Safety Profile In Japanese Patients Research Articles

A randomized, double-blind, phase II study of ramucirumab plus docetaxel vs placebo plus docetaxel in Japanese patients with stage IV non-small cell lung cancer after disease progression on platinum-based therapy

ObjectivesRamucirumab plus docetaxel prolongs survival in patients with non-small cell lung cancer (NSCLC) with disease progression after platinum-based therapy. This phase II, double-blind, randomized, placebo-controlled study assessed efficacy and safety of second-line ramucirumab-docetaxel in Japanese patients with NSCLC. Materials and methodsPatients with NSCLC with progression after platinum-based therapy (28 Japanese sites; 19 December, 2012 to 22 May, 2015) were randomized (computer-generated sequence) to ramucirumab 10mg/kg or placebo, followed by docetaxel 60mg/m2 (Day 1, 21-day cycle). Prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) monotherapy was prohibited in the primary population, but EGFR mutation-positive NSCLC patients who were treated with EGFR-TKI were enrolled as a separate exploratory population. Primary endpoint was progression-free survival (PFS); secondary outcomes included overall survival, tumor response rates, and safety. Investigator tumor assessments were used for the efficacy endpoints. ResultsIn the primary population (N=160 randomized, n=157 treated), median (95% CI) PFS was longer with ramucirumab-docetaxel (5.22 [3.52–6.97] months; n=76) than with placebo-docetaxel (4.21 [2.83–5.62] months; n=81); hazard ratio 0.83 (95% CI 0.59–1.16). Median (95% CI) overall survival was 15.15 (12.45–26.55) months with ramucirumab-docetaxel and 14.65 (11.93–24.44) months with placebo-docetaxel (hazard ratio [95% CI] 0.86 [0.56–1.32]). Objective response rate (28.9% vs 18.5%) and disease control rate (78.9% vs 70.4%) were numerically greater with ramucirumab-docetaxel than with placebo-docetaxel. Incidence and severity of most adverse events were similar, but febrile neutropenia was more common with ramucirumab-docetaxel (34.2%) than with placebo-docetaxel (19.8%). ConclusionSecond-line ramucirumab-docetaxel improved PFS similar to that seen in the REVEL trial with a manageable safety profile in Japanese patients with NSCLC.

Regorafenib for advanced gastrointestinal stromal tumors following imatinib and sunitinib treatment: a subgroup analysis evaluating Japanese patients in the phase III GRID trial

The randomized, double-blind, placebo-controlled GRID trial tested the oral multikinase inhibitor regorafenib in 199 patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib, and showed a significant improvement in progression-free survival (PFS) versus placebo [hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.19-0.39; p < 0.0001]. A subgroup analysis of Japanese patients in the GRID study was performed to compare the efficacy and safety of oral regorafenib 160 mg once daily with matching placebo, in combination with best supportive care. The primary study endpoint was progression-free survival (PFS); safety was evaluated through the incidence of adverse events (AEs). Seventeen Japanese patients were randomized to regorafenib (n = 12) or placebo (n = 5). Patient demographics were consistent with those of the overall study population. PFS was significantly longer with regorafenib than placebo (HR 0.08; 95 % CI 0.02-0.45; p = 0.000164). Centrally assessed disease control rates were 58 % and 20 % in the regorafenib and placebo groups, respectively (p = 0.080796). Treatment-related adverse events (AEs) were reported in all regorafenib-treated patients and 60 % of placebo recipients; the most frequent AE was hand-foot skin reaction (HFSR) (92 % versus 20 %, respectively). Regorafenib showed efficacy and a manageable safety profile in Japanese patients with advanced GIST, consistent with the overall GRID study population. AEs, such as HFSR and maculopapular rash, were observed more frequently in Japanese patients. Although dose modification was frequently reported, only one patient with hepatic failure discontinued regorafenib because of AEs.

Abstract C68: Phase I study of administration of LY2523355, an Eg5 inhibitor, for 3 consecutive days every 3 weeks in Japanese patients with refractory solid tumors.

