Nozomu Fuse

Background/Objectives: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of taxanes and platinum-based agents, impairing quality of life. Duloxetine is the only drug with proven efficacy, but is often limited by tolerability. AT-04 is a portable alternating magnetic field device that activates descending pain modulatory systems and has shown safety in other pain settings. This investigator-initiated trial evaluated the efficacy and safety of AT-04 for persistent CIPN. Methods: We conducted a randomized, double-blind, sham-controlled, multicenter phase II study. Patients with CIPN lasting ≥12 weeks after chemotherapy and pain NRS ≥ 4 were enrolled. Participants used AT-04 or sham devices twice daily for 12 weeks. The primary endpoint was the change in pain NRS on day 85. Secondary endpoints included tingling NRS, numbness NRS, CIPN20 subscales, and safety. Results: Twenty-eight patients were randomized (14 per arm). No significant difference was observed in pain NRS on day 85 {AT-04: −1.74 ± 0.6 vs. sham device: −1.45 ± 0.6; one-sided p = 0.36, effect size (ES) = 0.48}. CIPN20 motor scores improved with AT-04 on days 29 (−9.82 ± 13.8 vs. 0.74 ± 8.7, respectively; p = 0.035, ES = 0.92) and 57 (−11.81 ± 10.6 vs. −0.54 ± 6.7, respectively; p < 0.01, ES = 1.26). Among patients whose last chemotherapy had ended >1 year earlier (n = 16), motor scores improved from days 29 (−12.43 ± 10.3 vs. 2.38 ± 8.9, respectively; p < 0.01, ES = 1.55) to 85 (−11.76 ± 10.1 vs. −0.07 ± 11.5, respectively; p = 0.049, ES = 1.08), while sensory/autonomic scales showed trends. No treatment-related adverse events occurred in the AT-04 group. Conclusions: AT-04 did not significantly reduce pain NRS but improved motor function in CIPN patients, especially in those >1 year after chemotherapy. AT-04 may be a promising non-pharmacological option; larger confirmatory trials are required.

TPS3156 Background: Approximately 7% of advanced solid malignancies have FGFR gene alterations. However, standard treatment for FGFR-altered malignancies has not been established. Moreover, circulating tumor DNA (ctDNA) analysis has a potential to accurately identify FGFR alterations by assessing spatial and temporal intratumoral heterogeneity, which have shown to be associated with a poor prognosis and resistance to anti-cancer therapy. Methods: We are conducting an investigator-initiated multicenter phase II basket-type trial to investigate efficacy and safety of TAS-120, a highly selective covalent pan-FGFR inhibitor, for the patients with advanced solid malignancies with FGFR alterations identified by ctDNA analysis as a part of the Nationwide Cancer Genome Screening Project (GOZILA study, UMIN000029315). Eligibility criteria include histologically confirmed unresectable advanced or recurrent solid tumors regardless of histology of origin; ECOG PS of 0 or 1; refractory or intolerant to the standard therapies; and clonal FGFR alterations (FGFR1-3 gain-of-function mutations, FGFR1,2 amplifications and FGFR2,3 fusions) identified by a 73-gene sequencing ctDNA panel (Guardant360). Enrolled patients will receive TAS-120 20 mg once daily, orally, in a 21 day-cycle. The primary endpoint is to clarify objective response rate (ORR) assessed by investigators per RECIST v1.1. The secondary endpoints are to evaluate progression-free survival, duration of response, time to treatment failure, disease control rate, overall survival, ORR by central determination, and incidence of adverse events. Target sample size is determined as 26 to test the null hypothesis of ORR as 5% with one-sided alpha level of 2.5% and power of 80% to detect an expected value of ORR as 25%. Furthermore, tumor tissue and ctDNA will be serially collected and analyzed to investigate the resistance mechanisms and provide clinically meaningful biomarker which may be used for identifying and implementing treatment changes. Clinical trial information: 194624.

