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Doi T.,National Cancer Center Hospital East | Takiuchi H.,Osaka Medical College | Ohtsu A.,National Cancer Center Hospital East | Fuse N.,National Cancer Center Hospital East | And 9 more authors.
British Journal of Cancer | Year: 2012

BACKGROUND: This phase I first-in-human study was conducted in Japanese patients to investigate the safety, pharmacokinetics (PKs), and determine the maximum tolerated dose (MTD) of oral TAK-285, a novel dual erbB protein kinase inhibitor that specifically targets human epidermal growth factor receptor (EGFR) and HER2. METHODS: The TAK-285 dose was escalated until MTD was determined. A second patient cohort received TAK-285 at the MTD for at least 4 weeks. RESULTS: In all, 26 patients received TAK-285 at doses ranging from 50 to 400 mg once daily (q.d.) or twice daily (b.i.d.); 20 patients made up the dose escalation cohort and the remaining 6 patients were the repeated administration cohort. TAK-285 was well tolerated. Dose-limiting toxicities noted in two patients who received 400 mg b.i.d. were grade 3 increases in aminotransferases and grade 3 decreased appetite. Consequently, the MTD was determined to be 300 mg b.i.d. Absorption of TAK-285 was rapid after oral dosing, and plasma exposure at steady-state increased in a dose-proportional fashion for doses ranging from 50 to 300 mg b.i.d. A partial response was observed for one patient with parotid cancer who received 300 mg b.i.d. CONCLUSION: The toxicity profile and PK properties of oral TAK-285 warrant further evaluation. © 2012 Cancer Research UK. All rights reserved.


Boku N.,St. Marianna University School of Medicine | Sugihara K.,Tokyo Medical and Dental University | Kitagawa Y.,Keio University | Hatake K.,Hematology of Cancer Institute Hospital | And 8 more authors.
Japanese Journal of Clinical Oncology | Year: 2014

Objective: Panitumumab was approved in Japan in April 2010 for the treatment of Kirsten rat sarcoma-2 virus oncogene wild-type unresectable and recurrent colorectal cancer. We conducted a post-marketing surveillance study to evaluate the safety and effectiveness of panitumumab. Methods: After panitumumab was commercially available in Japan, all patients to be treated with panitumumab were enrolled. Data on baseline characteristics, treatment outcome, and incidence and severity of adverse drug reactions were collected. Results: In total, 3091 patients were registered. In the safety analysis set (n = 3085), panitumumab was administered as monotherapy (40.7%) or combination therapy (59.4%). The median treatment duration was 113 days (range: 1-559 days), and 451 (14.6%) patients received panitumumab for ≥ 10 months. The overall incidence rate of adverse drug reactions was 84.1%, and the most common adverse drug reaction was skin disorders (78.4%). The incidence rates (all grades) of interstitial lung disease, infusion reaction, electrolyte abnormalities and cardiac disorders were 1.3% (mortality rate: 0.6%), 1.5, 19.3 and 0.2%, respectively. The median survival time of patients treated with panitumumab monotherapy as the third-line, or later, therapy was 10.3 months. Conclusion: This post-marketing survey in clinical practice confirmed the safety and effectiveness of panitumumab. The benefit/risk balance for panitumumab in Japanese patients with unresectable colorectal cancer remains favorable. © The Author 2014.


Ogura M.,Red Cross | Tobinai K.,National Cancer Center Hospital | Hatake K.,Cancer Institute Hospital | Ishizawa K.,Tohoku University | And 10 more authors.
Cancer Science | Year: 2014

