Safety, tolerability, and pharmacokinetics of amuvatinib from three phase 1 clinical studies in healthy volunteers

Choy, Gavin; Joshi-Hangal, Rajashree; Oganesian, Aram; Fine, Gil D.; Rasmussen, Scott; Collier, Jo; Kissling, J.; Sahai, Amarpal; Azab, Mohammad; Redkar, Sanjeev

doi:10.1007/s00280-012-1821-2

Cited by 5 publications

(3 citation statements)

References 17 publications

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“…The plasma levels of the drug were generally low and highly variable. This limitation led to the development of a new lipid-suspension capsule formula that was tested in healthy volunteers in another phase I clinical trial [64] and showed better bioavailability compared to the dry powder capsule formula. Both formulas were well tolerated and showed a good safety profile.…”

Section: Kit and Pdgfra Inhibitorsmentioning

confidence: 99%

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

Alturkmani

Pessetto

Godwin

2015

Expert Opinion on Investigational Drugs

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Introduction Gastrointestinal stromal tumor (GIST) is the most common non-epithelial malignancy of the GI tract. With the discovery of KIT and later PDGFRA gain-of-function mutations as factors in the pathogenesis of the disease, GIST was the quintessential model for targeted therapy. Despite the successful clinical use of imatinib mesylate, a selective receptor tyrosine kinase (RTK) inhibitor that targets KIT, PDGFRA and BCR-ABL, we still do not have treatment for the long-term control of advanced GIST. Areas covered This review summarizes the drugs that are under investigation or have been assessed in trials for GIST treatment. The article focuses on their mechanisms of actions, the preclinical evidence of efficacy, and the clinical trials concerning safety and efficacy in humans. Expert opinion It is known that KIT and PDGFRA mutations in GIST patients influence the response to treatment. This observation should be taken into consideration when investigating new drugs. RECIST was developed to help uniformly report efficacy trials in oncology. Despite the usefulness of this system, many questions are being addressed about its validity in evaluating the true efficacy of drugs knowing that new targeted therapies do not affect the tumor size as much as they halt progression and prolong survival.

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Section: Kit and Pdgfra Inhibitorsmentioning

confidence: 99%

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

Alturkmani

Pessetto

Godwin

2015

Expert Opinion on Investigational Drugs

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“…Phase 1 clinical studies have shown single-agent amuvatinib to be safe and well tolerated [ 12 , 13 ], with amuvatinib exposures significantly improved when lipid-suspension capsules rather than dry-powder capsules are administered [ 12 ]. In addition, Mita et al [ 14 ] showed preliminary evidence of anti-tumor activity and durable SD (up to 708 days) with amuvatinib administered at varying dose levels in combination with standard chemotherapy agents.…”

Section: Introductionmentioning

confidence: 99%

A phase 2, open-label, multi-center study of amuvatinib in combination with platinum etoposide chemotherapy in platinum-refractory small cell lung cancer patients

et al. 2017

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Background: Amuvatinib (MP-470) is a multi-targeted kinase inhibitor with potent activity against c-Kit, synergistic with DNA-damaging agents. We evaluated amuvatinib in combination with platinum-etoposide (EP) chemotherapy by objective response rate, survival, and tolerability in platinum-refractory small cell lung cancer (SCLC) patients.Methods: This study used a Simon 2-stage design requiring ≥3 centrally confirmed responses in the first 21 subjects. Subjects received EP with 300 mg amuvatinib orally three times daily in cycles of 21 days. A three-day amuvatinib run-in period before EP occurred in Cycle 1. Subjects received the same EP chemotherapy regimen given prior to progression/relapse.Results: Among 23 subjects treated, we observed four PRs (17.4%) per RECIST 1.1, only two of which were centrally confirmed (8.7%, response duration 119, 151 days). Three subjects (13%) had confirmed stable disease. c-Kit H-score was ≥100 in two subjects whose respective durations of disease control were 151 and 256 days.Conclusions: The addition of amuvatinib to EP chemotherapy in unselected, platinum-refractory SCLC did not meet the primary endpoint of ≥3 confirmed responses in stage 1. However, high c-Kit expression in two subjects with durable disease control suggests the potential for further study of amuvatinib in SCLC patients with high c-Kit expression.

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“…79 Inhibition of AXL using 13 reversed EMT in murine breast cancer stem cells, reducing self-renewal and restoring sensitivity to chemotherapy. 80 After phase I evaluation in patients with solid tumors, 81 13 entered a phase II clinical trial in patients with NSCLC in combination with standard of care chemotherapy (platinum and etoposide, structures not disclosed). Despite favorable safety and preliminary clinical activity in the first stage of this phase II, Astex Pharmaceuticals announced discontinuation of its clinical development in 2012.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

AXL Inhibitors in Cancer: A Medicinal Chemistry Perspective

2015

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Dysregulation of the AXL receptor tyrosine kinase has been associated with many types of cancer. It has not been until recently, however, that targeting AXL has come under the spotlight because of ever accumulating evidence of its strong correlation with poor prognosis and drug resistance. The entry of the first AXL-branded inhibitor in clinical trials in 2013 marked an important milestone for the clinical validation of AXL as an anticancer target. Nevertheless, to weigh the current contribution and potential future impact of AXL inhibition in the clinic, it is fundamental to recognize that several kinase inhibitors approved or in clinical development have AXL as either a prominent secondary or even the primary target. Through this review, the chemical and biological properties of the main inhibitors targeting AXL (either intentionally or unintentionally) will be discussed, along with the prospects and challenges to translate AXL inhibitors into a bona fide therapeutic option.

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Safety, tolerability, and pharmacokinetics of amuvatinib from three phase 1 clinical studies in healthy volunteers

Abstract: Amuvatinib LSC, 300 mg every 8 h, is being studied in cancer patients based on the improved exposure and similar safety profile to amuvatinib DPC. A lipid-based formulation approach may be a useful tool for other low aqueous soluble compounds.

Cited by 5 publications

References 17 publications

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

A phase 2, open-label, multi-center study of amuvatinib in combination with platinum etoposide chemotherapy in platinum-refractory small cell lung cancer patients

AXL Inhibitors in Cancer: A Medicinal Chemistry Perspective

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