Background Adjuvant chemotherapy with XELOX (capecitabine plus oxaliplatin) has been shown to be beneficial following resection of gastric cancer in South Korean, Chinese, and Taiwanese patients. This phase II study (J-CLASSIC-PII) was undertaken to evaluate the feasibility of XELOX in Japanese patients with resected gastric cancer. Methods Patients with stage II or III gastric cancer who underwent curative D2 gastrectomy received adjuvant XELOX (eight 3-week cycles of oral capecitabine, 1000 mg/m² twice daily on days 1–14, plus intravenous oxaliplatin 130 mg/m² on day 1). The primary endpoint was dose intensity. Secondary endpoints were safety, proportion of patients completing treatment, and 1-year disease-free survival (DFS) rate. Results One hundred patients were enrolled, 76 of whom completed the study as planned. The mean dose intensity was 67.2 % (95 % CI, 61.9–72.5 %) for capecitabine and 73.4 % (95 % CI, 68.4–78.4 %) for oxaliplatin, which were higher than the predefined age-adjusted threshold values of 63.4 % and 69.4 %, respectively, and the study therefore met its primary endpoint. The 1-year DFS rate was 86 % (95 % CI, 77–91 %). No new safety signals were identified. Conclusions The feasibility of adjuvant XELOX in Japanese patients with resected gastric cancer is similar to that observed in South Korean, Chinese, and Taiwanese patients in the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) study. Based on findings from this study and the CLASSIC study, the XELOX regimen can be considered an adjuvant treatment option for Japanese gastric cancer patients who have undergone curative resection.

The mutation in KRAS exon 2 is a validated biomarker of resistance to anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC). Several reports have confirmed associations of other RAS mutations with resistance to anti-EGFR therapy. However, the impact of BRAF and PIK3CA mutations on the efficacy of anti-EGFR therapy remains controversial. Little is known about the frequencies and clinicopathological features of these mutations, as well as the therapeutic effects of anti-EGFR therapy in mCRC patients with these mutations, especially in the Asian population. In this retrospective observational study, frequencies and clinicopathological features of KRAS, NRAS, BRAF and PIK3CA mutations were evaluated in patients with mCRC. Among patients treated with anti-EGFR therapy, objective response, progression-free survival (PFS), and overall survival (OS) were evaluated according to gene status. Among 264 patients, mutations in KRAS exon 2, KRAS exons 3 or 4, NRAS, BRAF and PIK3CA were detected in 34.1%, 3.8%, 4.2%, 5.4% and 6.4%, respectively. Thus, a total of 12.1% of patients without KRAS exon 2 mutations had other RAS mutations. Primary rectal tumors tended to be more frequently observed in RAS mutant tumors. BRAF mutations were more frequently observed with right-sided colon, poorly differentiated or mucinous adenocarcinoma, and peritoneal metastasis. Among the 66 patients with KRAS exon 2 wild-type tumors treated with anti-EGFR agents, PFS (5.8 vs. 2.2 months) and OS (17.7 vs. 5.2 months) were significantly better in patients with all wild-type tumors (n = 56) than in those with any of the mutations (n = 10). The response rate also tended to be better with all wild-type tumors (26.8 vs. 0%). Other RAS and BRAF mutations were observed in KRAS exon 2 wild-type tumors, which were associated with some clinicopathological features and resistance to anti-EGFR therapy in our patient cohort.

This study was conducted to investigate whether human epidermal growth factor receptor 2 (HER2) status, epidermal growth factor receptor (EGFR) status, and c-MET status are independent prognostic factors for advanced gastric cancer patients who received standard chemotherapy.

Increased serum human epidermal growth factor receptor 2 levels have been found in metastatic breast cancer patients and are correlated with human epidermal growth factor receptor 2 overexpression in tumor cells. However, the prevalence of serum human epidermal growth factor receptor 2 in gastric cancer patients has not been elucidated. We retrospectively analyzed formalin-fixed paraffin-embedded tumor tissues and serum samples from 96 advanced gastric cancer patients. Human epidermal growth factor receptor 2 expression and gene amplification in tumor cells were determined by immunohistochemistry and fluorescence in situ hybridization. Serum human epidermal growth factor receptor 2 levels were measured using a chemiluminescent immunoassay. Human epidermal growth factor receptor 2 positivity in tumor cells was defined as immunohistochemistry 2+ with fluorescence in situ hybridization positive or immunohistochemistry 3+ with any fluorescence in situ hybridization results. All tissue samples and serum samples were successfully measured. Nineteen patients (20%) were human epidermal growth factor receptor 2-positive in tumor cells. The median serum human epidermal growth factor receptor 2 level was 9.3 ng/ml (range, 5.0–332.4 ng/ml), and serum human epidermal growth factor receptor 2 levels were significantly separated according to human epidermal growth factor receptor 2 status in tumor cells (P < 0.0001, Wilcoxon's rank sum test); median serum human epidermal growth factor receptor 2 levels in human epidermal growth factor receptor 2-negative patients and -positive patients were 8.9 (range, 5.0–20.5) and 24.0 (range, 9.7–332.4), respectively. There were 15 serum human epidermal growth factor receptor 2-positive patients (16%) using a cutoff value of 15 ng/ml. The sensitivity and the specificity of serum human epidermal growth factor receptor 2 with respect to human epidermal growth factor receptor 2 positivity in tumor cells were 53 and 94%, respectively. Serum human epidermal growth factor receptor 2 measurements cannot be substituted for tissue human epidermal growth factor receptor 2 diagnosis in advanced gastric cancer patients. However, serum human epidermal growth factor receptor 2 levels are associated with human epidermal growth factor receptor 2 overexpression in tumor cells. Further investigations of clinical significance of serum human epidermal growth factor receptor 2 as a predictive marker and a therapy-monitoring marker are warranted.

