Phase I first-in-human study of TAK-285, a novel investigational dual HER2/EGFR inhibitor, in cancer patients

Doi, Toshihiko; Takiuchi, Hiroya; Ohtsu, Atsushi; Fuse, Nozomu; Goto, Masahiro; Yoshida, Midori; Dote, Nobuhito; Kuze, Yoji; Jinno, Fumihiro; Fujimoto, Minoru; Takubo, T; Nakayama, N.; Tsutsumi, Rie

doi:10.1038/bjc.2011.590

Cited by 36 publications

(18 citation statements)

References 27 publications

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“…The initial phase I study in primarily Japanese patients with advanced cancers demonstrated good tolerance of TAK-285, with elevation in aminotransferases and hyporexia being the most prominent grade 3 dose-limiting toxicities 86. In the U.S., a multicenter phase I study designed to determine the pharmacokinetics in a more diverse population of patients with advanced cancer was recently completed, and the results are forthcoming 87.…”

Section: Small Molecule Her/egfr Inhibitors Other Than Lapatinibmentioning

confidence: 99%

Treating Breast Cancer in the 21st Century: Emerging Biological Therapies

et al. 2013

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For many years, the medical treatment of breast cancer was reliant solely on cytotoxic chemotherapy. However, over the past twenty years, treatment has evolved to a more target-directed approach. We now employ tailored therapy based on the presence or absence of receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER2). We expect this trend to continue, as agents that use novel approaches to target HER2, as well as targeting different portions of the HER signaling pathway, are in various stages of development. Notably, pertuzumab, a humanized monoclonal antibody that binds to a different domain of the extracellular portion of the HER2 receptor than trastuzumab, was recently approved for use, as was lapatinib, a small-molecule tyrosine kinase inhibitor. Patients with triple negative breast cancer, particularly those with the BRCA mutation, have more limited treatment options and carry a worse prognosis than those who are hormone receptor positive. However, recent data has shown that PARP inhibitors may have significant anti-tumor effect in those with this subtype of breast cancer. Novel agents that inhibit mTOR, PI3K, the insulin-like growth factor, heat shock protein 90, and histone deacetylase have shown promise in phase I-III trials and offer exciting new possibilities for the treatment of this often fatal disease. As we are presented with an ever increasing number of treatment options, the timing and combinations of therapeutic agents used becomes ever more complex in the age of personalized care, but we are hopeful that ultimately this will lead to improved patient outcomes.

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Section: Small Molecule Her/egfr Inhibitors Other Than Lapatinibmentioning

confidence: 99%

Treating Breast Cancer in the 21st Century: Emerging Biological Therapies

et al. 2013

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“…In the distinct set of TKI collections, the HER2‐targeted lapatinib has been marketed for treatment of breast cancer; this drug exhibit broad‐spectrum sensitivity to both wild‐type HER2 and its diverse variants 17. The TAK‐285 is dual ErbB protein kinase inhibitor that specifically targets EGFR and HER2 18. The gefitinib and erlotinib are the first‐line therapeutic agents for NSCLC and some other cancers 19…”

Section: Methodsmentioning

confidence: 99%

Combination of In Silico Analysis and In Vitro Assay to Investigate Drug Response to Human Epidermal Growth Factor Receptor 2 Mutations in Lung Cancer

