Combination with standard chemotherapy shows promise in overcoming treatment resistance
In a small, phase I clinical trial, Johns Hopkins Kimmel Cancer Center researchers say they show for the first time that the experimental drug guadecitabine (SGI-110) is safe in combination with the chemotherapy drug irinotecan and may overcome resistance to irinotecan in patients with metastatic colorectal cancer. Results of the study are expected to be presented April 17 at the American Association for Cancer Research (AACR) Annual Meeting 2016 in New Orleans (abstract CT017).
Guadecitabine works to reverse a so-called epigenetic change in cancer cells known as methylation, which may alter genetic activity in cells in a way that can block the action of tumor-suppressing genes, pushing cells to become cancerous and resistant to therapy. By reversing this change in cancer cells, the drug restores cancer cells’ vulnerability to drugs such as irinotecan.
The clinical trial included 22 patients with metastatic colorectal cancer who had been treated previously with irinotecan and whose disease was progressing. The patients were divided into four groups, each receiving different doses of guadecitabine in combination with irinotecan, over an average period of four months.
During the study, 15 patients had at least one imaging scan to retest the extent and location of their cancers — with 12 patients experiencing stable disease — for more than the four-month period, on average, and one patient experiencing a partial response to the treatment (measured as at least a 30 percent reduction in the size of the tumors.)
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,” says Nilofer Azad, M.D., professor of oncology at the Johns Hopkins University School of Medicine.
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,” says Valerie Lee, M.D., a fellow at the Johns Hopkins Kimmel Cancer Center. “However, it seemed that patients were responding at all levels of the drug.”
Among the side effects of the combined treatment, 16 patients experienced neutropenia, a low count of the infection-fighting white blood cells called neutrophils; five patients with neutropenia had fevers; three patients became anemic; and two patients developed thrombocytopenia, a lowered count of blood-clotting platelets. Other side effects included diarrhea (three patients), fatigue (two patients) and dehydration (two patients). There was one death during the study, possibly resulting from febrile neutropenia caused by the treatment.
The current study was based on previous studies in the laboratory of Nita Ahuja, M.D., director of the Sarcoma and Peritoneal Surface Malignancy Program and professor of surgery at the Johns Hopkins University School of Medicine, which showed that guadecitabine limited the growth of colorectal cancer cell lines when combined with irinotecan, says Azad.
The drug combination is being tested in an ongoing phase II clinical trial (NCT01896856) in a larger group of metastatic colorectal cancer patients at multiple institutions to determine the effectiveness of the dual therapy compared with chemotherapy regimens that do not include guadecitabine, says Azad.
Scientists leading the new study will also look for biomarkers in patients that could help determine which of them are most likely to benefit from guadecitabine and irinotecan. Lee says the research team will measure the amount of methylation in patients’ cells when they begin their treatment and the presence of genes associated with irinotecan resistance, among other possible biomarkers.
In 2015, there were more than 130,000 people in the U.S. diagnosed with colon cancers. Five-year survival rates among people with localized colon cancers are more than 90 percent, but they are only 20 percent in those with metastatic cancer.
Guadecitabine is an experimental drug that has not been approved for use by the U.S. Food and Drug Administration. 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.
Other scientists who contributed to the research include Judy Wang, Anup Sharma, Zachary Kerner, Stephen Baylin, Ellen Lilly, and Thomas Brown from Johns Hopkins; Anthony El Khoueiry from the University of Southern California; Henk Verheul and Elske Gootjes from Vrije Universiteit in the Netherlands; and Peter Jones from the Van Andel Research Institute.
The news release discusses the findings of a small study that was designed to assess the safety of the experimental drug guadecitabine for use in conjunction with the conventional drug irinotecan to treat metastatic colorectal cancer. Phase 1 studies are designed to evaluate safety, observe side effects and identify the maximum tolerated dose (MTD). As such, the toxicity profile would be expected to be rather high. The study found that guadecitabine did cause some adverse side effects. The most concerning being low white blood cell count (neutropenia) in 73% of the subjects. One subject died from infection related to the low white blood cell count. However, the study also reported that there were positive effects with some patients — although the release clearly notes that this study was not designed to assess beneficial outcomes. Calling the drug “safe” in the headline may be a bit of a stretch, but otherwise the release does a good job of explaining the study, describing the fact that the drug is in the earliest stages of clinical testing, potential harms, and the study’s ties to the company that manufactures guadecitabine.