134 Background: We conducted a phase I/II trial of chemoradiotherapy (CRT) concurrent with S-1 and cisplatin to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate the efficacy and safety in patients with esophageal carcinoma. Methods: Eligibility criteria included histologically proven squamous cell or adeno carcinoma of the thoracic esophagus, clinical stage II/III excluded T4, PS 0-1, age 20 to 75, and no prior treatment. Chemotherapy consisted of administration of S-1 60-80 mg/m²/day on days 1-14, and cisplatin at 75 mg/m²on day 1, repeated twice every 4 weeks. Single daily radiation of 1.8 Gy in 28 fractions (total 50.4Gy) was given concurrently starting on day 1. For patients achieving an objective response after CRT, two additional cycles of chemotherapy were administered. The phase I part adopted the 3+3 cohort design. Planned sample size of 75 patients was calculated based on the weighting of threshold values of CR rate according to the registered proportion of T1-2 and T3. Results: Patient accrual was terminated early due to slow enrollment after 44 eligible patients were accrued from May 2007 to Sep 2011. Patient backgrounds were: 40 males, with median age 62 years, PS 0/1 (39/5), squamous cell carcinoma / adenocarcinoma (43/1), T1/T2/T3 (14/8/22) and N0/N1 (7/36). In the phase I part, two of six patients experienced DLTs at each level of S-1 (S-1 60 or 80 mg/m2/day). Considering treatment compliance, RD was determined as S-1 60 mg/m2/day. The CR rate, primary endpoint of phase II, was 59.5% (22/37; 90%CI, 44.6-73.1%; the weighted threshold, 57.2%; p=0.46) on central review. In the phase II part, 3-year progression-free survival was 47.3% and 3-year overall survival was 61.9%. Grade 3 or 4 toxicity in phase II part included leukopenia (57.9%) neutropenia (50%), hyponatremia (28.9%), anorexia (21.1%), anemia (18.4%), thrombocytopenia (18.4%), and febrile neutropenia (2.6%). No treatment-related deaths were observed. Conclusions: Although CRT with S-1 plus cisplatin showed acceptable toxicity and favorable 3-year survival, this study did not meet its primary endpoint. Clinical trial information: 000000710.

Purpose The safety, tolerability, and pharmacokinetic (PK) interactions of MK-0646 in combination with cetuximab and irinotecan were investigated in Japanese patients with advanced colorectal cancer. Methods Twenty patients were treated in the following study arms in combination with cetuximab and irinotecan: A [MK-0646 (10 mg/kg) weekly starting on Day 22], B [MK-0646 (15 mg/kg) on Day 8, followed by 7.5 mg/kg every 2 weeks], or C [MK-0646 (10 mg/kg) on Day 1 and weekly starting on Day 22]. Dose limiting toxicities (DLTs) were evaluated during a prespecified 4-week period in arms A and B. Full PK sampling was performed to evaluate the PK interactions. Results One of the 6 evaluable patients in arm A developed a DLT (grade 3 hyperglycemia); no DLTs occurred in the 6 patients in arm B. Common treatment-related adverse events included leukopenia, neutropenia, dermatitis acneiform, paronychia, nausea, stomatitis, diarrhea, and decreased appetite. The co-administration of cetuximab and irinotecan with MK-0646 increased the MK-0646 AUC_0–168h by 25 %, with MK-0646 accumulation from the previous dose contributing to the observed increase. The co-administration of MK-0646 with cetuximab and irinotecan did not affect the PK of cetuximab and irinotecan, but reduced the C _max (from 16.8 to 13.0 ng/mL) and the AUC_0–24h (by 13 %) of SN-38, the active metabolite of irinotecan. Conclusions The triple combination of MK-0646, cetuximab, and irinotecan was well tolerated in Japanese patients with advanced colorectal cancer. These results indicate a minimal potential for PK interactions between MK-0646 and cetuximab and between MK-0646 and irinotecan/SN-38.