A placebo-controlled, double-blind, randomized study of recombinant thrombomodulin (ART-123) to prevent oxaliplatin-induced peripheral neuropathy.

PURPOSE: The purpose of this clinical study was to be the first to explore whether ART-123, a recombinant human soluble thrombomodulin, prevents oxaliplatin-induced peripheral neuropathy (OIPN). METHODS: This randomized, phase IIa trial enrolled stage II/III colon cancer patients who received adjuvant mFOLFOX6 chemotherapy. Participants were randomly allocated to 3 arms in a double-blind manner: placebo (placebo: days 1-3); 1-day ART (ART-123: day 1, placebo: days 2-3); and 3-day ART (ART-123: days 1-3). ART-123 (380 U/kg/day) or placebo was infused intravenously before each 2-week cycle of mFOLFOX6. OIPN was assessed with the Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity-12 (FACT/GOG-Ntx-12) score by participants and the NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) by investigators. RESULTS: Seventy-nine participants (placebo n = 28, 1-day ART n = 27, 3-day ART n = 24) received study drugs. The least-squares mean FACT/GOG-Ntx-12 scores at cycle 12 from the mixed effect model for repeated measures were 28.9 with placebo, 36.3 with 1-day ART (vs. placebo: 7.3 [95% CI 1.9 to12.8, p = 0.009]), and 32.3 with 3-day ART (vs. placebo: 3.4 [95% CI -.1 to 9.0, p = 0.222]). The cumulative incidence of NCI-CTCAE grade ≥ 2 sensory neuropathy at cycle 12 was 64.3% with placebo, 40.7% with 1-day ART (vs. placebo: -23.5 [95% CI -48.4 to 4.0], p = 0.108), and 45.8% with 3-day ART (vs. placebo: -18.5 [95% CI -44.2 to 9.4], p = 0.264). Common adverse events were consistent with those reported with mFOLFOX6; no severe bleeding adverse events occurred. CONCLUSION: ART-123 showed a potential preventive effect against OIPN with good tolerability. A larger study with 1-day ART is warranted. NCT02792842, registration date: June 8, 2016.

Double-blind, placebo-controlled, randomized phase II study of TJ-14 (Hangeshashinto) for infusional fluorinated-pyrimidine-based colorectal cancer chemotherapy-induced oral mucositis.

PURPOSE: Hangeshashinto (TJ-14, a Kampo medicine), which reduces the level of prostaglandin E2 and affects the cyclooxygenase activity, alleviates chemotherapy-induced oral mucositis (COM). We conducted a double-blind, placebo-controlled, randomized comparative trial to investigate whether TJ-14 prevents and controls COM in patients with colorectal cancer. METHODS: Ninety-three patients with colorectal cancer who developed moderate-to-severe COM (WHO grade ≧1) during any cycle of chemotherapy using FOLFOX, FOLFIRI, and/or XELOX treatment were randomly assigned to receive either TJ-14 (n = 46) or placebo (n = 47). Patients received the administration of placebo or TJ-14 for 2 weeks at the start of the next course of chemotherapy. Patients were assessed three times per week for safety and for COM incidence and its severity using the WHO grading. RESULTS: Ninety eligible patients (TJ-14; 43, placebo; 47) per protocol set analysis were included in the analysis after the key-opening. Although the incidence of grade ≧2 oral mucositis was lower for patients treated with TJ-14 compared to those treated with placebo, there was no significant difference (48.8 vs. 57.4 %; p = 0.41). The median duration of grade ≧2 mucositis was 5.5 versus 10.5 days (p = 0.018). No difference in other treatment toxicity was observed between the two groups, and patients exhibited high compliance in dosing administration. CONCLUSION: The present study results did not meet the primary endpoint. However, TJ-14 demonstrated a significant effect in the treatment of grade ≧2 mucositis in patients with colorectal cancer compared to the placebo.

[Current Status of Japanese Traditional Medicine 'Kampo' in Chemotherapy].