Brentuximab vedotin is an antibody-drug conjugate that selectively delivers the antimicrotubule agent monomethyl auristatin E into CD30-expressing cells. To assess its safety, pharmacokinetics, and efficacy in Japanese patients with refractory or relapsed CD30-positive Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, we carried out a phase I/II study. Brentuximab vedotin was given i.v. on day 1 of each 21-day cycle up to 16 cycles. In the phase I part of a dose-escalation design, three patients per cohort were treated at doses of 1.2 and 1.8 mg/kg. In the phase II part, a dose of 1.8 mg/kg was given to 14 patients (nine with Hodgkin's lymphoma and five with systemic anaplastic large-cell lymphoma). The median number of treatment cycles was 16 (range, 4-16). In the phase I part, no dose-limiting toxicity event was observed. In the total population, common adverse events included lymphopenia (80%), neutropenia (65%), leukopenia (65%), and peripheral sensory neuropathy (60%). Grade 3/4 adverse events in more than two patients were lymphopenia (50%) and neutropenia (15%). The pharmacokinetic profile was similar to that observed in the previous studies in the USA. In the phase II part, six patients (67%) with Hodgkin's lymphoma achieved an objective response with 56% of complete response rate, and five patients (100%) with systemic anaplastic large-cell lymphoma achieved an objective response with 80% of complete response rate. These results show that brentuximab vedotin has an acceptable safety profile and promising antitumor activity in the Japanese population. This trial was registered in JAPIC Clinical Trials Information (JapicCTI-111650). This phase I/II study was to investigate the tolerability, safety and efficacy of brentuximab vedotin. This study indicates that 1.8 mg/kg brentuximab vedotin given every 3 weeks has a manageable safety profile and has high overall tumor response rate in Japanese patients with relapsed or refractory Hodgkin lymphoma or systemic anaplastic large-cell lymphoma. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.


Okusaka T.,National Cancer Center Hospital | Ikeda M.,National Cancer Center Hospital East | Fukutomi A.,Shizuoka Cancer Center | Kobayashi Y.,Takeda Bio Development Center | And 3 more authors.
Japanese Journal of Clinical Oncology | Year: 2014

Objective: Previous Phase 1 studies have shown the acceptable safety profile of ganitumab- a fully human monoclonal antibody to insulin-like growth factor Type 1 receptor-in patients with advanced solid tumors. However, ganitumab 20 mg/kg in combination with gemcitabine had not been administered to patients with metastatic pancreatic cancer. To evaluate the safety, tolerability, pharmacokinetics and antitumor activity of ganitumab 20 mg/kg combined with gemcitabine 1000 mg/m2 as first-line therapy in patients with metastatic pancreatic cancer, we conducted a Phase 1b study. Methods: Eligible patients were adults with previously untreated metastatic adenocarcinoma of the pancreas. Patients received gemcitabine 1000 mg/m2 on Days 1, 8 and 15 plus ganitumab 20 mg/kg on Days 1 and 15 of each 28-day cycle. Gemcitabine was administered intravenously over 30-60 min. Ganitumab was administered intravenously over 60 min after completing gemcitabine infusion. Results: Six patients were enrolled and received the study treatment. All patients had thrombocytopenia and leukopenia. Other most common adverse events were neutropenia and nausea. One patient had a dose-limiting toxicity defined as Grade 3 neutropenia with fever. Exposure to ganitumab 20 mg/kg was not affected by the administration of gemcitabine. No apparent pharmacokinetic drug-drug interaction was observed. No anti-ganitumab antibodies were detected. Five patients had a measurable tumor region at baseline. Of these, four patients had a best response of stable disease. Conclusions: Ganitumab 20 mg/kg combined with gemcitabine 1000 mg/m2 was tolerable and showed an acceptable safety profile in patients with untreated metastatic pancreatic cancer. © The Author 2014. Published by Oxford University Press.


Tahara M.,National Cancer Center Hospital East | Onozawa Y.,Shizuoka Cancer Center | Fujii H.,Jichi Medical University | Monden N.,National Hospital Organization Shikoku Cancer Center | And 3 more authors.
Japanese Journal of Clinical Oncology | Year: 2014

