A phase I, first-in-human dose-escalation study of amuvatinib, a multi-targeted tyrosine kinase inhibitor, in patients with advanced solid tumors

Raoul Tibes, Gil Fine, Gavin Choy, Sanjeev Redkar, Pietro Taverna, Aram Oganesian, Amarpal Sahai, Mohammad Azab, Anthony W. Tolcher

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Purpose: Amuvatinib is a novel orally administered tyrosine kinase inhibitor with in vitro pharmacological activity against mutant KIT, platelet-derived growth factor receptor alpha (PDGFRα), and Rad51. Amuvatinib was investigated in a first-in-human, single-agent, phase I, accelerated titration, dose-escalation trial (clinicaltrials.gov identifier: NCT00894894) in patients with solid tumors refractory to prior therapies or for which no standard therapy existed. Methods: Twenty-two patients received amuvatinib dry powder capsules (DPC) from 100 to 1,500 mg daily in 28-day cycles. Safety, preliminary efficacy, pharmacologic activity, and pharmacokinetics were investigated. Results: No dose-limiting toxicities were reported with amuvatinib DPC up to 1,500 mg/day, given as one or in divided doses, for 1-6 cycles. No maximum tolerated dose was reached. Five patients had serious adverse events, all unrelated to treatment. Exposure levels were low and variable. One gastrointestinal stromal tumor (GIST) patient who previously failed imatinib and sunitinib had a 2-[18F]fluoro-2-deoxyglucose positron emission tomography response and clinical stable disease. A second GIST patient had decreased Rad51 expression in a skin punch biopsy on days 15 and 29. Conclusions: Amuvatinib shows in vitro inhibitory activity against multiple human tyrosine kinases including mutant KIT and PDGFRα and in vivo activity in human xenograft models in mice. Amuvatinib is also active as a DNA repair protein Rad51 inhibitor following chemotherapy. In this study, the amuvatinib DPC formulation was well tolerated up to 1,500 mg/day. While exposures were low and variable, a transient response in a refractory GIST patient warrants further investigation into single-agent amuvatinib in refractory GIST.

Original languageEnglish (US)
Pages (from-to)463-471
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume71
Issue number2
DOIs
StatePublished - Feb 2013

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Protein-Tyrosine Kinases
Tumors
Gastrointestinal Stromal Tumors
Neoplasms
Refractory materials
Powders
Platelet-Derived Growth Factor alpha Receptor
Capsules
Positron emission tomography
Pharmacokinetics
Chemotherapy
Maximum Tolerated Dose
MP470
Biopsy
Fluorodeoxyglucose F18
Deoxyglucose
Titration
Heterografts
Human Activities
Transient analysis

Keywords

  • Amuvatinib
  • GIST
  • KIT
  • MP-470
  • Phase I
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

A phase I, first-in-human dose-escalation study of amuvatinib, a multi-targeted tyrosine kinase inhibitor, in patients with advanced solid tumors. / Tibes, Raoul; Fine, Gil; Choy, Gavin; Redkar, Sanjeev; Taverna, Pietro; Oganesian, Aram; Sahai, Amarpal; Azab, Mohammad; Tolcher, Anthony W.

In: Cancer Chemotherapy and Pharmacology, Vol. 71, No. 2, 02.2013, p. 463-471.

Research output: Contribution to journalArticle

Tibes, Raoul ; Fine, Gil ; Choy, Gavin ; Redkar, Sanjeev ; Taverna, Pietro ; Oganesian, Aram ; Sahai, Amarpal ; Azab, Mohammad ; Tolcher, Anthony W. / A phase I, first-in-human dose-escalation study of amuvatinib, a multi-targeted tyrosine kinase inhibitor, in patients with advanced solid tumors. In: Cancer Chemotherapy and Pharmacology. 2013 ; Vol. 71, No. 2. pp. 463-471.
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AU - Choy, Gavin

AU - Redkar, Sanjeev

AU - Taverna, Pietro

AU - Oganesian, Aram

AU - Sahai, Amarpal

AU - Azab, Mohammad

AU - Tolcher, Anthony W.

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