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

Ann Oncol. 2018 Jan 1;29(1):139-144. doi: 10.1093/annonc/mdx688.


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.

Keywords: CIMP; colorectal cancer; nab-paclitaxel; small bowel adenosscarcinoma.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Adult
  • Aged
  • Albumins / adverse effects
  • Albumins / therapeutic use*
  • Animals
  • Cell Cycle Proteins / genetics
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • CpG Islands
  • DNA Methylation
  • DNA Mutational Analysis
  • Female
  • Humans
  • Intestine, Small / pathology*
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Neoplasm Proteins / genetics
  • Paclitaxel / adverse effects
  • Paclitaxel / therapeutic use*
  • Phenotype
  • Poly-ADP-Ribose Binding Proteins / genetics
  • Promoter Regions, Genetic
  • Ubiquitin-Protein Ligases / genetics
  • Xenograft Model Antitumor Assays


  • 130-nm albumin-bound paclitaxel
  • Albumins
  • Cell Cycle Proteins
  • Neoplasm Proteins
  • Poly-ADP-Ribose Binding Proteins
  • CHFR protein, human
  • Ubiquitin-Protein Ligases
  • Paclitaxel