Objective: In Japan, cisplatin/5-fluorouracil 80/800 (cisplatin 80 mg/m2, 5-fluorouracil 800 mg/m2) is widely used to treat recurrent/metastatic squamous cell carcinoma of the head and neck, whereas cisplatin/5-fluorouracil 100/1000 (1000 mg/m2/24 h by continuous intravenous infusion on Days 1-4 plus cisplatin 100 mg/m2 on Day 1 in 3-week cycles) is the standard treatment in Europe and North America. Methods: We prospectively evaluated the feasibility of cisplatin/5-fluorouracil 100/1000 in Japanese patients enrolled in the global Phase 3 study of panitumumab 9 mg/kg combined with cisplatin/5-fluorouracil 100/1000 (Arm 1) versus cisplatin/5-fluorouracil 100/1000 alone (Arm 2). Results: Twenty Japanese patients were enrolled and received treatment (Arm 1, n 1/4 13; Arm 2, n 1/4 7). Grade 3/4 adverse events included neutropenia, hypomagnesemia, stomatitis, hyponatremia, paronychia, febrile neutropenia, decreased appetite and hypokalemia. There were no fatal adverse events. Median overall survival was not estimable in Arm 1 and 15.4 months in Arm 2. Median progression-free survival was 6.9 months in Arm 1 and 5.7 months in Arm 2. The median number of infusions (cycles) of cisplatin was 5 in Arm 1 and 4 in Arm 2; the median number of infusions (cycles) of 5-fluorouracil was 6 in both arms. The mean administered dose for cisplatin was 93.6 mg/m2 in Arm 1 and 97.2 mg/m2 in Arm 2, and 3732.6 and 3880 mg/m2 in Arm 1 and Arm 2, respectively, for 5-fluorouracil. Conclusions: These results suggested that cisplatin/5-fluorouracil 100/1000 was feasible for the recurrent/metastatic squamous cell carcinoma of the head and neck in Japanese patients. © The Author 2014. Published by Oxford University Press.


Doi T.,National Cancer Center Hospital East | Murakami H.,Shizuoka Cancer Center | Ohtsu A.,National Cancer Center Hospital East | Fuse N.,National Cancer Center Hospital East | And 9 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2011

Purpose: Conatumumab is a fully human monoclonal agonist antibody against human death receptor 5 (DR5). The primary objectives of this phase 1 study were to assess the safety, tolerability, and pharmacokinetics (PK) of conatumumab in Japanese patients with advanced solid tumors. Methods: This is an open-label ascending dose study with a starting dose level of 3 mg/kg. Subsequent doses of 10 and 20 mg/kg were planned. Six patients were enrolled into 1 of 3 dose cohorts (3, 10, or 20 mg/kg) of conatumumab administered intravenously once every 2 weeks as a single agent. No conatumumab was administered on day 43 to allow the assessment of terminal PK parameters. The primary endpoints were the incidence of dose-limiting toxicities (DLTs) and assessment of PK parameters of conatumumab. Results: Eighteen patients received at least 1 dose of conatumumab. There were no DLTs observed as defined in the protocol. No patients had an adverse event leading to conatumumab discontinuation. Conatumumab demonstrated dose-linear kinetics. A best response of stable disease was reported in nine patients. Monocytes were found to express DR5 and showed a high degree of conatumumab receptor occupancy after treatment at all dose levels. Conclusions: Conatumumab administered up to 20 mg/kg once every 2 weeks was well tolerated in Japanese patients with advanced solid tumors. Adverse events and PK in these patients were similar to those in the first in human (FIH) study. © 2010 Springer-Verlag.


Doi T.,National Cancer Center Hospital East | Ohtsu A.,National Cancer Center Hospital East | Fuse N.,National Cancer Center Hospital East | Yoshino T.,National Cancer Center Hospital East | And 4 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2013

Purpose: To 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. Methods: Eligible 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. Results: From 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). Conclusion: Trebananib 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. © 2012 The Author(s).


