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Phase 1b trial of nintedanib in combination with bevacizumab in patients with advanced solid tumors.

ABSTRACT: PURPOSE:Vascular endothelial growth factor (VEGF) inhibitors have produced demonstrable but limited benefit for various cancers. One mechanism of resistance includes revascularization, secondary to upregulation of alternative pro-angiogenic platelet-derived growth factor receptor and fibroblast growth factor receptor pathways. Nintedanib is an oral, triple kinase inhibitor that blocks these pathways and may improve anti-tumor activity by overcoming resistance to anti-VEGF therapies. The primary objective of this first in-human study was to evaluate the safety and tolerability of nintedanib in combination with bevacizumab. METHODS:Patients were treated with escalating doses of nintedanib (150 mg or 200 mg oral twice daily) and bevacizumab (15 mg/kg once intravenously every 3 weeks) until disease progression or unacceptable toxicity using standard 3?+?3 phase 1 design. Plasma levels of angiogenic biomarkers were correlated with clinical outcomes. RESULTS:Eighteen patients with advanced tumors [lung (n?=?9), colon (n?=?8), and cervical (n?=?1)] previously treated with at least two lines of chemotherapy including bevacizumab (n?=?9, 50%) were enrolled. The highest dose of nintedanib was 200 mg twice a day with no observed dose-limiting toxicities (DLT). Common adverse events (AE) were fatigue (grade 1-3) and diarrhea (grade 1-2). Durable clinical response was observed in 55% patients pretreated with bevacizumab (1 complete and 4 stable response). Better disease control was correlated with higher than median baseline values for VEFGR2 and E-selectin, and lower levels for SDF-1?. CONCLUSION:Nintedanib was well-tolerated with bevacizumab with no DLT. Significant clinical activity was observed, including in bevacizumab-pretreated patients, suggesting nintedanib can overcome bevacizumab resistance.

SUBMITTER: Paluri R

PROVIDER: S-EPMC6490179 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Phase 1b trial of nintedanib in combination with bevacizumab in patients with advanced solid tumors.

Paluri Ravi R Madan Ankit A Li Peng P Jones Benjamin B Saleh Mansoor M Jerome Mary M Miley Deborah D Keef Jennifer J Robert Francisco F

Cancer chemotherapy and pharmacology 20190102 3

<h4>Purpose</h4>Vascular endothelial growth factor (VEGF) inhibitors have produced demonstrable but limited benefit for various cancers. One mechanism of resistance includes revascularization, secondary to upregulation of alternative pro-angiogenic platelet-derived growth factor receptor and fibroblast growth factor receptor pathways. Nintedanib is an oral, triple kinase inhibitor that blocks these pathways and may improve anti-tumor activity by overcoming resistance to anti-VEGF therapies. The ...[more]

PMID: 30603797

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Project description:Background:Angiogenesis and activation of the epidermal growth factor (EGFR) pathway play an essential role in tumor proliferation and metastasis. Targeting angiogenesis or EGFR alone does not yield adequate tumor control in most solid tumors. Overcoming intrinsic and/or acquired resistance may need a doublet or triplet therapy strategy. Herein, we report the safety and feasibility of dual EGFR blockade with EGFR monoclonal antibody and EGFR tyrosine kinase inhibitor combined with anti-VEGF antibody in advanced solid tumors. Methods:We conducted a phase I study combining erlotinib, cetuximab, and bevacizumab. Patients with advanced or metastatic solid tumors (excluding colorectal and non-small cell lung cancers) were analyzed for safety, toxicity profile, and response. Anti-tumor activity was evaluated per response evaluation criteria in solid tumors (RECIST 1.0). Results:Thirty-six patients received treatment on a range of dose-levels. The most frequent tumor types enrolled were cervical (n?=?10), head and neck squamous cell (n?=?10), and follicular thyroid (n?=?4) cancers. The most common treatment-related grade???2 adverse events were rash (56%), hypomagnesemia (17%), pruritus (11%), diarrhea (8%), and tumor-related bleeding (8%). Seventeen of 19 patients (89%) treated at the maximum tolerated dose did not present treatment-related dose-limiting toxicity. Fifteen (63%) of the 24 evaluable patients achieved a disease control (stable disease???4 months (n?=?14) and partial response (n?=?1). The median number of prior lines of therapies was 3 (range 1-10). Conclusions:The triplet combination of erlotinib, cetuximab, and bevacizumab was well tolerated, conferring clinical benefit in heavily pretreated patients. Future studies are warranted with second or third-generation EGFR tyrosine kinase triplet combinations in the EGFR pathway aberrant patients.Trial Registration: ClinicalTrials.gov Identifier: NCT00543504. Sponsor(s): National Cancer Institute (NCI), MD Anderson Cancer Center.

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Phase 1b trial of nintedanib in combination with bevacizumab in patients with advanced solid tumors.

Publications

Phase 1b trial of nintedanib in combination with bevacizumab in patients with advanced solid tumors.

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