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1.  Phase I Pharmacologic and Biologic Study of Ramucirumab (IMC-1121B), a Fully Human Immunoglobulin G1 Monoclonal Antibody Targeting the Vascular Endothelial Growth Factor Receptor-2 
Journal of Clinical Oncology  2010;28(5):780-787.
Purpose
To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics, and preliminary anticancer activity of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor (VEGFR)-2.
Patients and Methods
Patients with advanced solid malignancies were treated once weekly with escalating doses of ramucirumab. Blood was sampled for PK studies throughout treatment. The effects of ramucirumab on circulating vascular endothelial growth factor-A (VEGF-A), soluble VEGFR-1 and VEGFR-2, tumor perfusion, and vascularity using dynamic contrast-enhanced magnetic resonance imaging were assessed.
Results
Thirty-seven patients were treated with 2 to 16 mg/kg of ramucirumab. After one patient each developed dose-limiting hypertension and deep venous thrombosis at 16 mg/kg, the next lower dose (13 mg/kg) was considered the MTD. Nausea, vomiting, headache, fatigue, and proteinuria were also noted. Four (15%) of 27 patients with measurable disease had a partial response (PR), and 11 (30%) of 37 patients had either a PR or stable disease lasting at least 6 months. PKs were characterized by dose-dependent elimination and nonlinear exposure consistent with saturable clearance. Mean trough concentrations exceeded biologically relevant target levels throughout treatment at all dose levels. Serum VEGF-A increased 1.5 to 3.5 times above pretreatment values and remained in this range throughout treatment at all dose levels. Tumor perfusion and vascularity decreased in 69% of evaluable patients.
Conclusion
Objective antitumor activity and antiangiogenic effects were observed over a wide range of dose levels, suggesting that ramucirumab may have a favorable therapeutic index in treating malignancies amenable to VEGFR-2 inhibition.
doi:10.1200/JCO.2009.23.7537
PMCID: PMC2834394  PMID: 20048182
2.  Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor in Patients With Advanced Cancers 
Journal of Clinical Oncology  2009;27(31):5262-5269.
Purpose
This phase I, first-in-human study evaluated the safety, tolerability, pharmacokinetics, and maximum-tolerated dose (MTD) of an oral platelet-derived growth factor receptor inhibitor, CP-868,596.
Patients and Methods
Patients with advanced solid tumors were eligible. Dose escalations were performed in three groups with two formulations: uncoated on an empty stomach (UES), uncoated with food (UFED), and film-coated (FC) without food. Initial dose escalation in the UES group was followed by parallel escalations in the UFED and FC groups.
Results
Fifty-nine patients enrolled. CP-868,596 was escalated from 100 mg to 340 mg daily in the UES group, from 60 mg to 100 mg twice daily in the UFED group, and from 100 mg once daily to 140 mg twice daily in the FC group. MTDs were 200 mg daily in the UES group and 100 mg twice daily in the FC group; MTD was not reached at 100 mg twice daily in the UFED group. Dose-limiting toxicities included hematuria, increased ╬│-glutamyltransferase or ALT, insomnia, and nausea/vomiting. Most treatment-related AEs were of grades 1 to 2 severity; nausea, vomiting, and diarrhea were reported most frequently. Administration with food generally improved tolerability. CP-868,596 was absorbed slowly; systemic exposure parameters appeared to increase greater than proportionally with dose. Mean serum concentrations exceeded the preclinically predicted minimal efficacious concentration (ie, 16 ng/mL) at all dosages. Food and film coating apparently increased interpatient variability of the maximum observed plasma concentration and the area under the concentration-time curve. No objective responses were reported, and eight patients achieved stable disease (mean duration, 5.7 months).
Conclusion
CP-868,596 potentially demonstrated greater than dose-proportional pharmacokinetics. The recommended dosage of 100 mg twice daily with food was well tolerated. Additional development as a single agent in selected populations or in combination with chemotherapy in broader populations is warranted.
doi:10.1200/JCO.2009.21.8487
PMCID: PMC2773478  PMID: 19738123

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