A phase Ib study of capecitabine and ziv-aflibercept followed by a phase II single-arm expansion cohort in chemotherapy refractory metastatic colorectal cancer

Autor: Ace J. Hatch, Christel Rushing, Emily Bolch, Hope E. Uronis, S. David Hsu, James Leroy Wells, Abigail B. McLeod, Donna Niedzwiecki, Christy Arrowood, Kimberly L. Blackwell, John H. Strickler, P. Kelly Marcom, S. Yousuf Zafar, Michael A. Morse, Herbert Hurwitz, Ivy Altomare, Sherri Haley, Andrew B. Nixon, Fatima A. Rangwala, David Z. Chang
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Adult
Male
Oncology
Cancer Research
medicine.medical_specialty
Maximum Tolerated Dose
Bevacizumab
Colorectal cancer
Recombinant Fusion Proteins
lcsh:RC254-282
Cohort Studies
Capecitabine
03 medical and health sciences
0302 clinical medicine
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
Genetics
Mucositis
medicine
Clinical endpoint
Humans
030212 general & internal medicine
Neoplasm Metastasis
Aged
Neoplasm Staging
Aged
80 and over
business.industry
Ziv-aflibercept
Metastatic colorectal cancer
Middle Aged
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Survival Analysis
Oxaliplatin
Irinotecan
Receptors
Vascular Endothelial Growth Factor
Treatment Outcome
Tolerability
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Female
Advanced solid tumors
Colorectal Neoplasms
business
Research Article
medicine.drug
Zdroj: BMC Cancer, Vol 19, Iss 1, Pp 1-9 (2019)
BMC Cancer
ISSN: 1471-2407
Popis: Background Patients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options. In this phase Ib/II clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then we evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC. Methods All patients were required to have a Karnofsky Performance Status > 70% and adequate organ function. The phase Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies. Using a standard 3 + 3 design, we identified the MTD and RPTD for the combination. Fifty patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase II expansion cohort, and were treated at the RPTD. Prior EGFR antibody therapy was required for subjects with RAS wildtype tumors. The primary endpoint for the expansion cohort was progression-free survival (PFS) at two months. Secondary endpoints included objective response rate (ORR) and overall survival (OS). Results A total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion). The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1–14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle. In the expansion cohort, 72% of patients were progression-free at two months (95% confidence interval [CI], 60–84%). Median PFS and OS were 3.9 months (95% CI, 2.3–4.5) and 7.1 months (95% CI: 5.8–10.0), respectively. Among all patients evaluable for toxicity, the most common treatment related adverse events (all grade [%]; grade ≥ 3 [%]) included palmar-plantar erythrodysesthesia (41%; 6%), hypertension (33%; 22%), and mucositis (19%; 5%). RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes. Conclusion The combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability. PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study. Trial registration This clinical trial was registered in the www.clinicaltrials.gov system as NCT01661972 on July 31, 2012.
Databáze: OpenAIRE
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