A phase I open-label study of the safety, tolerability, and pharmacokinetics of pazopanib in combination with irinotecan and cetuximab for relapsed or refractory metastatic colorectal cancer
Abstract
Background Pazopanib is a multi-targeted tyrosine kinase inhibitor shown to be clinically active in the treatment of various cancer types. This study aimed to evaluate the maximum tolerated regimen (MTR), safety, and pharmacokinetics of pazopanib in combination with irinotecan and cetuximab in adult patients with relapsed or refractory metastatic colorectal cancer (mCRC).Patients and methods This was a Phase I, 3 + 3 design, open-label, dose-escalation study (NCT0050943; VEG108925) conducted in sequential cohorts to determine the MTR of pazopanib and irinotecan administered with cetuximab. Twenty-five patients received treatment in three dosing cohorts and were evaluated for safety and tolerability of the combination and pharmacokinetics of individual drugs.Results The MTR was determined to be 400 mg pazopanib per day orally in combination with 150 mg/m(2) irinotecan biweekly and 250 mg/m(2) cetuximab weekly by infusion. Neutropenia was the main dose-limiting toxicity. Pharmacokinetic results suggested that the overall systemic exposure to SN-38, the active metabolite of irinotecan, was affected by pazopanib to a greater extent than was the systemic exposure to irinotecan itself.Conclusions This study provided evidence for the manageable safety profile and feasibility of using the novel triplet combination of pazopanib, irinotecan, and cetuximab in patients with refractory mCRC. Further large-scale Phase II studies are warranted.
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Pazopanib combined with irinotecan and cetuximab showed manageable safety and feasibility in refractory mCRC.
“Pazopanib, a multitargeted tyrosine kinase inhibitor, combined with irinotecan and cetuximab showed manageable safety and feasibility in refractory mCRC [153].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [153]
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- Authors
- Bennouna, J., Deslandres, M., Senellart, H., de Labareyre, C., Ruiz-Soto, R., Wixon, C., Botbyl, J., Suttle, A. B., & Delord, J.-P.
- Affiliations
- Institut de Cancérologie de l'Ouest (FR)
- Institut universitaire du cancer de Toulouse Oncopole (FR)
- GlaxoSmithKline (United Kingdom) (GB)
- Corresponding author
- Delord, Jean-Pierre
- Venue
- Investigational New Drugs
- Published
- 2014-09-24
- Volume
- 33
- Issue
- 1
- Pages
- 138-147
- ISSN
- 0167-6997 (ISSN-L)
- 1573-0646
- OpenAlex
- W1964513792
- Cited by
- 26
- References
- 30
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 5 · 2019: 4 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 1
- FWCI
- 0.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Investigational New Drugs (publishedVersion)
- PubMed (publishedVersion)
- Funders
- GlaxoSmithKline
- Agence Nationale de la Recherche (ANR-11-PHUC-0001)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
- Keywords
- pazopanib, irinotecan, cetuximab, metastatic colorectal cancer, tyrosine kinase inhibitors, combination chemotherapy, maximum tolerated dose, dose-limiting toxicity, neutropenia, drug-drug interactions, VEGF inhibitors
- MeSH terms
- Cetuximab, Irinotecan, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Female, Humans, Indazoles, Male, Middle Aged, Neutropenia, Pyrimidines, Recurrence, Sulfonamides, Colorectal Neoplasms, Treatment Outcome, Drug Resistance, Neoplasm, Angiogenesis Inhibitors, Maximum Tolerated Dose, Protein Kinase Inhibitors, Topoisomerase I Inhibitors, Antibodies, Monoclonal, Humanized
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