Efficacy and safety of motesanib, an oral inhibitor of VEGF, PDGF, and Kit receptors, in patients with imatinib-resistant gastrointestinal stromal tumors.

Abstract

PURPOSE:

This multicenter phase 2 study assessed the tolerability and efficacy of motesanib, an oral inhibitor of Kit, platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptors (VEGFR), in patients with imatinib-resistant gastrointestinal stromal tumors (GIST).

METHODS:

Patients with advanced GIST who failed imatinib mesylate after ≥8 weeks of treatment with ≥600 mg daily received motesanib 125 mg orally once daily continuously for 48 weeks or until unacceptable toxicity or disease progression occurred. The primary endpoint was confirmed objective tumor response per RECIST and independent review. Secondary endpoints included progression-free survival (PFS), time to progression (TTP); objective response by (18)FDG-PET and by changes in tumor size and/or density (Choi criteria); pharmacokinetics and safety.

RESULTS:

In the patients evaluable for response (N = 102), the objective response rate was 3%; 59% of patients achieved stable disease, with 14% achieving durable stable disease ≥24 weeks; 38% had disease progression. Higher objective response rates were observed per (18)FDG-PET (N = 91) (30%) and Choi criteria (41%). The median PFS was 16 weeks (95% CI = 14-24 weeks); the median TTP was 17 weeks (95% CI = 15-24 weeks). The most common motesanib treatment-related grade 3 adverse events included hypertension (23%), fatigue (9%), and diarrhea (5%). Motesanib did not accumulate with daily dosing.

CONCLUSIONS:

In this study of patients with imatinib-resistant GIST, motesanib treatment resulted in acceptable tolerability and modest tumor control as evident in the proportion of patients who achieved stable disease and durable stable disease.

• Authors: Robert S Benjamin, Patrick Schöffski, Jörg Thomas Hartmann, Allan Van Oosterom, Binh Nguyen Bui, Justus Duyster, Scott Schuetze, Jean-Yves Blay, Peter Reichardt, Lee S Rosen, Keith Skubitz, Sheryl McCoy, Yu-Nien Sun, Daniel E Stepan, Laurence Baker
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 68 Issue 1 Pg. 69-77 (Jul 2011) ISSN: 1432-0843 [Electronic] Germany
• PMID: 20838998 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Indoles
• Oligonucleotides
• Piperazines
• Pyrimidines
• Niacinamide
• Imatinib Mesylate
• Protein-Tyrosine Kinases
• Proto-Oncogene Proteins c-kit
• Receptors, Platelet-Derived Growth Factor
• Receptors, Vascular Endothelial Growth Factor
• imetelstat

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Benzamides
• Disease-Free Survival
• Drug Resistance, Neoplasm
• Female
• Gastrointestinal Stromal Tumors (drug therapy, pathology, surgery)
• Humans
• Imatinib Mesylate
• Indoles (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Male
• Middle Aged
• Niacinamide (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Oligonucleotides
• Piperazines (therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins c-kit (antagonists & inhibitors)
• Pyrimidines (therapeutic use)
• Receptors, Platelet-Derived Growth Factor (antagonists & inhibitors)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors)
• Treatment Outcome