[Pharmacological Effects of CDK4 & 6 Selective Inhibitor Abemaciclib in Hormone Receptor-Positive Breast Cancer].

Abemaciclib, a selective cyclin dependent kinases 4 and 6(CDK4 & 6)inhibitor, is under development for the treatment of hormone receptor(HR)-positive, HER2-negative breast cancer. CDK4 & 6 inhibitors attenuate Rb phosphorylation resulting in a G1 arrest and tumor growth inhibition. Abemaciclib potently inhibits both CDK4 and CDK6, with 14-fold higher potency for CDK4-cyclin D1 complexes than CDK6-cyclin D3 in enzymatic assays. Low frequency of severe neutropenia requiring drug holiday in clinical trials of abemaciclib in breast cancer patients enables continuous daily dosing. Abemaciclib's preclinical difference in selectivity for CDK4 vs CDK6 could help explain its safety profile and ability to be dosed on a continuous schedule. Continuous inhibition of CDK4 & 6 by abemaciclib results in irreversible growth inhibition through induction of senescence and apoptosis in breast cancer cell lines. Abemaciclib shows its growth inhibitory effect particularly in estrogen receptor(ER)- positive breast cancer, and sensitivity to abemaciclib is associated with high ER levels and Rb positivity. In animals bearing ERpositive breast cancer, significant tumor growth inhibition was shown by single-agent and combination with anti-estrogen agents. Abemaciclib penetrates the blood-brain barrier and showed antitumor activity in glioma models. As described above, there are some characteristics demonstrate differences of abemaciclib and other CDK4 & 6 inhibitors. In clinical studies, abemaciclib has demonstrated efficacy and generally tolerable safety profile in HR-positive, HER2-negative breast cancer patients.

Effect of First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab on Advanced Gastric Cancer in East Asia: The Phase 2 RAINSTORM Randomized Clinical Trial.

Importance: Ramucirumab, a human IgG 1 antibody against vascular endothelial growth factor receptor 2, has been shown to improve progression-free survival and overall survival in patients with advanced gastric cancer in the second-line setting. Objective: To compare progression-free survival for S-1 and oxaliplatin plus ramucirumab with that for S-1 and oxaliplatin plus placebo in patients with advanced gastric cancer. Design, Setting, and Participants: This phase 2, double-blind randomized clinical trial (RAINSTORM [First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab in Patients With Advanced Gastric Cancer]) was conducted from October 12, 2015, to April 11, 2018, at 36 sites in Japan, South Korea, and Taiwan. Participants were chemotherapy-naive patients (n = 189) with metastatic gastric or gastroesophageal adenocarcinoma. Analyses of the full analysis set and safety population were conducted between November 27, 2017, and June 4, 2018. Interventions: Patients randomized to the ramucirumab plus S-1 and oxaliplatin arm received S-1, 80 to 120 mg/d twice daily, on days 1 to 14 and oxaliplatin, 100 mg/m2, on day 1 with ramucirumab, 8 mg/kg, on days 1 and 8 in part A (21-day cycle). Patients randomized to the placebo plus S-1 and oxaliplatin arm received the same S-1 and oxaliplatin dosage as well as placebo on days 1 and 8 in part A. Eligible patients received second-line paclitaxel, 80 mg/m2, on days 1, 8, and 15 and ramucirumab, 8 mg/kg, on days 1 and 15 in part B (28-day cycle). Main Outcomes and Measures: The primary end point was progression-free survival, analyzed using the stratified log-rank test; the hazard ratio (HR) was estimated using the stratified Cox proportional hazards regression model. Secondary end points included overall survival and adverse events. Results: In total, 189 patients were randomized and received treatment: 96 to the ramucirumab plus S-1 and oxaliplatin arm and 93 to the placebo plus S-1 and oxaliplatin arm. Among the 189 patients, 121 (64.0%) were male, and the median (range) age was 62.0 (26-84) years. Median progression-free survival was not prolonged in the ramucirumab plus S-1 and oxaliplatin arm compared with the placebo plus S-1 and oxaliplatin arm (6.34 [80% CI, 5.65-6.93] vs 6.74 [80% CI, 5.75-7.13] months; HR, 1.07; 80% CI, 0.86-1.33; P = .70). Median overall survival was 14.65 (80% CI, 12.39-15.67) months in the ramucirumab plus S-1 and oxaliplatin arm and 14.26 (80% CI, 13.83-17.31) months in the placebo plus S-1 and oxaliplatin arm (HR, 1.11; 80% CI, 0.89-1.40; P = .55). The most commonly reported grade 3 or higher treatment-emergent adverse events in the ramucirumab plus S-1 and oxaliplatin arm in part A were decreased neutrophil count (14 patients [14.6%]), hypertension (10 patients [10.4%]), and anemia (10 patients [10.4%]). Conclusions and Relevance: In this randomized clinical trial, the addition of ramucirumab to first-line S-1 and oxaliplatin treatment did not prolong progression-free survival or overall survival compared with S-1 and oxaliplatin alone among East Asian patients with advanced gastric cancer; no new safety signals for ramucirumab were identified. Trial Registration: ClinicalTrials.gov identifier: NCT02539225.

