Kazunori Uenaka

Pharmacokinetics, Pharmacodynamics, Tolerability, and Safety of Exenatide in Japanese Patients With Type 2 Diabetes Mellitus

In this single‐blind, parallel, placebo‐controlled study, the pharmacokinetics, pharmacodynamics, tolerability, and safety of subcutaneous exenatide were evaluated in 40 Japanese patients with type 2 diabetes. Patients were allocated to 4 groups and randomized to receive exenatide (n = 8/group) or placebo (n = 2/group), with all receiving placebo on day 1. On day 2, patients received single‐dose exenatide (2.5 μg [group A] or 5 μg [groups B, C, and D]) or placebo and then bid on days 3 to 5. On days 6 to 10, groups A and B continued on 2.5 and 5 μg bid; groups C and D received 10 and 15 μg bid, respectively. The last dose was given on the morning of day 10. All adverse events were mild or moderate in severity. Exenatide was generally well tolerated up to 10 μg. Exenatide was well absorbed with a median tmax of 1.5 hours and mean t1/2 of 1.6 hours; exposure increased with dose. Up to 10 μg, exenatide reduced postprandial glucose concentrations in a dose‐dependent fashion compared with placebo; decreases were similar for 10 and 15 μg. An Emax model demonstrated that doses higher than 2.5 μg were necessary for adequate glycemic response. Based on tolerability and pharmacokinetic/pharmacodynamic relationships, 5 and 10 μg exenatide may be considered for further clinical development in Japanese patients with type 2 diabetes.

Phase I study of LY2603618, a CHK1 inhibitor, in combination with gemcitabine in Japanese patients with solid tumors.

This phase I trial evaluated LY2603618, a selective inhibitor of the DNA damage checkpoint kinase 1, in combination with gemcitabine. Japanese patients with advanced solid tumors were enrolled. All patients received gemcitabine (1000 mg/m2 on days 1, 8, and 15 every 28 days) and either 170 mg (cohort 1) or 230 mg (cohort 2) of LY2603618. The primary objective was assessment of safety/tolerability. Pharmacokinetic/pharmacodynamic marker profiles were secondary objectives. Of the 17 patients enrolled, dose-limiting toxicities were observed in one patient in cohort 1 (n=7) and in two patients in cohort 2 (n=10). The most common grade 3 or more drug-related treatment-emergent adverse events were hematological. Three patients discontinued because of adverse events. Dose-dependent decreases in LY2603618 exposure were observed, but the LY2603618 pharmacokinetics at each dose were consistent within and between cycles and did not influence gemcitabine pharmacokinetics. Circulating plasma DNA decreased from baseline in all four patients who achieved a partial response. Administration of 170 or 230 mg of LY2603618 following a standard dose of gemcitabine showed acceptable safety and tolerability in Japanese patients with solid tumors.

Solanezumab was safe and well-tolerated for Asian patients with mild-to-moderate Alzheimer's disease in a multicenter, randomized, open-label, multi-dose study

Background: Solanezumab is a humanized anti-amyloid-b monoclonal antibody being developed as a passive-immunization treatment to slow the progression of AD. It recognizes a mid-domain epitope of the amyloid-b (Ab) peptide and elicits continuous changes of Ab dynamics. Although multiple doses of solanezumab are safe and well tolerated in non-Japanese, there are no data available in Asians. This is the first study to describe the safety and tolerability of multiple doses of solanezumab in Asian patients with mild-to-moderate AD. Methods: This study was a multicenter, randomized, open-label, parallel study in Japan. Duration was 5 days to 5 weeks in Period I (eligibility), 8 weeks in Period II (treatment), and 16 weeks in Period III (follow-up). Patients were randomized 1:1:1 to 3 solanezumab dose arms: iv infusions of 400 mg once every week (QW group), 400 mg once every four weeks (Q4W group) and 400 mg once every eight weeks (Q8W group). All patients visited every week and blood samples were taken for safety, pharmacokinetics, and pharmacodynamics. Results: Thirty five patients entered the study. Thirty three patients were randomly assigned to treatment, received at least one dose of study drug, and completed the study. Eighteen patients (54.5%) were female, fifteen patients (45.5%) were male, and their ages ranged from 56 to 84 years (mean 1⁄4 70.7). There were no serious adverse events related to solanezumab; although treatment-emergent adverse events (TEAEs) were reported in 8 patients from the Q8W group (66.7%), 5 patients from the Q4W group (50.0%), and 5 patients from the QW group (45.5%). Adverse events reported were mild or moderate except one event. Only one event (pain in extremity) was judged as severe but was not related to the study drug or a study procedure. There were no infusion reactions, MRI evidence of meningoencephalitis, or clinically meaningful laboratory abnormalities. Conclusions: Solanezumab was safe and well-tolerated up to 400 mg once a week in Asian (Japanese) AD patients.

