A small, phase I clinical trial indicates the experimental drug guadecitabine (SGI-110) is safe in combination with the chemotherapy drug irinotecan, and it may overcome resistance to irinotecan in patients with metastatic colorectal cancer, according to study findings presented at the American Association for Cancer Research (AACR) Annual Meeting 2016.1

Guadecitabine reverses methylation, a type of epigenetic change that can block the action of tumor-suppressing genes. Guadecitabine can restore cancer cells’ vulnerability to such drugs as irinotecan.

This phase 1, dose-escalation study included 22 patients with metastatic colorectal cancer who had been treated previously with irinotecan and whose disease was progressing. The patients were divided into 4 groups, each receiving different doses of guadecitabine in combination with irinotecan, over an average period of 4 months.

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Imaging scans were performed on 15 of the study’s participants, and 12 patients were found to have stable disease that lasted more than 4 months, on average. A partial response to treatment occurred in 1 patient, defined as at least a 30% reduction in tumor size.

Although the study’s main purpose was to test the safety rather than the effectiveness of guadecitabine doses, “we were very happy to see some patients who benefited from the combination of the therapies for many months to more than a year,” said Nilofer Azad, MD, professor of oncology at the Johns Hopkins University School of Medicine in Baltimore, Maryland.

The study also showed signs that guadecitabine reduced methylation among the cancer cells. “We did see that giving a higher dose of the drug seemed to produce a better methylation response among patients,” said Valerie Lee, MD, a fellow at the Johns Hopkins Kimmel Cancer Center, and first author of the study. “However, it seemed that patients were responding at all levels of the drug.”

The combined treatment had side effects that included neutropenia in 16 patients, febrile neutropenia in 5 patients, thrombocytopenia in 2 patients, diarrhea in 3 patients, fatigue in 2 patients, and dehydration in 2 patients. One death occurred on-study, which may have been due to the febrile neutropenia caused by the treatment.

Azad explained that the drug combination is being tested in an ongoing phase II clinical trial (NCT01896856) in a larger group of patients with metastatic colorectal cancer at multiple institutions to determine the effectiveness of the dual therapy compared with chemotherapy regimens that do not include guadecitabine.

The new study will also seek to identify biomarkers that pinpoint which patients are most likely to benefit from combining guadecitabine and irinotecan. Methylation levels are a likely candidate for serving as a biomarker.

Guadecitabine is an experimental drug that does not have US Food and Drug Administration approval. It is manufactured by Astex Pharmaceuticals, a supporter of the Johns Hopkins-led study. The research was also supported by the Van Andel Research Institute SU2C/AACR Epigenetics Dream Team.


1. Lee V, Wang J, El Khoueiry A, et al. A phase I study of guadecitabine (GUA) combined with irinotecan (IRI) in previously treated metastatic colorectal cancer (mCRC) patients. Presentation at: American Association for Cancer Research Annual Meeting; April 16-20, 2016; New Orleans, Louisiana. Abstract CT017.