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Purpose: TAS-117 is a highly potent and selective, oral, allosteric pan-AKT inhibitor under development for advanced/metastatic solid tumors. The safety, clinical pharmacology, pharmacogenomics and efficacy were investigated., Methods: This phase I, open-label, non-randomized, dose-escalating, first-in-human study enrolled patients with advanced/metastatic solid tumors and comprised three phases (dose escalation phase [DEP], regimen modification phase [RMP], and safety assessment phase [SAP]). The SAP dose and regimen were determined in the DEP and RMP. Once-daily and intermittent dosing (4 days on/3 days off, 21-day cycles) were investigated. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 of the DEP and RMP and incidences of adverse events (AEs) and adverse drug reactions (ADRs) in the SAP. Secondary endpoints included pharmacokinetics, pharmacodynamics, pharmacogenomics, and antitumor activity., Results: Of 66 enrolled patients, 65 received TAS-117 (DEP, n = 12; RMP, n = 10; SAP, n = 43). No DLTs were reported with 24-mg/day intermittent dosing, which was selected as a recommended dose in SAP. In the SAP, 98.5% of patients experienced both AEs and ADRs (grade ≥ 3, 67.7% and 60.0%, respectively). In the dose range tested (8 to 32 mg/day), TAS-117 pharmacokinetics were dose proportional, and pharmacodynamic analysis showed a reduction of phosphorylated PRAS40, a direct substrate of AKT. Four patients in the SAP had confirmed partial response., Conclusion: Oral doses of TAS-117 once daily up to 16 mg/day and intermittent dosing of 24 mg/day were well tolerated. TAS-117 pharmacokinetics were dose proportional at the doses evaluated. Antitumor activity may occur through AKT inhibition., Trial Registration: jRCT2080222728 (January 29, 2015)., (© 2024. The Author(s).)

Objective: Current strategies for the treatment of endometrial cancer in older adult patients require re-evaluation given the global trend in population aging, especially in Japan. We sought to evaluate initial treatment offered to older adult patients with endometrial cancer in Japan., Methods: We retrospectively analyzed data on the standard treatment by age group in patients with endometrial cancer who underwent surgery between January 2005 and December 2013 at the National Cancer Center Hospital (Tokyo, Japan). Patients were stratified into four groups according to age: a younger group, aged 64 years or younger; older adult group 1, aged 65-69 years; older adult group 2, aged 70-74 years; and older adult group 3, aged ≥75 years., Results: Among 551 patients with endometrial cancer diagnosed and treated at our hospital, data from 531 eligible patients were analyzed. The proportion of patients in the older adult groups 1 or 2 who received standard treatment was the same as in the younger group. However, significantly fewer patients in older adult group 3 received standard treatment compared with the younger group (26% vs. 71%, p = 0.0001). Furthermore, the proportion of patients in older adult group 3 who underwent standard surgery was significantly lower than that in the younger group (26% vs. 72%, p = 0.0001)., Conclusions: The results indicate that age 75 years and older might represent a cutoff for the development of age-based treatment strategies for endometrial cancer. This information could be used to determine the upper age limit for participation in clinical trials in Japan.

Purpose: We conducted a retrospective study to assess the outcomes of capecitabine for advanced breast cancer (ABC) after perioperative fluoropyrimidines (FPs)., Methods: The charts of patients with ABC who received capecitabine between 2008 and 2016 at the National Cancer Center Hospital (Tokyo, Japan) were reviewed. Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events (AEs) were compared between two groups: an FP group (prior perioperative FP use) and a non-FP group (no prior FP use)., Results: Overall, 288 patients (FP n = 105; non-FP n = 183) were analyzed. The two groups had similar patient characteristics. The FP group had significantly poorer PFS than the non-FP group (multivariate hazard ratio [HR] 1.33; 95% confidence interval [CI] 1.02-1.73; p = 0.036), although the OS did not differ significantly between the groups (multivariate HR 1.00; 95% CI 0.67-1.50; p = 0.994). With different cut-off values (relapse-free interval [RFI] = 3, 4, and 5 years), multivariate HRs for PFS were 1.32-1.67 (short RFI), and 1.00-1.25 (long RFI). A trend for a larger HR in the FP group compared to the non-FP group with short RFI than in that with long RFI was also seen for OS. Response rate (RR) and disease control rate (DCR) did not differ significantly between the groups (RR in FP vs non-FP 13.8 vs 21.0%; p = 0.173; DCR 54.0 vs 59.9%; p = 0.418). No significant difference in AEs existed between the groups., Conclusions: Extra caution is needed when capecitabine is considered for patients with ABC who used perioperative FP, especially those who had early recurrence.

Purpose: Predictors of response or disease control with oral medroxyprogesterone acetate (MPA) therapy in patients with metastatic or recurrence endometrial cancer remain to be elucidated. The purpose of this study was to clarify the effect of MPA in patients with endometrial cancer and identify markers that predict MPA efficacy., Methods: We retrospectively analyzed clinical and pathological factors in patients who received MPA. Expression of estrogen receptor, progesterone receptor (PgR), androgen receptor, and Ki67 index was assessed with residual tissue samples of endometrial cancer. Expression levels were evaluated semi-quantitatively using the Allred score. Correlations between expression levels and patients' characteristics, response to MPA, and survival were assessed., Results: We analyzed clinical factors in 40 patients and molecular pathological factors in 27 patients for MPA efficacy. The overall response rate was 35% in all 40 patients and there were 10 patients (25%) with continued complete or partial response for over 5 years. However, higher Allred score for PgR (p = 0.050) tended to be and lower Ki67 labeling index (p = 0.001) were significantly predictive factors for long-term complete or partial response over 5 years. Median progression-free survival was 6.4 (2-217) months and the 5-year progression-free survival rate was 32%. Multivariate analysis showed that Allred score ≥3 for PgR (p = 0.039) was the only significant predictive marker for long-term disease control. There were no severe adverse events that resulted in discontinuation of MPA., Conclusions: This study suggests the utility of MPA when the Allred score for PgR is ≥3. Future prospective studies are needed to confirm these findings.

Purpose: Weekly dose-dense paclitaxel (PTX) in combination with carboplatin (CBDCA) every 3 weeks (ddTC therapy) is a standard treatment for patients with advanced ovarian cancer. However, there is no detailed analysis of the feasibility of ddTC therapy in elderly patients with ovarian cancer., Methods: We identified patients diagnosed with ovarian, fallopian tube, or peritoneal cancer who received ddTC therapy at the National Cancer Center Hospital from April 2003 to April 2013. We assessed the feasibility of ddTC therapy in elderly patients aged 70 years or older (elderly group), comparing relative dose intensity (RDI) for PTX, CBDCA, and ddTC; adverse events; and rate of chemotherapy discontinuation to those in patients below 70 years of age (younger group)., Results: A total of 143 patients (elderly group, 22; younger group, 121) was analyzed. A comparison of RDI between these two groups showed no significant differences for PTX, CBDCA, and ddTC. Nonhematological and hematological toxicity profiles of the elderly and younger groups were similar, except that severe peripheral neuropathy (Grade 2 or higher) was more common in the elderly group. There was no significant difference in the rate of chemotherapy discontinuation (elderly group, 13.6 % vs. younger group, 7.4 %, p = 0.397)., Conclusions: Our study showed that ddTC therapy was feasible for elderly patients. However, to prevent severe neuropathy, PTX dose reduction deserves consideration.