According to the National Cancer Institute, colorectal cancer is the third most common type of cancer in the United States for both men and women. And while 5-year survival statistics are good for colorectal cancer patients who are diagnosed while the cancer is still localized (90.1 percent), the 5-year survival rate drops to 13.5 percent for patients whose colorectal cancer has metastasized. The development of new treatment options for patients with metastatic colorectal cancer is worth covering. However, this early trial is small, and so preliminary, that one wonders about the potential value. Presumably the ongoing phase II trial mentioned in the release will shed more substantial light on the potential benefits associated with the guadecitabine-irinotecan combination. Perhaps a news release would be more fitting once those results are in.
We’ll rate this “Not Applicable” given the very early nature of the study and the fact that guadecitabine is clearly still far from approval for treating colorectal cancer so it would be difficult to put a precise dollar figure on it. It’s worth noting, however, that guadecitabine is also being considered for use in treating acute myeloid leukemia (AML) — and is much further along in development for that clinical application. In fact, there is already discussion about whether the potential benefits associated with using guadecitabine to treat AML outweigh the fact that other drugs are available in generic form (and are therefore less expensive). In short, while we don’t expect a release to place a dollar amount on the use of guadecitabine, we always like to see the issue of cost addressed in some way.
The release does a good job here in two ways. First, the release makes clear that the goal of this study was not to assess benefits, but to assess potential harms. That places the findings — and the study design — in context. Second, the release notes that 15 of the 22 patients had at least one imaging scan to track the extent and location of their cancers. Twelve of those 15 patients had “stable” disease, while one saw a 30 percent decrease in the size of the tumors.
The headline is problematic, but we’ll talk about that under the “Unjustifiable Language” criterion. The rest of the release does a good job of describing potential harms. The release discusses eight potential harms, defines them and offers numbers on all of them (e.g., “two patients developed thrombocytopenia, a lowered count of blood-clotting platelets”). That’s very good. Two things would have made it even better. First, the release could have included an explanation of what the observed adverse effects actually mean. For example, how severe was the thrombocytopenia? And how much of a risk does that pose to a patient’s health — are we talking about the potential for bruising easily? Or a high risk of bleeding to death? Second, it wasn’t clear if the dose of guadecitabine was related to observed effects. I.e., were patients who received higher doses of guadecitabine more likely to exhibit adverse effects?
The release does a nice job here. The release sets the tone in its first sentence, which begins with: “In a small, phase I clinical trial…”. The release clearly explains the goals of the clinical trial, the number and type of patients involved, and the study design. The only thing that could have made things more clear would be if the release had told readers the size of the doses each of the four study groups received — and whether dose size was related to observed effects.
No disease mongering here.
The release clearly states that the study was supported by Astex Pharmaceuticals, which manufactures guadecitabine.
There are a lot of drugs, and drug combinations, that are approved for use in colorectal cancer chemotherapy. Given that the release explicitly states that the study was not done to assess the potential benefits of guadecitabine, we don’t expect it to compare the drug’s performance to those other drugs.
The release makes clear that this was a preliminary trial and that a phase II trial is ongoing. That’s good. In addition, the release states: “Guadecitabine is an experimental drug that has not been approved for use by the U.S. Food and Drug Administration.” That’s great. We wish all releases were this straight-forward about drug/treatment availability.
As noted above, there are a lot of drugs and combinations approved for use in colorectal cancer chemotherapy. The release does a good job of explaining how guadecitabine may act against colorectal cancer. There are currently two FDA approved drugs that are classified as DNA methyltransferase inhibitors; decitabine (Dacogen) and azacitidine (Vidaza). Both had been used in clinical trials in the treatment of colon cancer.
The bulk of the release is very good in this regard, but the first thing readers see is the headline. That doesn’t mean the headline is more important, but it does mean that the headline is subject to additional scrutiny. And the headline here reaches too far. Here’s the headline: “Experimental drug guadecitabine found safe in patients with colorectal cancer.” Here’s an excerpt from lower down in the release: “16 patients experienced neutropenia, a low count of the infection-fighting white blood cells called neutrophils; five patients with neutropenia had fevers; three patients became anemic; and two patients developed thrombocytopenia, a lowered count of blood-clotting platelets. Other side effects included diarrhea (three patients), fatigue (two patients) and dehydration (two patients). There was one death during the study, possibly resulting from febrile neutropenia caused by the treatment.” The word “safe” is relative when discussing chemotherapy treatment, but when most readers see something described as “safe” they assume that means it won’t harm them. For that reason, it’s a stretch to apply the word “safe” to any treatment in which a sample size of 22 patients is associated with this many adverse outcomes, and may have contributed to a death.