Ramucirumab for the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma following disease progression on first-line platinum- or fluoropyrimidine-containing combination therapy in Japanese patients: a phase 2, open-label study.

BACKGROUND: Ramucirumab, a monoclonal antibody vascular endothelial growth factor receptor-2 antagonist, given as monotherapy improved survival in a global phase 3 study (REGARD) of patients with gastric cancer. However, REGARD did not include Japanese patients. This study evaluated the efficacy and safety of ramucirumab monotherapy in Japanese patients with advanced gastric cancer. METHODS: This multicenter, open-label, nonrandomized phase 2 study (Clinicaltrials.gov: NCT01983878) was performed at 16 Japanese sites. Patients with advanced gastric or gastroesophageal junction cancer after disease progression following first-line chemotherapy received intravenous ramucirumab 8 mg/kg every 2 weeks. Primary efficacy outcome: 12-week progression-free survival rate (PFS). RESULTS: Thirty-six patients were enrolled. The 12-week PFS rate was 23.8% [90% confidence interval (CI) 12.4-37.2); the primary outcome was not met as the lower limit of the CI was outside the threshold of 16%. Median PFS was 6.6 weeks (90% CI 6.1-7.1). No patients achieved an objective response, and 11 (31%) patients achieved disease control. Median overall survival was 8.6 months (90% CI 5.7-10.7). The most frequent treatment-emergent adverse events (TEAEs) were diarrhea (9/36; 25%) and decreased appetite (8/36; 22%). Three patients reported Grade ≥ 3 ileus; all other Grade ≥ 3 TEAEs were reported by ≤ 2 patients. The most frequent adverse events of special interest (AESIs) were hypertension (10/36; 28%), bleeding/hemorrhage (7/36; 19%), and proteinuria (7/36; 19%). All Grade ≥ 3 AESIs were reported by ≤ 2 patients. CONCLUSIONS: These findings suggest that ramucirumab monotherapy has clinical activity and a manageable safety profile in Japanese patients with gastric cancer after disease progression following first-line chemotherapy.

Dose-escalation study of tabalumab with bortezomib and dexamethasone in Japanese patients with multiple myeloma.

B-cell activating factor (BAFF) promotes the survival and adhesion of multiple myeloma (MM) cells. Tabalumab (LY2127399) is an anti-BAFF monoclonal antibody. This phase 1, multicenter, open-label, nonrandomized, dose-escalation study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of tabalumab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory MM (RRMM). Sixteen patients received intravenous i.v. tabalumab 100 mg (Cohort 1, n = 4) or i.v. tabalumab 300 mg (Cohort 2, n = 12) in combination with oral dexamethasone 20 mg/day and i.v. or s.c. bortezomib 1.3 mg/m(2) . All patients had treatment-emergent adverse events (TEAE) possibly related to study treatment; the most common TEAE were thrombocytopenia (81.3%), lymphopenia (43.8%) and increased alanine aminotransferase (43.8%). Two (20.0%) dose-limiting toxicities were observed, both in Cohort 2 (tabalumab 300 mg), which was below the predefined cutoff for tolerability (<33%). The pharmacokinetics of tabalumab were similar when bortezomib was coadministered i.v. versus s.c. The overall response rate was 56.3%, suggesting that the combined treatment was effective. In conclusion, combined treatment with these three agents was well tolerated in this population of Japanese patients with RRMM. The study was registered at www.clinicaltrials.gov (NCT01556438).