Advancements in cancer chemotherapy and the introduction of Japanese traditional medicine"Kampo"have been successful in improving the prognosis of malignant tumors. Many Kampo drugs have been used in the treatment of adverse effects. We investigated the safety and efficacy of Hangeshashinto in the prevention and treatment of chemotherapy-induced oral mucositis in patients with gastric and colorectal cancer. Hangeshashinto was shown to reduce the risk of development of mucositis. We also investigated the efficacy of Goshajinkigan in the prevention of chemotherapy-induced neurotoxicity. Goshajinkigan appears to have a promising effect in delaying the onset of neurotoxicity of gradeB2 without reducing the efficacy of treatment. Kampo drugs such as Rikkunshito, Jyuzentaihoto, and Hochuekkito have also been used successfully in the prevention and treatment of chemotherapy-induced adverse effects. It is very important to know the efficacy and safety of Kampo drugs for alleviating the adverse effects of anticancer drugs in patients undergoing cancer treatment with chemotherapy.

Goshajinkigan oxaliplatin neurotoxicity evaluation (GONE): a phase 2, multicenter, randomized, double­blind, placebo­controlled trial of goshajinkigan to prevent oxaliplatin­induced neuropathy.

PURPOSE: Oxaliplatin-induced peripheral neurotoxicity (OPN) is frequent and potentially severe, but successful treatment of this condition is still an unmet clinical need. We aimed to determine whether treatment with goshajinkigan (TJ-107), a traditional Japanese medicine, is better than placebo in preventing OPN in patients with advanced or recurrent colorectal cancer patients treated with standard FOLFOX regimens. METHODS: In this phase 2, randomized, double-blind, placebo-controlled study, patients undergoing oxaliplatin-based chemotherapy were randomized to receive either oral TJ-107 (7.5 g) or matching placebo daily. The severity of OPN was assessed according to the Common Toxicity Criteria for Adverse Events at baseline, every 2 weeks until the 8th cycle, and every 4 weeks thereafter until the 26th week. The primary endpoint was the incidence of grade 2 or greater OPN until the 8th cycle of chemotherapy. RESULTS: Analyses were done by intention to treat. Eighty-nine patients were randomly assigned to receive either TJ-107 (n = 44) or placebo (n = 45) between May 2009 and March 2010. The incidence of grade 2 or greater OPN until the 8th cycle was 39 and 51 % in the TJ-107 and placebo groups, respectively (relative risk (RR), 0.76; 95 % CI, 0.47­1.21). The incidence of grade 3 OPN was 7 % (TJ-107) vs. 13 % (placebo) (0.51, 0.14­1.92). No concerns regarding toxicity emerged with TJ-107 treatment. CONCLUSIONS: TJ-107 appears to have an acceptable safety margin and a promising effect in delaying the onset of grade 2 or greater OPN without impairing FOLFOX efficacy.

Multi-center phase II study of FLOX for advanced colorectal cancer patients in Japan: SWIFT 3 study.

AIM: This is a multicenter phase II study to assess the efficacy and toxicity of the 5-FU, leucovorin, and oxaliplatin (FLOX) (SWIFT 3) regimen in Japanese patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS: Fifty-two patients were enrolled and evaluated from 12 institutions. The median age was 66 years, with 40.4% of patients with colon cancer and 59.6% with rectal cancer. RESULTS: Forty-one patients underwent chemotherapy for first-line therapy and 11 patients for second-line. The response rate for first-line was 46.3% and that for second-line was 9.1%. The response rates categorized by metastatic sites were 59.4% for liver, 33.3% for lung, and 22.2% for lymph nodes. Grade 3/4 neutropenia occurred in 21.2% and Grade 3/4 non-hematologic toxicity in 46.1%. There were no deaths within 60 days following the administration. CONCLUSION: Standard FLOX regimen can be administered for Japanese patients. It is suggested that FLOX is an appropriate option for adjuvant therapy in CRC.