| General information |
| Database: | DB00687 |
| Objective: | Amuvatinib is a novel orally administered tyrosine kinase inhibitor with in vitro pharmacological activity against mutant KIT, plateletderived growth factor receptor alpha (PDGFR¦Á), and Rad51. Amuvatinib was investigated in a firstinhuman, singleagent, phase I, accelerated titration, doseescalation trial ( clinicaltrials.gov identifier: NCT00894894) in patients with solid tumors refractory to prior therapies or for which no standard therapy existed. |
| Authors: | Tibes R, et al |
| Title: | a phase I, firstinhuman doseescalation study of amuvatinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumors. |
| Journal: | Cancer Chemother Pharmacol |
| Year: | 2013 |
| PMID: | 23178951 |
| Trial Design |
| Clinical Trial Id: | NCT00894894 |
| Agent: | amuvatinib
|
| Target: | mutant KIT, plateletderived growth factor receptor alpha (PDGFR¦Á), and Rad51
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | a phase I, firstinhuman doseescalation study |
| Key Patients Feature: | Eligible patients had a histological or cytological diagnosisof unresectable or metastatic solid tumor cancer refractoryto standard therapies or for whom no standard therapyexisted. Patients with refractory lymphoma (Hodgkin¡¯s ornonHodgkin¡¯s lymphoma) were permitted in the study.Patient entry criteria included adults (aged C18 years) ofeither sex with a C70 Karnofsky Performance Status (KPS);adequate bone marrow (hemoglobin C9 g/dL, absoluteneutrophil count C1.5 9 109/L, and platelet countC100 9 109/L); normal renal, hepatic, and cardiac function; no active central nervous system metastases (primarybrain tumors were permitted); no prior anticancer treatmentwithin 3 weeks of screening or 5 halflives of previousagent and no prior radiation within 4 weeks; no Cgrade 2toxicity (other than alopecia) continuing from prior anticancer therapy; no lifethreatening illness, medical condition, or organ system dysfunction that compromised thepatient¡¯s safety, interfered with drug absorption or metabolism, or affected study outcomes; no serious uncontrolledactive infection, uncontrolled or symptomatic arrhythmias, congestive heart failure and/or myocardial infarction; andno prior immunosuppressive therapy other than corticosteroids at stable doses for at least 2 weeks before screening.All patients of childbearing potential were required to usean acceptable method of contraception from screening to3 months following the last dose of amuvatinib. |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | patients received amuvatinib dry powder capsules (DPC) from 100 to 1, 500 mg daily in 28day cycles. |
| Primary End Point: | Safety, preliminary efficacy, pharmacologic activity, and pharmacokinetics |
| Secondary End Point: | NA |
| Patients Number: | 22 |
| Trial Results |
| DLT_MTD: | No doselimiting toxicities were reported with amuvatinib DPC up to 1, 500 mg/day, given as one or in divided doses, for 16 cycles. No maximum tolerated dose was reached. Five patients had serious adverse events, all unrelated to treatment |
| Objective Response Rate: | NA |
| Disease Control Rate: | 0.98 |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | No treatmentrelated deaths, no treatmentrelated serious adverse events, and no treatmentrelated grade 4 adverse events were reported in the 22 patients, all of whom who experienced at least one adverse event. Five patients reported serious adverse events. |
| Conclusions: | Amuvatinib shows in vitro inhibitory activity against multiple human tyrosine kinases including mutant KIT and PDGFR¦Á 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 mgday. While exposures were low and variable, a transient response in a refractory GIST patient warrants further investigation into singleagent amuvatinib in refractory GIST. |