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Phase II Study of Motesanib in Japanese Patients with Advanced Gastrointestinal Stromal Tumors with Prior Exposure to Imatinib Mesylate

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Phase II Study of Motesanib in Japanese Patients with Advanced Gastrointestinal Stromal Tumors with Prior Exposure to Imatinib Mesylate Cancer Chemother Pharmacol (2010) 65:961–967 DOI 10.1007/s00280-009-1103-9 ORIGINAL ARTICLE Phase II study of motesanib in Japanese patients with advanced gastrointestinal stromal tumors with prior exposure to imatinib mesylate Akira Sawaki · Yasuhide Yamada · Yoshito Komatsu · Tatsuo Kanda · Toshihiko Doi · Masato Koseki · Hideo Baba · Yu-Nien Sun · Koji Murakami · Toshirou Nishida Received: 24 May 2009 / Accepted: 29 July 2009 / Published online: 19 August 2009 © The Author(s) 2009. This article is published with open access at Springerlink.com Abstract according to the Common Terminology Criteria for Purpose Motesanib (AMG 706) is a multitargeted anti- Adverse Events (version 3). cancer agent with an inhibitory action on the human vascu- Results Of 35 enrolled and treated patients, no patient lar endothelial growth factor receptor, the platelet-derived showed a complete response, and one patient showed a par- growth factor receptor, and the cellular stem-cell factor tial response (PR). Seven had stable disease (SD) for at receptor (KIT). The aim of this single-arm phase II clinical least 24 months, two of whom continued to have SD for study was to assess the eYcacy and safety of single-agent more than 2 years. The median progression-free survival motesanib in Japanese patients with advanced gastrointesti- time was 16.1 weeks. Motesanib was well tolerated; com- nal stromal tumors with prior exposure to imatinib monly reported treatment-related adverse events were mesylate. hypertension, diarrhea, and fatigue. Anemia was the only Methods All patients had experienced progression or hematological toxicity that was reported. relapse while undergoing with imatinib as 400 mg/day or Conclusions One patient showed PR, and seven patients higher. The patients were administered 125 mg of motesa- showed SD more than 24 weeks. Motesanib was found to nib once daily. The primary endpoint was overall response. be safe and well tolerated. The observed toxicities were EYcacy was evaluated according to the Response Evalua- consistent with Phase I study Wndings. tion Criteria in Solid Tumor, and safety was assessed A. Sawaki (&) M. Koseki Department of Gastroenterology, Department of Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, National Hospital Organization Kure Medical Center, Chikusa-ku, Nagoya, Aichi 464-8681, Japan Hiroshima, Japan e-mail: [email protected] H. Baba Y. Yamada Department of Surgical Pathology, Gastrointestinal Oncology Division, Kumamoto University Hospital, Kumamoto, Japan National Cancer Center Hospital, Tokyo, Japan Y.-N. Sun Y. Komatsu Department of Pharmacokinetics and Drug Metabolism, Department of Gastroenterology, Amgen Inc., Thousand Oaks, CA, USA Hokkaido University Hospital, Hokkaido, Japan K. Murakami T. Kanda PET Center, Dokkyo University School of Medicine, Digestive and General Surgery 2 Division, Tochigi, Japan Niigata University Hospital, Niigata, Japan T. Nishida T. Doi Department of Digestive Surgery, Division of Gastrointestinal Oncology, Osaka University Hospital, Osaka, Japan National Cancer Center Hospital East, Chiba, Japan 123 962 Cancer Chemother Pharmacol (2010) 65:961–967 Keywords Motesanib · Angiogenesis inhibitor · growth factor receptors 1, 2, and 3, as well as the cellular Gastrointestinal stromal tumor (GIST) KIT, the platelet-derived growth factor receptor (PDGFR), and the glial-derived nerve growth factor family ligand RET. The safety and pharmacokinetic (PK) proWle of Introduction motesanib were evaluated in a Phase I, monotherapy, open- label, dose-Wnding study [10]. In this study, motesanib Gastrointestinal stromal tumor (GIST) is a rare stromal showed clinical activity in patients with advanced refrac- neoplasm that predominantly arises from the muscularis tory solid tumors; SD was observed in a signiWcant propor- propria layers, representing the most common mesenchy- tion of the patients, although the overall tumor response mal tumor of the gastrointestinal tract. Although the pri- rate was low. mary therapy for nonmetastatic GIST is surgical resection, The above Wndings prompted us to conduct a Phase II there still remain unresectable cases of advanced or meta- study to evaluate the eYcacy, safety, and PK of motesanib static GIST. Unresectable GISTs are resistant to conven- in Japanese patients with advanced GIST, after failure or tional chemotherapy and radiotherapy [1]. Before imatinib withdrawal of imatinib mesylate due to resistance or intol- mesylate was introduced in clinical practice, the prognosis erance. for patients with unresectable GIST was dismal, with a median survival period of 22 months [2]. The critical transforming and oncogenic mechanisms of Materials and methods GISTs are activating mutations in the stem-cell factor receptor, KIT tyrosine kinase [3]. About 5% of GISTs are Patients caused by activating mutations of the platelet-derived growth factor receptor alpha (PDGFRA), and are indepen- Japanese patients with pathologically conWrmed advanced dent of c-kit mutations [4]. The c-kit and PDGFRA muta- or metastatic GIST were eligible for this study if they met tions appear to be alternative and mutually exclusive the following criteria; age ¸ 20 years; a proven KIT posi- oncogenic mechanisms in GIST. tive or activating mutation of PDGFR; prior imatinib mesy- Imatinib mesylate blocks the constitutively activated late therapy of 400 mg/day or more for at least 8 weeks; form of KIT in GISTs, and has dramatically improved the disease progression or relapse while on previous treatment outcome for patients with unresectable GIST [5]. Treatment with imatinib mesylate; at least one tumor lesion measur- with imatinib mesylate results in partial response (PR) or able by a computed tomographic (CT) scan or magnetic stable disease (SD) in approximately 80% of patients with resonance imaging (MRI); an Eastern Cooperative Oncol- advanced or metastatic GIST [6], and the 2-year survival ogy Group (ECOG) performance status (PS) of 0 to 2; a life rate of these patients is reported to be 70% [7]. expectancy of more than 3 months; adequate organ func- However, approximately 10–15% of advanced GIST tions as deWned by: neutrophils ¸1.5 £ 103 cells/mm3, patients will suVer a progressive disease (PD) despite treat- platelets ¸1.0 £ 104 cells/mm3, hemoglobin ¸9.0 g/dl, ment with imatinib mesylate. Many of the patients who ini- serum creatinine ·2.0£ upper limit of normal (ULN), tially responded to imatinib mesylate therapy experience tumor urine protein quantitative value of ·1+ on dipstick or progression after an average of 2 years of treatment [7, 8]. 30 mg/dl in urinalysis, aspartate aminotransferase Sunitinib is an orally administered receptor tyrosine ·2.5 £ ULN (5.0 £ ULN in patients with liver metastasis), kinase (RET) inhibitor that targets multiple kinases and is alanine aminotransferase ·2.5 £ ULN (5.0 £ ULN in used as a second-line treatment for patients with imatinib- patients with liver metastasis), alkaline phosphatase resistant or -intolerant GIST. A Phase III double-blind, pla- ·2.5 £ ULN (5.0 £ ULN in patients with bone or liver cebo-controlled trial comparing sunitinib with placebo metastasis), and total bilirubin ·2.0 £ ULN. This protocol showed that the time to progression was signiWcantly was approved by the Institutional Review Board at each longer in the sunitinib group than in the placebo group (6.3 study site. All patients provided written informed consent. versus 1.5 months). Adverse reactions, though observed, were acceptable [9]. However, despite initial response or Study design stabilization, the disease developed resistance in most patients after approximately 7 months. Because no thera- This study was an open-label and multicenter Phase II clin- pies are available for patients with GIST once imatinib and ical study. The primary endpoint was the objective response sunitinib fail, there exists a need for alternative agents that rate to a once daily oral treatment with 125 mg motesanib block the signaling pathways in GIST cells. in patients with advanced GISTs who experienced disease Motesanib is a novel, synthetic, small molecule that progression or relapse while on imatinib mesylate treat- strongly and selectively inhibits vascular endothelial ment. (Sunitinib was not approved for imatinib-resistant 123 Cancer Chemother Pharmacol (2010) 65:961–967 963 GIST until 2 years after their study was completed.) The received at least one dose of motesanib. The objective secondary endpoints were duration of response, progres- response rate and its two-sided 95% conWdence interval sion-free survival (PFS), time to response, overall survival, (95% CI) were calculated. The CI was constructed by the and PK proWles of motesanib in Japanese patients with exact method described by Collett [10]. For a PFS, calcu- advanced GISTs. lated as the number of days between the Wrst dose of The dose was Wrstly reduced to 100 mg, and if need be, motesanib and the date when radiological evidence of dis- to 75 mg in the second time. If the grade 3 adverse event ease progression is determined (date of CT scan/MRI), or (AE) is not adequately controlled with appropriate support- death (regardless of cause), whichever comes Wrst (date of ive care or a grade 4 AE occurs, motesanib was withheld. PD or death minus date of Wrst dose of motesanib), Kaplan– Once the grade 3 or 4 AE has resolved to baseline or grade Meier curve (with two-sided 95% CI) was generated and its ·1 for nonhematologic toxicities or baseline or grade ·2 standard error was calculated using Greenwood’s formula.
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