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/m2. 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).

Abstract B48: A phase 1 study of an antisense oligonucleotide against survivin (LY2181308) in Japanese patients with solid tumors

Background: Survivin is a protein known to regulate apoptosis and cell division and highly expressed in various types of cancers. The inhibition of survivin is expected to normalize the cell cycle and selectively eradicate tumor cells. LY2181308 is a second generation antisense oligonucleotide (ASO) designed to complementarily bind to human survivin mRNA and to inhibit the gene/protein expression, which in turn should restore the normal apoptotic pathway in cancer cells. To evaluate the tolerability, pharmacokinetics (PK), and anti‐tumor effect of LY2181308 in Japanese patients (pts) with solid tumors, a phase 1 dose‐escalation study was conducted. Methods: The primary objective of this study was to evaluate the tolerability of LY2181308 up to 750 mg. The secondary objectives included evaluation of PK and anti‐tumor response. Dose‐escalation cohorts include 3–6 pts starting at 400 mg with sequential escalations to 600 and 750 mg. The treatment schedule consisted in a loading dose of 3 consecutive daily intravenous infusions over 3 hours, followed by a maintenance weekly intravenous infusion over 3 hours. Results: A total of 14 pts (11 male /3 female) were enrolled into 3 cohorts (4 at 400 mg; 4 at 600 mg; 6 at 750 mg): median age = 60 (44–73). The median treatment period was 2.0 cycle (1–4). Of the 14 pts, 12 pts were evaluable for dose limiting toxicities (DLTs, 3 at 400 mg; 3 at 600 mg; 6 at 750 mg); 2 pts each at 400 mg and 600 mg were excluded due to early disease progression. Only 1 pt at 750 mg reported DLTs; Grade 3 elevations in ALT/AST/ ‐GTP. All 14 pts were evaluable for safety and PK. The most frequent adverse events (AEs) were hyperhidrosis, prothrombin time ratio increased, and pyrexia. Most AEs were CTCAE Grade 1 or 2. No deaths or study discontinuations due to any adverse events were reported. One serious AE (Grade 3 blood bilirubin increased) was observed in 1 pt with pancreatic cancer (600 mg); this toxicity was not judged to be causally related to the study drug due to disease progression. Abnormalities of blood coagulation values, commonly observed with second generation ASOs, were reported in most pts; they were all Grade 1. The plasma PK profile primarily illustrated tissue distribution, and only a small percentage of the plasma exposure (∼7%) was eliminated under the terminal elimination t½. The terminal elimination t½ was ∼21 days. The geometric mean AUC0‐∞ and Cmax following 750‐mg dose on Day3 were 324000 ng*h/mL and 66700 ng/mL, which were comparable with those of non‐Japanese pts. The terminal t½ was derived from a 4‐compartment model which was found to fit adequately the data. Consistent with the long terminal t½, the PK analyses showed that the clearance to tissue and elimination clearance were low to moderate (i.e ∼2 L/h and ∼30 L/h, respectively) and that the volume of distribution was high (>10000 L). Of the 14 pts, 12 pts who had target lesions were evaluable for anti‐tumor response. Eleven pts were Progressive Disease, and 1 pt was Stable Disease. Conclusions: LY2181308 monotherapy in doses of up to 750 mg was confirmed to be tolerable for Japanese pts with solid tumors. LY2181308 showed very long half‐life and was considered to be extensively distributed into tissues based on the rapid decrease of plasma LY2181308 concentration after the administration. Further investigations in combination with other anti‐tumor drugs are ongoing. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B48.

