With a new phase 2 clinical trial underway, researchers at Roswell Park Cancer Institute are hoping to bring the use of checkpoint inhibitors into the treatment realm for ovarian cancer. Soon patients will be enrolled on to the trial which is testing a novel triplet of Keytruda (pembrolizumab), intravenous Avastin (bevacizumab) and oral low-dose Cytoxan (cyclophosphamide).
In an interview with CURE, Emese Zsiros, M.D., Ph.D., F.A.C.O.G., assistant professor of oncology in the Department of Gynecologic Oncology AND the Center for Immunotherapy at Roswell Park Cancer Institute, discussed the trial, as well as what role microbiomes play in the response patients have to immunotherapy agents.
Can you give a brief overview of your study and what you hope to find?
This is a new phase 2 clinical trial that enrolls patients who have recurrent ovarian cancer, epithelial ovarian cancer and fallopian tube cancer, which is all in the same category of disease. And during this study, we give them a drug combination of Keytruda, an immune checkpoint inhibitor produced by Merck. It's a combination with IV Avastin and oral low-dose Cytoxan.
The IV Avastin and the oral cyclophosphamide is somewhat the standard of care and accepted second line treatment for patients with recurrent ovarian cancer. But the addition of Keytruda has not been tried before. So this trial will enroll a total of 40 patients with recurrent ovarian cancer. Our main objective is to take a look at any improvement in PFS and also to look at toxicities to make sure that the combination of these three drugs is safe.
Do you have a prediction of what kind of toxicities you may see?
Keytruda is a checkpoint inhibitor, so by its nature, it activates the immune system. As a result of that, there are some patients who experience autoimmune reactions. Most of the time these reactions are very mild and easily reversed by discontinuing the medication. The major autoimmune reactions that were seen in prior studies were reactions against the lungs or colon, so pneumonitis or colitis. Some patients have issues with thyroid disorders-- either hyperthyroidism or hypothyroidism -- hepatitis, and very rarely diabetes. Again, these reactions are very rare and most of the time they're very mild. By discontinuing the drug or potentially giving steroids, you can reverse these immune-related adverse events.
As far as the Avastin, it's a monoclonal antibody. When you give this drug to patients, it has a very unique toxicity that comes from this drugs. But again, this is usually a very well-tolerated drug, but the side effects would be potential high blood pressure, wound-healing complications or some issues with kidneys, like creating more protein in the kidneys. Again, these side effects are typically really mild and by discontinuing the drug are reversible.
With the oral Cytoxan, we don't really expect to have any major drug toxicities. With the combination of these three drugs, we're not really sure, but hopefully we will not see any additional toxicities.
Where are you with the study now? Are you still enrolling patients?
We have opened our trial in the beginning of September and have enrolled our first five patients. Per our protocol, we enrolled five patients and they all have to go through three cycles to make sure that there are no major toxicities with this triple-drug combination. Some of them are just getting to the end of the third cycles and have seen no significant toxicities.
So once we have gone through three cycles with all of these five patients who are a part of the safety-leading cohort, we will be able to enroll the other 35 patients. We expect to start enrolling the other patients in the beginning of January.
Keytruda is relatively new to ovarian cancer. What do you expect?
In general, we have noticed that there are certain types of cancers, like melanoma, that generally tend to activate the immune system better. Using medications that activate the immune system even further has a larger clinical benefit and more patients tend to respond.
Patients with ovarian cancer generally don't have a very strong immediate response against ovarian cancer cells. As a result of that, currently giving this drug as a single agent might not translate into a large clinical response. So that's why we came up with a combination of these three medications. We're hoping that with the use of Avastin, we will normalize the tumor vessels to make the immune cells capable of going to the tumor microenvironment and recognize the cancer cells. Also, with the oral Cytoxan we're hoping to downregulate some of the mechanisms in the immune system that prevent T cells from getting activated.
We put the scientific rationale together because we found that with this triplet combination we have a much better chance to target the cancer cells and have the immune cells go to the tumor micro-environement and recognize the cancer cells more efficiently.
What are microbiomes? What role can they play in ovarian cancer and specificaly this trial?
Microbiomes are micro-organisms that inhabit our body. They consist of bacteria, along with some viruses. They call our body their home. Many of them will never cause any harm or disease to our bodies. However, they do play a vital function in our health and overall well-being. Microbiota, which consists of bacteria, is fundamental to break down nutrients and help food absorption. They also produce hormones and some neurotransmitters and communicate with the brain for general well-being and overall good health. They have also been associated with immune function. We know that people who have a certain type of bacteria in their gut have a little bit of a stronger immune system and potentially better response to better immune response against cancer cells. So this was only shown in animals so far with different composition of bacteria in their gut. When they give them these new immune therapy drugs, they saw a very marked response against cancer cells.
So we have proposed in this clinical trial that people collect stool samples, skin samples, and vaginal samples because all of these areas in our body contain a lot of bacteria and we will try to examine what are the composition of bacteria in our gut, vagina or skin has any role in response to these new immunogenic agents.
What do you see for this research in the next five or 10 years? Can this lead to an approval or a shift in the treatment paradigm?
We're really hoping that immunotherapy will help to improve the survival of patients with ovarian cancer. We know that about 30 percent of patients with melanoma had a remarkable clinical results. We hope to achieve the same in our ovarian cancer patient population.
Again, in earlier clinical trials when this drug was given itself, it only showed about a 15 percent response. But we're hoping that with this new drug combination that has good scientific rationale, we will be able to improve the response rate in our patient population as well.