had a benefit from docetaxel treatment (HR(docetaxel vs erlotinib) = 0.35, 95% CI 0.15–0.79, p = 0.011) compared with the TT patients (HR(docetaxel vs erlotinib) = 0.72, 95% CI 0.52–1.01, p = 0.056) in terms of PFS.

Epirubicin-vinorelbine intravenous combination followed by oral vinorelbine as first-line treatment in metastatic breast cancer

Epirubicin and vinorelbine are considered active drugs in metastatic breast cancer. The optimal duration of a chemotherapy regimen for metastatic breast cancer patients is still unknown. Nevertheless, epirubicin has a dose-limiting cardiotoxicity. Vinorelbine is also available as oral formulation. In a multicenter phase II study, we analyzed the feasibility and the efficacy of a maximum of six cycles of i.v. epirubicin plus vinorelbine, followed by oral vinorelbine. We enrolled 30 patients with metastatic breast cancer. Each patient received epirubicin (75 mg/m2 on day 1) and vinorelbine (25 mg/m2 on days 1-8), every 3 weeks, for three cycles or six cycles in case of objective response or stable disease. When a clinical benefit was obtained, patients received oral vinorelbine (60 mg/m2 on days 1-8 every 3 weeks for three cycles). The regimen demonstrated to be active and well tolerated in metastatic breast cancer, and 6-8 months represented the optimal treatment duration. Maintenance therapy with oral vinorelbine was feasible, effective, safe and well accepted by the patients.

Enzymuria in carboplatin nephrotoxicity.

Urinary excretion of N-acetyl-beta-glucosaminidase (NAG) is an early marker of nephrotoxicity. NAG activity was assayed by the fluorimetric method of Leaback and Walker in 17 patients treated (22 courses) with carboplatin (CBDCA, 220–550 mg/m2) before infusion and 24, 48, 72 and 96 h after. Increased excretion of NAG, a sensitive index of renal tubular damage, was observed following 10 of the 22 courses. A transient increase in plasma creatinine and/or abnormal proteinuria was observed in 6 cases. Impaired renal function prior to therapv seems to be a predisposing factor to the nephrotoxicity.