Abstract C121: A non-randomized, open-label, single-arm, phase 2 study of LY2875358 in Asian patients with MET diagnostic positive, advanced gastric cancer

Introduction: MET is expressed in gastric cancer and associated with poor clinical outcome. LY2875358 (LY) is a humanized immunoglobin G4 (IgG4) monoclonal bivalent antibody blocking ligand-dependent and independent MET signaling. In preclinical studies, LY showed single agent anti-tumor activity for MET amplified gastric cancer in xenograft models. Based on these results, a non-randomized, multicenter, single-arm, open-label, Phase 2 study was conducted to evaluate the antitumor activity of LY in patients (pts) with MET diagnostic positive (+), advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Methods: Pts with MET diagnostic (+), advanced gastric or GEJ adenocarcinoma, who had received 2 prior chemotherapies, were administered LY 2000 mg as flat dose intravenously every 2 weeks (Q2W) on a 28 day cycle. MET diagnostic (+) tumor status was determined by immunohistochemistry (IHC). The primary objective was to evaluate the activity of LY in terms of progression-free survival (PFS) rate at 8 weeks (+ 3 days). Secondary objectives were to assess other efficacy variables (eg overall response rate, disease control rate [DCR], PFS, overall survival [OS]), toxicity and safety profile of LY, and pharmacokinetics (PK). The exploratory objectives included evaluation of pharmacodynamics, pharmacogenomics, and exploratory biomarkers. Results: Tumor samples of 65 pts were screened for MET expression by IHC and 15 pts (23.1%) with MET diagnostic (+) were enrolled in this study. Fifteen pts (5 female, 10 male) from Asia (Japan 8, Korea 7) with a median age of 63 years (range 39-74) were enrolled. PFS rate at 8 weeks was 47% (70% Confidence Interval [CI]: 33%, 59%). There was no partial response according to RECIST, while shrinkage of tumor size was observed in 3 out of 15 pts. DCR was 40.0%, with stable disease shown in 6 out of 15 pts. Median PFS was 8.3 weeks (95% CI: 4.1, 12.1) with stable disease for up to a maximum of 37.1 weeks. Median OS was 17.1 weeks (95% CI: 6.3, Not Available). A total of 12 pts (80%) experienced at least 1 LY-related treatment-emergent adverse event (TEAE). Common LY-related TEAE (all grades) included constipation and hypoalbuminemia (3 pts [20%] each). LY-related TEAEs with Grade ≥ 3 were hyponatremia and hyperuricemia (2 events in 1 patient), and hyperkalemia (1 patient). Serious adverse events were reported in 6 patients, none of which was related to LY. There was no TEAE leading to death or study treatment discontinuation. PK profiles were similar to those observed in previous studies of LY monotherapy, which were conducted in the United States, and the majority of patients were Caucasian. Exploratory biomarker analysis (IHC data) will be presented at the venue. Conclusion: LY 2000 mg Q2W showed a well-tolerated safety profile with a limited single agent activity in heavily pretreated patients with MET diagnostic (+), advanced gastric or GEJ adenocarcinoma. Citation Format: Hyun Cheol Chung, Taroh Satoh, Do-Youn Oh, Se Hoon Park, Shigenori Kadowaki, Volker Wacheck, Ayuko Yamamura, Kazunori Uenaka, Xuejing Aimee Wang, Sameera R. Wijayawardana, Toshihiko Doi. A non-randomized, open-label, single-arm, phase 2 study of LY2875358 in Asian patients with MET diagnostic positive, advanced gastric cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C121.