Phase II study of the Multikinase inhibitor of angiogenesis, Linifanib, in patients with metastatic and refractory colorectal cancer expressing mutated KRAS

Summary Background Targeting angiogenesis in advanced colorectal cancer (CRC) has been one of the many factors prolonging survival. Bevacizumab was the first agent to demonstrate this, but even after progression on bevacizumab, continued VEGF-inhibition continues to improve survival. Combining epide...

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Bibliographic Details
Published in:Investigational new drugs 2017-08, Vol.35 (4), p.491-498
Main Authors: Chan, Emily, Goff, Laura W., Cardin, Dana B., Ancell, Kristin, Smith, Stephen James, Whisenant, Jennifer G., Ye, Fei, Berlin, Jordan D.
Format: Article
Language:English
Subjects:
Adult
Aged
Angiogenesis
Angiogenesis Inhibitors - adverse effects
Angiogenesis Inhibitors - therapeutic use
Anticancer properties
Antitumor agents
Arthralgia
Bevacizumab
Cancer
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Diarrhea
Disease-Free Survival
Dosage
Drug Resistance, Neoplasm
Epidermal growth factor
Fatigue
Female
Humans
Hypertension
Indazoles - adverse effects
Indazoles - therapeutic use
K-Ras protein
Kaplan-Meier Estimate
Lung Neoplasms - diagnostic imaging
Lung Neoplasms - drug therapy
Lung Neoplasms - secondary
Male
Medicine
Medicine & Public Health
Metastases
Metastasis
Middle Aged
Monoclonal antibodies
Mutation
Nausea
Oncology
Pain
Patients
Pharmacology/Toxicology
Phase II Studies
Phenylurea Compounds - adverse effects
Phenylurea Compounds - therapeutic use
Protein Kinase Inhibitors - adverse effects
Protein Kinase Inhibitors - therapeutic use
Proteinuria
Proto-Oncogene Proteins p21(ras) - genetics
Studies
Survival
Targeted cancer therapy
Thrombocytopenia
Tomography, X-Ray Computed
Toxicity
Treatment Outcome
Vascular endothelial growth factor
Vomiting
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Summary:Summary Background Targeting angiogenesis in advanced colorectal cancer (CRC) has been one of the many factors prolonging survival. Bevacizumab was the first agent to demonstrate this, but even after progression on bevacizumab, continued VEGF-inhibition continues to improve survival. Combining epidermal growth factor receptor monoclonal antibodies with standard frontline therapies have also improved clinical outcomes, yet the improved benefit is not observed in patients with mutant KRAS . Thus, an unmet medical need exists to develop additional therapeutic options for patients with KRAS mutant CRC. Methods Patients received the anti-angiogenic agent linifanib at the recommended phase II dose of 17.5 mg. Primary endpoint was objective response rate (ORR), with a goal of 10%. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Simon’s optimal two-stage design was used to assess futility. Linifanib was considered inactive if two or fewer patients among the first 30 achieved an objective response. Results Thirty patients were enrolled on study. Grade 3 treatment-related toxicities occurring in at least two patients were fatigue, hypertension, proteinuria, diarrhea, nausea, oral pain, vomiting, thrombocytopenia, and arthralgia. Although no responses were observed, 63.5% of patients achieved stable disease. The median PFS and OS were 4.7 months and 9.5 months, respectively. Stopping rules for lack of clinical efficacy led to study closure. Conclusion Despite observing zero responses, a majority of patients had stable disease and eight patients had stable disease lasting longer than 5 months. These results suggest that linifanib has some anti-tumor activity in KRAS mutant metastatic and refractory CRC.
ISSN:0167-6997
1573-0646
DOI:10.1007/s10637-017-0458-8