Wang

et al. 2015

Molecular Informatics

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The epidermal growth factor receptor 2 (HER2) has been established as an important target of HER2-positive lung cancer, but somatic mutations in HER2 kinase domain are frequently observed that may cause drug resistance and sensitivity for tyrosine kinase inhibitors (TKIs). In this study, the response profile of 14 small-molecule TKIs upon 11 clinical HER2 mutations was investigated systematically using a synthetic strategy that integrated in silico analysis and in vitro assay to explore the structural basis, energetic property and biological implication underlying the intermolecular interactions of TKIs with wild-type and variant HER2. It is found that most clinical mutations are far away from HER2 active site and thus can only address modest or moderate effect on inhibitor binding. However, few single-point substations such as D769H and D769Y as well as the gatekeeper mutation T798 M were predicted to cause strong resistance for an array of TKIs by reshaping the geometric feature and physiochemical property of the active site. Furthermore, inhibitor response to the most common insertion mutation in HER2 exion 20 (HER2(YVMA) ) was examined in detail; the response can be grouped into three classes: sensitization, resistance and insusceptibility. The Bcr-Abl inhibitor bosutinib and EGFR inhibitor gefitinib were selected as the representatives of, respectively, sensitization and insusceptibility to perform kinase assay against the GST-tagged, recombinant kinase domains of wild-type HER2(WT) and HER2(YVMA) variant. As expected, the biological activity of bosutinib was improved by ∼160-fold due to the insertion, while gefitinib exhibited low inhibitory potency on both HER2(WT) and HER2(YVMA) (IC50>100 μM). Structural analysis revealed an intensive network of hydrogen bonds and hydrophobic interactions in HER2(YVMA) bosutinib complex, whereas only few nonspecific van der Waals contacts were observed at the complex interface of HER2(YVMA) with gefitinib.

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“…The treatment was generally well tolerated, and 1 patient with parotid cancer experienced a partial response [25]. The present phase 1 study was undertaken to evaluate the safety (MTD, recommended phase 2 dose [RP2D], dose-limiting toxicities [DLTs]), antitumor activity, and pharmacokinetic properties of TAK-285 in patients with advanced cancer refractory to standard cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Phase 1 dose-escalation, pharmacokinetic, and cerebrospinal fluid distribution study of TAK-285, an investigational inhibitor of EGFR and HER2

et al. 2013

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SummaryIntroduction This phase 1 study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, cerebrospinal fluid (CSF) distribution, and preliminary clinical activity of the receptor tyrosine kinase inhibitor TAK-285. Methods Patients with advanced, histologically confirmed solid tumors and Eastern Cooperative Oncology Group performance status ≤2 received daily oral TAK-285; daily dose was escalated within defined cohorts until MTD and recommended phase 2 dose (RP2D) were determined. Eleven patients were enrolled into an RP2D cohort. Blood samples were collected from all cohorts; CSF was collected at pharmacokinetic steady-state from RP2D patients. Tumor responses were assessed every 8 weeks per Response Evaluation Criteria in Solid Tumors. Results Fifty-four patients were enrolled (median age 60; range, 35–76 years). The most common diagnoses were cancers of the colon (28 %), breast (17 %), and pancreas (9 %). Escalation cohorts evaluated doses from 50 mg daily to 500 mg twice daily; the MTD/RP2D was 400 mg twice daily. Dose-limiting toxicities included diarrhea, hypokalemia, and fatigue. Drug absorption was fast (median time of maximum concentration was 2–3 h), and mean half-life was 9 h. Steady-state average unbound CSF concentration (geometric mean 1.54 [range, 0.51–4.27] ng/mL; n = 5) at the RP2D was below the 50 % inhibitory concentration (9.3 ng/mL) for inhibition of tyrosine kinase activity in cells expressing recombinant HER2. Best response was stable disease (12 weeks of nonprogression) in 13 patients. Conclusions TAK-285 was generally well tolerated at the RP2D. Distribution in human CSF was confirmed, but the free concentration of the drug was below that associated with biologically relevant target inhibition.

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Phase I first-in-human study of TAK-285, a novel investigational dual HER2/EGFR inhibitor, in cancer patients

Cited by 36 publications

References 27 publications

Treating Breast Cancer in the 21st Century: Emerging Biological Therapies

Treating Breast Cancer in the 21st Century: Emerging Biological Therapies

Combination of In Silico Analysis and In Vitro Assay to Investigate Drug Response to Human Epidermal Growth Factor Receptor 2 Mutations in Lung Cancer

Phase 1 dose-escalation, pharmacokinetic, and cerebrospinal fluid distribution study of TAK-285, an investigational inhibitor of EGFR and HER2

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