[Chemotherapy using gemcitabine hydrochloride for malignant lymphoma].

This report summarizes the use of gemcitabine for the treatment of malignant lymphoma. Gemcitabine is a deoxycytidine antagonist that has characteristics different from those of the deoxycytidine antagonist cytarabine(Ara-C). International guidelines based on the results of recent clinical studies recommend the use of gemcitabine as monotherapy and in combination therapy, particularly for relapsed and refractory malignant lymphomas. Clinical studies on gemcitabine monotherapy up to 2012 reported response rates of 51-75% for peripheral T -cell lymphoma and cutaneous T-cell lymphoma. Regarding combination therapy, the GDP regimen consisting of gemcitabine, dexamethasone, and cisplatin was associated with response rates of 62-70% for relapsed or refractory Hodgkin lymphoma and 45-53% for relapsed or refractory non-Hodgkin lymphoma, thereby displaying comparable efficacy to existing salvage chemotherapy regimens. The GDP regimen has a favorable safety profile and is also associated with favorable autologous transplantation rates, which suggests its potential as induction chemotherapy before autologous transplantation. Concerning adverse reactions requiring clinical caution, lung disorder was reported in 8 of 27 patients(30%)who received a regimen of gemcitabine in combination with bleomycin.

A phase I study of tasisulam sodium using an albumin-tailored dose in Japanese patients with advanced solid tumors.

PURPOSE: This phase I study was designed to determine the maximum tolerated dose (MTD) and the dose to be recommended for a future phase II study of tasisulam sodium in Japanese patients with advanced, refractory solid tumors. Safety, pharmacokinetics and preliminary anti-tumor activities were assessed. Due to high-affinity albumin binding, an albumin-tailored dose to reduce the variability in tasisulam exposure was also studied. METHODS: A dose escalation scheme of tasisulam was used over 4 dose levels. Dose levels 1-3 targeted the maximum plasma concentration (C max) of 300, 340, and 360 µg/mL. Dose level 4 used an albumin-tailored range of C max-targeted doses to achieve an albumin-corrected exposure (AUCalb) of 1,200-6,400 µg h/mL, the range chosen for global tasisulam studies. Tasisulam was administered intravenously on day 1 of each 21-day (dose levels 1 and 2) or 28-day (dose levels 3 and 4) cycle. RESULTS: The major adverse events were related to bone marrow suppression, particularly neutropenia and thrombocytopenia. Dose-limiting toxicities (DLTs) were not observed until dose level 4, where 3 out of 6 patients experienced DLT, despite a tendency toward lower AUCalb variability (CV %) in the albumin-tailored dose group (38 %) compared with the targeted C max groups (50-236 %). CONCLUSIONS: Tasisulam in doses up to dose level 3 (target C max 360 µg/mL) was well tolerated. Although albumin-tailored dosing provided less AUCalb variability, a MTD that aligns with other global tasisulam studies was not identified. A lower AUCalb range may be required for the Japan population.

[Safety profiles of gemcitabine hydrochloride(GEMZAR®)in Japanese clinical studies].

To elucidate the detailed profiles of major adverse events associated with gemcitabine hydrochloride, such as myelosuppression and interstitial pneumonitis (IP), we reanalyzed the results from Japanese clinical studies conducted by Eli Lilly Japan K. K. in patients with various types of cancer. Myelosuppression was clearly apparent after starting therapy at 2-3 weeks in the 28- day course monotherapy group, and at 2 weeks in the 21-day course combination therapy group with paclitaxel, cisplatin, or docetaxel. Increases in the number of courses did not necessarily lead to worsening of myelosuppression. IP possibly related to gemcitabine was seen in 6 out of 5 23 monotherapy patients and 5 out of 233 combination therapy patients. Five of these 11 patients were diagnosed in the first course; however, another patient was diagnosed with IP in Course 6. Two of these patients died of IP, one of whom had a past history of interstitial lung disease. These results indicate that ample attention should be paid to myelosuppression 2-3 weeks after the start of therapy, and to IP during the entire course of therapy.