Safety and pharmacokinetics of motesanib in combination with gemcitabine and erlotinib for the treatment of solid tumors: a phase 1b study

Background: This phase 1b study assessed the maximum tolerated dose (MTD), safety, and pharmacokinetics of motesanib (a small-molecule antagonist of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) administered once daily (QD) or twice daily (BID) in combination with erlotinib and gemcitabine in patients with solid tumors. Methods: Patients received weekly intravenous gemcitabine (1000 mg/m2) and erlotinib (100 mg QD) alone (control cohort) or in combination with motesanib (50 mg QD, 75 mg BID, 125 mg QD, or 100 mg QD; cohorts 1-4); or erlotinib (150 mg QD) in combination with motesanib (100 or 125 mg QD; cohorts 5 and 6). Results: Fifty-six patients were enrolled and received protocol-specified treatment. Dose-limiting toxicities occurred in 11 patients in cohorts 1 (n = 2), 2 (n = 4), 3 (n = 3), and 6 (n = 2). The MTD of motesanib in combination with gemcitabine and erlotinib was 100 mg QD. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. Frequently occurring motesanib-related adverse events included diarrhea (n = 19), nausea (n = 18), vomiting (n = 13), and fatigue (n = 12), which were mostly of worst grade < 3. The pharmacokinetics of motesanib was not markedly affected by coadministration of gemcitabine and erlotinib, or erlotinib alone. Erlotinib exposure, however, appeared lower after coadministration with gemcitabine and/or motesanib. Of 49 evaluable patients, 1 had a confirmed partial response and 26 had stable disease. Conclusions: Treatment with motesanib 100 mg QD plus erlotinib and gemcitabine was tolerable. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone.Dusan Kotasek, Niall Tebbutt, Jayesh Desai, Stephen Welch, Lillian L Siu, Sheryl McCoy, Yu-Nien Sun, Jessica Johnson, Adeboye H Adewoye and Timothy Pric

Epidemiology of neuroendocrine cancers in an Australian population

Objective The aim was to explore incidence, mortality and case survivals for invasive neuroendocrine cancers in an Australian population and consider cancer control implications. Methods Directly age-standardised incidence and mortality rates were investigated from 1980 to 2006, plus disease-specific survivals. Results Annual incidence per 100,000 increased from 1.7 in 1980–1989 to 3.3 in 2000–2006. A corresponding mortality increase was not observed, although numbers of deaths were low, reducing statistical power. Increases in incidence affected both sexes and were more evident for female lung, large bowel (excluding appendix), and unknown primary site. Common sites were lung (25.9%), large bowel (23.3%) (40.9% were appendix), small intestine (20.6%), unknown primary (15.0%), pancreas (6.5%), and stomach (3.7%). Site distribution did not vary by sex (p = 0.260). Younger ages at diagnosis applied for lung (p = 0.002) and appendix (p\0.001) and older ages for small intestine (p\0.001) and unknown primary site (p\0.001). Five-year survival was 68.5% for all sites combined, with secular increases (p\0.001). After adjusting for age and diagnostic period, survivals were higher for appendix and lower for unknown primary site, pancreas, and colon (excluding appendix). Conclusions Incidence rates are increasing. Research is needed into possible aetiological factors for lung and largebowel sites, including tobacco smoking, and excess body weight and lack of exercise, respectively; and Crohn’s disease as a possible precursor condition.

An open-label, single-arm phase two trial of gefitinib in patients with advanced or metastatic castration-resistant prostate cancer

OBJECTIVE: To determine whether the oral epidermal growth factor receptor (EGFR) inhibitor gefitinib (ZD1839, Iressa®) has clinical efficacy in patients with castration-resistant prostate cancer (CRPC). METHODS: Multicenter open-label phase 2 study. Fifty-one male patients with CRPC and rising PSA levels were enrolled to obtain the target enrollment of 38 patients who completed at least 3 months of treatment with continuous gefitinib 500 mg/d. The primary end point was the prostate-specific antigen (PSA) response rate, as defined by a confirmed 50% decline in serum PSA. RESULTS: One patient had a confirmed PSA response, giving a response rate of 2.0% (95% CI 0.1-10.4%). The median time to progression was 28 days and the median time on study was 85 days. The majority of patients had a stable performance status while on study. Of the 51 patients who received at least 1 dose of gefitinib, 13 patients had a dose reduction and 9 patients withdrew because of an adverse event. CONCLUSIONS: There was minimal evidence of single-agent gefitinib activity in CRPC. The treatment was associated with clinically relevant toxicities, which responded to dose interruption or reduction.4 page(s