Phase 2 study of the combination of merimepodib with peginterferon-alpha2b, and ribavirin in nonresponders to previous therapy for chronic hepatitis C.

BACKGROUND/AIMS: While combination of peginterferon-alpha (PEG-IFN) and ribavirin (RBV) therapy is the current standard of care for chronic hepatitis C (CHC), only 44-51% of genotype-1 patients achieve a sustained virological response (SVR), and both agents produce treatment-limiting toxicities. In the hepatitis C virus (HCV) replicon system, merimepodib (MMPD), a novel, selective inhibitor of inosine monophosphate dehydrogenase, has shown potent antiviral effects. METHODS: This randomized, placebo-controlled, double-blind study evaluated the safety and antiviral activity of PEG-IFN-alpha2b and RBV combined with either placebo, 25mg MMPD every 12h (q12h), or 50mg MMPD q12h in interferon-alpha (IFN) and RBV nonresponders. After 24 weeks of treatment, subjects with undetectable HCV RNA were proposed to continue assigned treatment for up to 24 additional weeks. RESULTS: The PEG-IFN-alpha, RBV, and MMPD combination was well tolerated at both doses. After 24 weeks, the proportion of HCV RNA undetectable subjects was 8/11 (73%) in the 50-mg MMPD group, 2/10 (20%) in the 25-mg MMPD group, and 3/10 (30%) in the placebo group (P=0.02, Jonckheere-Terpstra test for increasing dose response). Ten subjects entered and completed an extension study, at Week 48, 2 of 2 (100%) of the 25-mg and 3 of 5 (60%) of the 50-mg subjects remained HCV RNA undetectable, compared with 3 of 3 (100%) of the placebo subjects. At Follow-up Week 24, 2 (100%) of the 25-mg , and 1 (25%) of the 50-mg subjects remained undetectable, compared with 1 (33%) of the placebo subjects. Pharmacokinetic and pharmacodynamic analyses showed a correlation between MMPD exposure and early virological response at week 12, but not with hemoglobin decreases often associated with RBV. CONCLUSIONS: In conclusion, PEG-IFN-alpha2b and RBV combined with 50 mg MMPD q12h was well tolerated and induced virological response with undetectable HCV RNA in IFN-alpha and RBV nonresponders.

Safety of cisplatin combined with continuous 5-FU versus bolus 5-FU and leucovorin, in metastatic gastrointestinal cancer (FFCD 9404 randomised trial).

BACKGROUND: The objective of this phase III study was to compare the safety and efficacy of FLP (modulation of 5-FU (Fluorouracil) by folinic acid or leucovorin (LV) and cisplatin vs. FP (5-FU combined with Cisplatin) as a first line chemotherapy in advanced oesophageal, gastric and pancreatic cancer. PATIENTS AND METHODS: 232 patients with measurable lesions were randomised to receive at the first cycle either FP (arm A: 5-FU 800 mg/m2/d in continuous infusion 5 days and cisplatin 100 mg/m2 on day 1 or 2), or FLP (arm B: LV, 100 mg/m2/d in bolus 5 days, followed by 5-FU 350 mg/m2/d in 1 h infusion 5 days and cisplatin 100 mg/m2 on day 1 or 2). In case of no grade 3-4 haematological and diarrhoea toxicity, the dose of 5-FU was increased to 1000 mg/m2/d and 400 mg/m2/d in the two arms respectively, for the subsequent cycles until disease progression. RESULTS: The distribution of primary tumours was: 19 squamous cell carcinoma of the oesophagus, 19 oesophageal adenocarcinoma, 91 gastric and 97 pancreatic adenocarcinoma. Safety remained acceptable and comparable in the two arms except for the severe grade 3-4 mucositis, which was lower in arm B (4.5 vs. 16.4%, p < 0.009). Efficacy in terms of tumour response and survival was similar in the two arms, showing an objective response rate (after external review) of 18.6% (95% confidence interval (CI) 11.4-25.8%) in arm A vs. 15% (95% CI 8.5-21.6%) in arm B, an overall median survival of 24 weeks in arm A vs. 24.7 in arm B (p = 0.83) and a progression-free median survival of 12.4 weeks vs. 12.1 in arms A and B, respectively (p = 0.91). CONCLUSION: The FLP regimen is substantially equivalent to FP in terms of safety and quality of life, as well as for antitumour efficacy in these carcinomas; the only slight advantage of FLP in this study concerns mucositis. Based on these results, FLP could be used as an alternative to FP when appropriate.