PubMed | Takeda Bio Development Center
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

318 Background: AMG 479 is a fully human monoclonal antibody against human IGF-1R that inhibits the survival and proliferative signals driven by IGF-1 and -2.Patients (Pts) were enrolled into 1 of 3 dose cohorts (6, 12 or 20 mg/kg) of single-agent AMG 479 administered intravenously Q2W. Dose-limiting toxicity (DLT) was assessed for the first 28 days. The primary objectives were to assess the safety, tolerability, and pharmacokinetics (PK) of AMG 479 in Japanese pts with advanced solid tumors. An exploratory pharmacodynamic (PD) analysis was done to investigate the relationship between exposure and changes in the level of circulating factors in IGF-1R pathway (IGFBP-3 and total IGF-1).Nineteen pts with ECOG 0-1 (6 in cohort 1 and 3, 7 in cohort 2) received at least 1 dose of AMG 479. Median age was 58.0 years. Tumor types included: breast (4), gastric (3), rectal (2), NSCL (2), thymic (2), and other cancers (6). Enrollment has been completed; 5 pts remained on study as of 15 March 2010. No DLTs were observed. Three serious adverse events (SAE) were reported, only respiratory tract haemorrhage in a subject with thymic carcinoma was considered by the investigator to be related to AMG 479. The most common grade 3 AEs were neutropenia (21%), leukopenia (16%) and lymphopenia (11%). There was a trend of dose-dependency on severity of thrombocytopenia, but not on that of neutropenia. No neutralizing anti-AMG 479 antibodies were detected. PK was dose-linear and similar to PK in non-Japanese pts. Tumor response data were available for 17 pts. Stable disease (defined as a lack of progression at the first 8-week assessment) as best response was reported in 6 pts and progressive disease was reported in 11 pts. Exploratory PD marker analysis demonstrating exposure dependent changes will be presented.AMG 479 up to 20 mg/kg was tolerable in Japanese pts with advanced solid tumors. The AE and PK profiles were similar to those previously observed in non-Japanese pts. An international phase 3 study in metastatic pancreatic cancer pts is planned based on the promising results from phase 1b/2 study (ASCO 2010, Abs 4035). [Table: see text].


Osaka Japan, August 1, 2013 --- Takeda Pharmaceutical Company Limited (“Takeda”) announced today its decision to transfer the current business of Takeda Bio Development Center Limited (“Takeda Bio”) to Takeda under the agreement concluded between both parties. Dedicated oncology therapeutic area expertise will be maintained within Japan, with direct accountability to the Global Oncology Therapeutic Area Unit. The clinical development of Takeda’s oncology products pipeline in Japan for which Takeda Bio has been responsible will be handled by Takeda’s Pharmaceutical Development Division, and after the completion of the transfer scheduled in April 2014, Takeda Bio will be dissolved. Takeda Bio has demonstrated track record of success including the regulatory approval in Japan of Vectibix® (generic name: panitumumab), a treatment for unresectable, advanced or recurrent colorectal cancer with wild-type KRAS, and also an NDA submission of brentuximab vedotin for the treatment of malignant lymphoma. Takeda Bio is currently conducting Phase 3 clinical trials of trebananib for ovarian cancer, orteronel for prostate cancer, and motesanib diphosphate for advanced non-squamous non-small cell lung cancer, among other trials. All the clinical trials will continue as currently planned under the responsibility and coordination of Takeda's Pharmaceutical Development Division. With the transfer of the business of Takeda Bio, Takeda’s development operations for both oncology and non-oncology pipelines in Japan will be fully integrated, supporting increased efficiencies and enhanced decision-making.  These actions are part of Takeda’s global initiatives to enhance its robust and efficient operating model. Note: Takeda Bio with renewed name in April 2008 restarted as Takeda’s wholly owned subsidiary, and prior to that, it had been wholly owned subsidiary of Amgen Inc. (Thousand Oaks, Calif.) in Japan. The launch of Takeda Bio was based on the agreement between Amgen Inc. and Takeda in February 2008, when both parties also agreed that Takeda licensed development pipeline from Amgen. (1)    Company name: Takeda Bio Development Center Limited (2)    Location: Marunouchi Eiraku Building, 1-4-1, Marunouchi, Chiyoda-ku, Tokyo, Japan (3)    Legal Representative: Haruo Kitado (4)    Business: Development of pharmaceutical products (5)    Established: March 26, 1992 (6)    Capital stock: 975 million yen (7)    Shares: Non-listed (8)    Shareholders of Takeda Bio: wholly owned subsidiary of Takeda Pharmaceutical Company Limited (9)    Number of employees: 108 (as of July 1, 2013)

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