Abstract Background: Eg5, a mitotic motor kinesin, plays an essential role in bipolar spindle formation. Clinical studies on LY2523355 (Litronesib), an allosteric Eg5 inhibitor, were ongoing in several countries. This Phase I study evaluated the tolerability, safety and pharmacokinetics of LY2523355 in Japanese patients with refractory solid tumors to determine the recommended dose for further studies. Methods: This was an open-label, dose-escalation study. LY2523355 was intravenously administered over 60 min on days 1, 2, and 3 every 3 weeks at 1 of 3 dose levels: 2, 4, and 5 mg/m2/day. Doses were escalated in a classic 3 + 3 design. Toxicity was assessed with NCI-CTCAE. Tumor responses were assessed according to the RECIST. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia for &amp;gt;7 days, grade 4 thrombocytopenia or grade 3 thrombocytopenia requiring platelet transfusion, a neutrophil count of &amp;lt;500/μL with a fever of &amp;gt;38.5°C that lasted for &amp;gt;2 days, or grade ≥3 non-hematologic toxicity. G-CSF was used to treat grade 4 neutropenia or grade 3 febrile neutropenia. Results: Twelve patients were treated at doses of 2 (n = 3), 4 (n = 3), and 5 (n = 6) mg/m2/day. The male-to-female ratio was 7:5 and the median age was 61.5 years. The tumor types were non-small cell lung cancer (n = 2), colorectal cancer (n = 3), small cell lung cancer (n = 2), angiosarcoma (n = 1), breast cancer (n = 1), esophageal cancer (n = 1), gastric cancer (n = 1), and ovarian cancer (n = 1). The main toxicities were neutropenia and leukopenia (100%). Grade 4 neutropenia was observed in 83% of patients; neutrophil levels recovered to &amp;gt;500/μL within 7 days with G-CSF support in all patients. Grade 3 febrile neutropenia was observed in 2 (66%) patients at 4 mg/m2/day and in 6 (100%) patients at 5 mg/m2/day, but these were manageable with appropriate antibiotics administration. DLT was not noted up to 5 mg/m2/day, the dose used in parallel overseas Phase II studies. In pharmacokinetic analysis, exposure of LY2523355 increased dose-proportionally across these doses. None of the predictive factors, including gender, were associated with pharmacokinetic parameters or toxicity. The pharmacokinetic parameters were similar to those observed in Western populations. No objective tumor responses were observed. Conclusions: The recommended dose of LY2523355 with therapeutic G-CSF use for further studies was determined to be 5 mg/m2/day on days 1, 2, and 3 with a manageable safety profile in Japanese patients with refractory solid tumors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C68. Citation Format: Yutaka Fujiwara, Hiroshi Nokihara, Noboru Yamamoto, Yasuhide Yamada, Hiroshi Wakui, Shinji Nakamichi, Hidenori Mizugaki, Satoru Kitazono, Hironori Kanda, Kohei Suzuki, Shiro Akinaga, Tomohide Tamura. Phase I study of administration of LY2523355, an Eg5 inhibitor, for 3 consecutive days every 3 weeks in Japanese patients with refractory solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C68.

A phase I study of EMD 525797, a novel humanized monoclonal antibody to human integrin alpha v, in Japanese patients with solid tumor.

e13510 Background: Integrin alpha v, in association with several integrin beta subunits, plays critical roles in migration, invasion, proliferation, and survival of both tumor and endothelial cells and represents an attractive target for cancer treatment. EMD 525797 is a humanized monoclonal IgG2 antibody specifically targeting integrin alpha v. Methods: The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of EMD 525797 were assessed in Japanese patients with advanced solid tumors, treated with intravenous infusions of 250, 500, 1000, or 1500 mg of EMD 525797 (given over 1 h), who received 3 doses (weeks 1, 3, and 5) before response assessment during week 6. Thereafter, patients without progressive disease could receive further doses every 2 weeks. Dose-limiting toxicities (DLTs) were assessed over the first 4 weeks and safety was monitored until 31 days after the last administration of EMD 525797. Results: A total of 27 patients were treated. Regarding the primary site of disease, 17 patients had colorectal cancer, 3 pancreatic cancer, 2 gastrointestinal stromal tumors (GIST), 1 esophageal cancer, 1 gastric cancer, 1 rectal carcinoid, 1 cholangiocarcinoma, 1 hepatocellular carcinoma, and 1 leiomyosarcoma. Twenty-five patients (92.6%) experienced treatment-emergent adverse events (TEAEs); nausea (25.9%), headache (22.2%), pyrexia (22.2%), stomatitis (22.2%), and vomiting (22.2%) were the most common. None of these TEAEs was greater than grade 3 by NCI-CTCAE version 4.0 and no DLT was observed. Fourteen (51.9%) of the TEAEs were possibly related to EMD 525797. Two patients, 1 with GIST and 1 with rectal carcinoid, had longer than expected exposure time (&gt;84 days). EMD 525797 showed a non-linear PK profile. Distribution volume and clearance after EMD 525797 administration did not show apparent ethnic difference considering body weight influence. Conclusions: EMD 525797 was well tolerated in Japanese patients. The safety profile in Japanese patients was comparable to the results from Caucasian patients. In some patients EMD 525797 treatment duration was longer than expected. Clinical trial information: NCT01327313.

