Phase II study of nab-paclitaxel in refractory small bowel adenocarcinoma and CpG island methylator phenotype (CIMP)-high colorectal cancer

M. J. Overman, L. Adam, K. Raghav, J. Wang, B. Kee, D. Fogelman, C. Eng, E. Vilar, R. Shroff, A. Dasari, R. Wolff, J. Morris, Enusha Karunasena, R. Pisanic, Nilofer Azad, S. Kopetz

Research output: Contribution to journalArticle

Abstract

Background: Hypermethylation of promoter CpG islands [CpG island methylator phenotype (CIMP)] represents a unique pathway for the development of colorectal cancer (CRC), characterized by lack of chromosomal instability and a low rate of adenomatous polyposis coli (APC) mutations, which have both been correlated with taxane resistance. Similarly, small bowel adenocarcinoma (SBA), a rare tumor, also has a low rate of APC mutations. This phase II study evaluated taxane sensitivity in SBA and CIMP-high CRC. Patients and methods: The primary objective was Response Evaluation Criteria in Solid Tumors version 1.1 response rate. Eligibility included Eastern Cooperative Oncology Group performance status 0/1, refractory disease, and SBA or CIMP-high metastatic CRC. Nab-paclitaxel was initially administered at a dose of 260 mg/m2 every 3 weeks but was reduced to 220 mg/m2 owing to toxicity. Results: A total of 21 patients with CIMP-high CRC and 13 with SBA were enrolled from November 2012 to October 2014. The efficacy-assessable population (patients who received at least three doses of the treatment) comprised 15 CIMP-high CRC patients and 10 SBA patients. Common grade 3 or 4 toxicities were fatigue (12%), neutropenia (9%), febrile neutropenia (9%), dehydration (6%), and thrombocytopenia (6%). No responses were seen in the CIMP-high CRC cohort and two partial responses were seen in the SBA cohort. Median progression-free survival was significantly greater in the SBA cohort than in the CIMP-high CRC cohort (3.2 months compared with 2.1 months, P=0.03). Neither APC mutation status nor CHFR methylation status correlated with efficacy in the CIMP-high CRC cohort. In vivo testing of paclitaxel in an SBA patient-derived xenograft validated the activity of taxanes in this disease type. Conclusion: Although preclinical studies suggested taxane sensitivity was associated with chromosomal stability and wild-type APC, we found that nab-paclitaxel was inactive in CIMP-high metastatic CRC. Nab-paclitaxel may represent a novel therapeutic option for SBA.

Original languageEnglish (US)
Article numbermdx688
Pages (from-to)139-144
Number of pages6
JournalAnnals of Oncology
Volume29
Issue number1
DOIs
StatePublished - Jan 1 2018

    Fingerprint

Keywords

  • CIMP
  • Colorectal cancer
  • Nab-paclitaxel
  • Small bowel adenosscarcinoma

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Overman, M. J., Adam, L., Raghav, K., Wang, J., Kee, B., Fogelman, D., Eng, C., Vilar, E., Shroff, R., Dasari, A., Wolff, R., Morris, J., Karunasena, E., Pisanic, R., Azad, N., & Kopetz, S. (2018). Phase II study of nab-paclitaxel in refractory small bowel adenocarcinoma and CpG island methylator phenotype (CIMP)-high colorectal cancer. Annals of Oncology, 29(1), 139-144. [mdx688]. https://doi.org/10.1093/annonc/mdx688