A phase I/II study of nintedanib and capecitabine for refractory metastatic colorectal cancer

Author:

Boland Patrick M12ORCID,Ebos John M L3,Attwood Kristopher4,Mastri Michalis3,Fountzilas Christos2,Iyer Renuka V2,Banker Christopher5,Goey Andrew K L5,Bies Robert6,Ma Wen Wee7,Fakih Marwan8ORCID

Affiliation:

1. Department of Medical Oncology, Rutgers Cancer Institute of New Jersey , New Brunswick, NJ, USA

2. Department of Medicine, Roswell Park Comprehensive Cancer Center , Buffalo, NY, USA

3. Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center , Buffalo, NY, USA

4. Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center , Buffalo, NY, USA

5. Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center , Buffalo, NY, USA

6. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo , Buffalo, NY, USA

7. Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic , Cleveland, OH, USA

8. Department of Medicine, City of Hope Comprehensive Cancer Center , Duarte, CA, USA

Abstract

Abstract Background Nintedanib is a tyrosine kinase inhibitor with efficacy in bevacizumab-resistant colorectal cancer models. This phase I/II study evaluated the recommended phase II dose and efficacy of nintedanib and capecitabine in refractory metastatic colorectal cancer. Methods Key eligibility criteria included refractory metastatic colorectal cancer and ECOG performance status of 1 or lower. The primary endpoint was 18-week progression-free survival (PFS). A 1-sided binomial test (at α = .1) compared the observed 18-week PFS with a historic control of .25. Results Forty-two patients were enrolled, including 39 at the recommended phase II dose. The recommended phase II dose was established to be nintedanib 200 mg by mouth twice daily and capecitabine 1000 mg/m2 by mouth twice daily. The protocol was evaluated for efficacy in 36 patients. The 18-week PFS was 42% (15/36 patients; P = .0209). Median PFS was 3.4 mo. Median overall survival was 8.9 mo. Sixteen (44%) patients experienced a grade 3/4 adverse event, most commonly fatigue (8%), palmoplantar erythrodysesthesia (8%), aspartate aminotransferase elevation (6%), asthenia (6%), pulmonary embolus (6%), and dehydration (6%). Osteopontin levels at cycle 1, day 1 and cycle 3, day 1 as well as ΔCCL2 levels correlated to disease control at 18 weeks. Conclusions The combination of nintedanib and capecitabine is well tolerated. Clinical efficacy appears to be superior to regorafenib or tipiracil hydrochloride monotherapy. Further investigation of similar combinations is warranted. ClinicalTrials.gov identifier NCT02393755

Funder

National Comprehensive Cancer Network

Boehringer Ingelheim

Publisher

Oxford University Press (OUP)

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