Phase I study of primary treatment with 5-FU, oxaliplatin, irinotecan, levofolinate, and panitumumab combination chemotherapy in patients with advanced/recurrent colorectal cancer involving the wild-type RAS gene: the JACCRO CC-14 study.

BACKGROUND: FOLFOXIRI is now regarded as the chemotherapy regimen that offers the best platform for the treatment of colorectal cancer. However, the safety and efficacy of FOLFOXIRI + panitumumab has not been demonstrated. We conducted a phase I study to determine the recommended dose of FOLFOXIRI + panitumumab as first-line treatment for RAS wild-type metastatic colorectal cancer (mCRC). METHODS: Patients received combination therapy consisting of panitumumab (6 mg/kg on day 1) + FOLFOXIRI [irinotecan (CPT-11), oxaliplatin (L-OHP) 85 mg/m2, and folinate (LV) 200 mg/m2] on day 1, followed by fluorouracil (5-FU) 3200 mg/m2 infused as a 46-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of RAS wild-type mCRC patients. A decrease in CPT-11 dose was planned (started at level 1: CPT-11 165 mg/m2). RESULTS: Seven patients were enrolled, and six were assessed for safety and efficacy. Maximum tolerated dose was not reached at level 1; all patients were treated at these levels. The common Grade 3 or 4 relevant toxicities were diarrhea (50%), hypokalemia (33%) and stomatitis (33%). No treatment-related deaths occurred. Of the six patients assessed four had partial response and the two others had stable disease; hence, the response rate was 66.7% (95% confidence interval 28.9-100%) and the disease control rate was 100%. Time to protocol treatment failure was 7.2 (1.4-7.3) months. CONCLUSION: The FOLFOXIRI + panitumumab chemotherapy regimen was well tolerated by our patients with mCRC and showed promising anti-tumor activity. The recommended phase II dose was determined to be the same as the standard doses of this regimen used worldwide.

[Efficacy of Rebamipide Gargle against Chemotherapy-induced Oral Mucositis].

Chemotherapy-induced oral mucositis (CIOM) is a severe adverse event resulting from cancer chemotherapy. Toxic free radicals and pro-inflammatory cytokines produced by anticancer drugs have been reported to be associated with CIOM. Rebamipide has been shown to increase gastric endogenous prostaglandin E2 and I2, to promote gastric epithelial mucin, and to behave as an oxygen free-radical scavenger in addition to other anti-inflammatory actions. We developed a gargle solution of rebamipide, adding ultrahydrogel for mucosal protection and to maintain rebamipide on the oral mucosa. A 300 mL rebamipide gargle solution combines 600 mg rebamipide, 3 g high molecular-weight polyethylene oxide, 1.2 g carrageenan, pineapple flavoring, and water. The efficacy of the rebamipide gargle was evaluated in 175 patients with CIOM from November 2009 to December 2012, each instructed to use the rebamipide gargle 5-6 times daily. The severity of CIOM was assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). Their CTCAE scores (3/2/1/0) changed from n=13/64/98/0 to 0/10/103/62, respectively, after initiation of the rebamipide gargle (p<0.01; paired t-test). The median duration to best response was 14 days (range: 1-49). CTCAE scores decreased in 132 patients (75.4%), including 62 (35.4%) who achieved grade 0. There were no unexpected safety events. Rebamipide gargle was well tolerated and demonstrated to have significant therapeutic efficacy against CIOM.

[Evaluation of usability of an anticancer drug after changing it to liquid formulation].

Although the advantages of a liquid formulation over a lyophilized one have been mentioned, few studies have quantified the differences between the two. For the purpose of clarifying the advantages of a liquid formulation, we carried out a comparison of ELPLAT I. V. INFUSION SOLUTION, which is a liquid formulation of oxaliplatin, and ELPLAT FOR INJECTION, which is a lyophilized formulation of oxaliplatin. Since multiple factors(such as skill in drug preparation and the dosage)as well as the formulation influenced the preparation time, each factor was assessed by a Latin square design. The mean preparation time was 62. 39 seconds for the liquid formulation and 171. 22 seconds for the lyophilized formulation, and a decrease of approximately two minutes(p<0. 0001)was observed with the liquid formulation. Furthermore, after linear regression analysis of multiple factors, shortening of the preparation time was found to be related to the liquid formulation. The preparation time was significantly shortened according to the level of skill in drug preparation with the liquid formulation, but not the lyophilized formulation. This was because the total preparation time was relatively long for the lyophilized formulation. Superior usability of liquid formulation was shown by our quantification of the advantages of liquid oxaliplatin.