Phase 1 study of trebananib (AMG 386), an angiogenesis targeting angiopoietin-1/2 antagonist, in Japanese patients with advanced solid tumors

PurposeTo evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of trebananib (AMG 386)—a first-in-class angiopoietin-1/2 antagonist peptide-Fc fusion protein—in Japanese patients, we conducted a phase 1, dose escalation study.MethodsEligible patients were men or women, aged between 20 and 74 years, who had histologically or cytologically confirmed advanced solid tumors refractory to standard treatment. Trebananib (3, 10, and 30 mg/kg) was administered intravenously over 60 min in weekly cycles.ResultsFrom June 2009 to April 2010, a total of 18 patients (6 for each dose cohort) were enrolled into the study. Trebananib was tolerated at all dose levels. No dose-limiting toxicities were observed. The most common adverse events were peripheral edema, constipation, fatigue, and pyrexia. Exposure to trebananib appeared to increase according to the dose administered. Serum clearance appeared to be similar across the dose range with the mean terminal-phase half-life ranging from 93.9 to 95.9 h. No neutralizing antibodies were detected. Tumor response was assessed in 18 patients. Of these, one patient with colon cancer in the 3-mg/kg cohort and one with bladder cancer in the 30-mg/kg cohort had partial responses as their best responses. These 2 patients were on treatment at the time of data cutoff (January 17, 2012).ConclusionTrebananib was tolerated and showed acceptable safety profile in Japanese patients with advanced solid tumors. The pharmacokinetic profiles were similar to those in the previous studies in the United States. Trebananib also showed evidence of durable antitumor activity in some patients.

Phase I study of TLR9 agonist PF‐3512676 in combination with carboplatin and paclitaxel in patients with advanced non‐small‐cell lung cancer

This phase I, open-label study investigated the Toll-like receptor 9 agonist, PF-3512676, in combination with carboplatin and paclitaxel in Japanese patients with advanced, non-small-cell lung cancer (NSCLC). Patients (n = 12) with treatment-naive stage IIIB or IV NSCLC received single-agent PF-3512676 subcutaneously once during the first 7 days (monotherapy phase) in three escalating dose levels (0.1, 0.2, and 0.4 mg/kg) followed by a combination phase during which patients received 0.1 or 0.2 mg/kg PF-3512676 subcutaneously on days 8 and 15 of each 3-week cycle of carboplatin (area under the curve, 6 mg x min/mL) and paclitaxel (200 mg/m(2)). Safety and pharmacokinetics of PF-3512676 were assessed during monotherapy and combination therapy phases. PF-3512676 was tolerable as monotherapy or in combination with chemotherapy in patients with NSCLC. Most common treatment-related, non-hematologic adverse events (AEs) throughout the study were injection-site reactions (n = 12, 100%) and flu-like symptoms (n = 11, 91.7%) that were each grade 1 or 2 in all but one patient. All patients experienced neutropenia and leukopenia (>or=grade 3 in 11 [91.7%] and seven [58.3%] patients, respectively). One patient in dose level 2 had a dose-limiting toxicity: grade 3 rash and grade 3 increase in gamma-glutamyltransferase during combination therapy. Mean PF-3512676 half-life ranged from 4.8 to 21.6 h (longer with higher doses). Four (33%) patients had objective responses (one complete response, three partial responses), and seven (58%) patients achieved stable disease. PF-3512676 as monotherapy and in combination with chemotherapy had an acceptable safety profile in Japanese patients with treatment-naive NSCLC.