Abstract
Background This phase I study evaluated the pharmacokinetics and pharmacodynamics of CEP-11981, an oral vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, in patients with advanced, relapsed, or refractory solid tumors. Methods Oral CEP-11981 dose escalations followed a modified Fibonacci sequence (from 3.0 to 4.2, 5.9, 11.8, 19.7, 29.6, 41.4, 55.0, 73.0, 97.4, and 126.6 mg/m2). The maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), tumor response, and safety were evaluated. Results CEP-11981 was tolerated at doses between 3.0 and 97.4 mg/m2. The MTD of CEP-11981 was determined to be 97.4 mg/m2, with DLTs observed at the 126.6 mg/m2 dose. The DLTs were grade 4 neutropenia in 1 patient and grade 3 T-wave inversion with chest heaviness and fatigue in 1 patient. All 3 events resolved on stopping CEP-11981. The most frequently reported adverse events of any grade were fatigue, nausea, diarrhea, decreased appetite, abdominal pain, back pain, vomiting, constipation, headache, dizziness, and dyspnea. Treatment-related grade 3/4 neutropenia was observed in the highest-dose cohorts (2 patients at 97.4 mg/m2 and 1 patient at 126.6 mg/m2), indicating some off-target inhibition. VEGF inhibition was greatest in the higher-dose groups. Although no patient experienced complete or partial response, 44 % patients achieved stable disease when measured at ≥ 6 weeks, which occurred more frequently in cohorts receiving ≥ 73.0 mg/m2. Conclusions In patients with recurrent or refractory solid tumors, disease stabilization was achieved. Despite acceptable tolerability of CEP-11981 at the MTD, further development by the sponsor has ceased.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1258-1268 |
| Number of pages | 11 |
| Journal | Investigational New Drugs |
| Volume | 32 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 1 2014 |
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Keywords
- Dose-finding study
- Multitargeted inhibition
- Safety profile
- Tie-2
- Tyrosine kinase inhibitor
- Vascular endothelial growth factor
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)
- Oncology
- Medicine(all)
Cite this
An open-label study to determine the maximum tolerated dose of the multitargeted tyrosine kinase inhibitor CEP-11981 in patients with advanced cancer. / Pili, Roberto; Carducci, Michael A; Brown, Peter; Hurwitz, Herbert.
In: Investigational New Drugs, Vol. 32, No. 6, 01.12.2014, p. 1258-1268.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - An open-label study to determine the maximum tolerated dose of the multitargeted tyrosine kinase inhibitor CEP-11981 in patients with advanced cancer
AU - Pili, Roberto
AU - Carducci, Michael A
AU - Brown, Peter
AU - Hurwitz, Herbert
PY - 2014/12/1
Y1 - 2014/12/1
N2 - Background This phase I study evaluated the pharmacokinetics and pharmacodynamics of CEP-11981, an oral vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, in patients with advanced, relapsed, or refractory solid tumors. Methods Oral CEP-11981 dose escalations followed a modified Fibonacci sequence (from 3.0 to 4.2, 5.9, 11.8, 19.7, 29.6, 41.4, 55.0, 73.0, 97.4, and 126.6 mg/m2). The maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), tumor response, and safety were evaluated. Results CEP-11981 was tolerated at doses between 3.0 and 97.4 mg/m2. The MTD of CEP-11981 was determined to be 97.4 mg/m2, with DLTs observed at the 126.6 mg/m2 dose. The DLTs were grade 4 neutropenia in 1 patient and grade 3 T-wave inversion with chest heaviness and fatigue in 1 patient. All 3 events resolved on stopping CEP-11981. The most frequently reported adverse events of any grade were fatigue, nausea, diarrhea, decreased appetite, abdominal pain, back pain, vomiting, constipation, headache, dizziness, and dyspnea. Treatment-related grade 3/4 neutropenia was observed in the highest-dose cohorts (2 patients at 97.4 mg/m2 and 1 patient at 126.6 mg/m2), indicating some off-target inhibition. VEGF inhibition was greatest in the higher-dose groups. Although no patient experienced complete or partial response, 44 % patients achieved stable disease when measured at ≥ 6 weeks, which occurred more frequently in cohorts receiving ≥ 73.0 mg/m2. Conclusions In patients with recurrent or refractory solid tumors, disease stabilization was achieved. Despite acceptable tolerability of CEP-11981 at the MTD, further development by the sponsor has ceased.
AB - Background This phase I study evaluated the pharmacokinetics and pharmacodynamics of CEP-11981, an oral vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, in patients with advanced, relapsed, or refractory solid tumors. Methods Oral CEP-11981 dose escalations followed a modified Fibonacci sequence (from 3.0 to 4.2, 5.9, 11.8, 19.7, 29.6, 41.4, 55.0, 73.0, 97.4, and 126.6 mg/m2). The maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), tumor response, and safety were evaluated. Results CEP-11981 was tolerated at doses between 3.0 and 97.4 mg/m2. The MTD of CEP-11981 was determined to be 97.4 mg/m2, with DLTs observed at the 126.6 mg/m2 dose. The DLTs were grade 4 neutropenia in 1 patient and grade 3 T-wave inversion with chest heaviness and fatigue in 1 patient. All 3 events resolved on stopping CEP-11981. The most frequently reported adverse events of any grade were fatigue, nausea, diarrhea, decreased appetite, abdominal pain, back pain, vomiting, constipation, headache, dizziness, and dyspnea. Treatment-related grade 3/4 neutropenia was observed in the highest-dose cohorts (2 patients at 97.4 mg/m2 and 1 patient at 126.6 mg/m2), indicating some off-target inhibition. VEGF inhibition was greatest in the higher-dose groups. Although no patient experienced complete or partial response, 44 % patients achieved stable disease when measured at ≥ 6 weeks, which occurred more frequently in cohorts receiving ≥ 73.0 mg/m2. Conclusions In patients with recurrent or refractory solid tumors, disease stabilization was achieved. Despite acceptable tolerability of CEP-11981 at the MTD, further development by the sponsor has ceased.
KW - Dose-finding study
KW - Multitargeted inhibition
KW - Safety profile
KW - Tie-2
KW - Tyrosine kinase inhibitor
KW - Vascular endothelial growth factor
UR - http://www.scopus.com/inward/record.url?scp=84927558984&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84927558984&partnerID=8YFLogxK
U2 - 10.1007/s10637-014-0147-9
DO - 10.1007/s10637-014-0147-9
M3 - Article
C2 - 25152243
AN - SCOPUS:84927558984
VL - 32
SP - 1258
EP - 1268
JO - Investigational New Drugs
JF - Investigational New Drugs
SN - 0167-6997
IS - 6
ER -