A phase I open-label study of the safety, tolerability, and pharmacokinetics of pazopanib in combination with irinotecan and cetuximab for relapsed or refractory metastatic colorectal cancer.

BACKGROUND: Pazopanib is a multi-targeted tyrosine kinase inhibitor shown to be clinically active in the treatment of various cancer types. This study aimed to evaluate the maximum tolerated regimen (MTR), safety, and pharmacokinetics of pazopanib in combination with irinotecan and cetuximab in adult patients with relapsed or refractory metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: This was a Phase I, 3 + 3 design, open-label, dose-escalation study (NCT0050943; VEG108925) conducted in sequential cohorts to determine the MTR of pazopanib and irinotecan administered with cetuximab. Twenty-five patients received treatment in three dosing cohorts and were evaluated for safety and tolerability of the combination and pharmacokinetics of individual drugs. RESULTS: The MTR was determined to be 400 mg pazopanib per day orally in combination with 150 mg/m(2) irinotecan biweekly and 250 mg/m(2) cetuximab weekly by infusion. Neutropenia was the main dose-limiting toxicity. Pharmacokinetic results suggested that the overall systemic exposure to SN-38, the active metabolite of irinotecan, was affected by pazopanib to a greater extent than was the systemic exposure to irinotecan itself. CONCLUSIONS: This study provided evidence for the manageable safety profile and feasibility of using the novel triplet combination of pazopanib, irinotecan, and cetuximab in patients with refractory mCRC. Further large-scale Phase II studies are warranted.

Rationale and delineation of a composite index of relative antitumoural efficacy (In-RATE).

Over the last decades, the development of new drugs has allowed cancer patients to experience several lines of chemotherapy, the objective of which is a long term stabilization of the tumour. The objectives of this work was to delineate a composite index of relative antitumoural efficacy (In-RATE) of a regimen over another, including response rate (RR), median time to progression (TTP) and progression rate (PR). When considering two treatments a and b, the In-RATE was defined as RRa/RRb x TTPa/TTPb x PRb/PRa. Values significantly superior or inferior to 1 reveal an advantage for treatment a or b, respectively. The applicability of the In-RATE to published randomized trials in four frequent tumour types (colorectal, non-small cell lung, advanced ovarian and metastatic breast cancers) was suggested to more precisely distinguish the effects of different drugs, and sometimes to detect a significant difference when the published data did not conclude to statistical difference.

Decision making process in oncology practice: is the information available and what should it consist of?

In terms of systemic chemotherapy, the oncologist is often faced with the difficulty to discriminate between several options, at least according to evidence-based medicine. The aim of the present report was to assess to what extent the efficacy-related parameters required for the decision making process are reported in clinical trials. The analysis was restricted to lung, breast, colorectal and ovarian cancers. It included 135 phase II trials published in 1999, and 79 phase III trials published between 1991 and 2000. Response duration was mentioned in one-half and one-fourth of phases II and III trials, respectively. Only one-half of the trials reported time to progression (TTP). Finally, 28% of phase II and 44% of phase III trials reported RR, TTP and progression rates. The study indicates that the information available from reported clinical trials needs to be upgraded and homogenised in order to improve the decision making process in oncology.

Epidemiology of genital herpes simplex virus infections in a community-based sample in France: results of the HERPIMAX study.

OBJECTIVE: The objective of this study was to provide information on the prevalence of herpes simplex infections in the general population in Europe. GOALS: The goals of this study were to determine the prevalence of clinically probable genital herpes and the relationship between serotype and clinical expression in a French community-based sample. STUDY: A total of 4410 subjects chosen at random were serotyped for herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). Data on symptoms were obtained by questionnaire allowing retrospective diagnosis of clinically probable genital herpes. RESULTS: Questionnaire data and serotype were available for 3192 subjects. Seroprevalences of HSV-1 and HSV-2 were 65.6% and 15.5%, respectively. Prevalence of clinically probable genital herpes was 11.8%, identified in 11.1% of HSV-1-positive subjects and 26.8% of HSV-2-positive subjects, with a lower prevalence in those coinfected with both virus types. CONCLUSIONS: Clinically probable genital herpes was observed in one fourth of subjects with HSV-2 infections and in some subjects with HSV-1 infection. Coinfection with HSV-1 appeared to protect against symptom expression in subjects infected with HSV-2.