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Cholangiocarcinoma (CCA) is the medical term for a rare type of cancer that occurs in the bile duct(s). Each year, < 6 out of 100,000 people will be diagnosed with 

. Bile ducts are tubes—about the size of a pencil eraser—that are part of the digestive system. They connect the gallbladder and liver to the small intestine and carry bile that helps digest food. Cancer develops in the bile ducts, as in other organs, when the genes inside the cells are abnormal. These are called gene mutations. When this happens, the instructions the gene would normally give a cell about when to grow, when to repair, and when to die become irregular. This causes the cell to grow and divide without stopping, resulting in tumors. It also pushes some of the healthy cells out of the way. Doctors don’t yet know what causes the genes to change in the first place, but they know that some things, like liver disease, can increase the risk for this kind of cancer. (Mayo Clinic, 2020; 

If CCA is caught in its very early stages, it can sometimes be managed by surgically removing the tumor. In most cases, patients in the early stages of CCA don’t experience symptoms and/or even know they have cancer. By the time they begin to experience symptoms, it is unlikely that the cancer will be manageable with surgery. Radiation therapy is one kind of treatment that may be used in such cases. It uses high energy x-rays or other types of radiation to kill cancer cells or stop them from growing. This therapy can be given either through a machine that will send beams of radiation to the area of the tumor or with special radioactive substances that will be sealed and placed in the body near or in the tumor. Another treatment option that may be used is chemotherapy. Chemotherapy is a medication or combination of medications that cause cancer cells to die and stop dividing. Chemotherapy has widespread effects, however, and kills both cancer cells and healthy cells. Different types of chemotherapy drugs work in different ways, so they are often combined. The widespread effect of chemotherapy accounts for many of its side effects and reduces the ability to fight infections. Immunotherapy is another treatment option. It boosts the body’s own immune system to help it fight off the cancer. The treatment types described may be used in various sequence combinations depending on the specific needs of the patient.

Finding an effective therapy for patients who have not responded well to their first treatment is particularly difficult, and the challenge becomes greater with each subsequent treatment. Targeted therapy is an option that can be used in CCA for patients who have failed prior therapy. Unlike chemotherapy, which affects all cells of the body, targeted therapy drugs aim primarily at specific molecules that help cancer cells grow and survive and less at healthy cells. (

American Society of Clinical Oncology, 2020

) Targeted therapy drugs work in several ways to stop cancer cell growth: They can block chemical messages that signal cancer cells to keep growing, target hormones involved in cancer growth, and/or block signals that cause formation of new blood vessels needed for cell growth. When a specific molecular target has been identified for a certain cancer type, drugs that act on that target to prevent or reverse its effect can be studied and developed for clinical use. Targeted therapy is important because people with certain tumor gene alterations may not respond well to standard chemotherapy or other standard-of-care options. Unfortunately, many different types of gene alterations have been identified from some cancers, and few, if any, have been identified for other types of cancer. Treatments are not yet available for all targets that have been identified, and many patients do not have these mutations.

Doctors look for gene mutations by taking a sample of tissue or blood and doing special laboratory tests to look for different molecular markers that indicate gene alterations. These markers are the targets for treatment and help doctors and their patients choose the best treatment. About 50% of of patients with CCA have a specific marker, or gene alteration; 25% of patients have an alteration in a gene called 

 (fibroblast growth factor receptor gene) (

https://www.emjreviews.com/oncology/article/the-importance-of-molecular-testing-in-the-treatment-of-cholangiocarcinoma/

; https://www.qedtx.com/cholangiocarcinoma/). One type of alteration called an 

 fusion has been identified as an important treatment target. In April 2020, the FDA approved pemigatinib for patients with 

 fusions who have not responded to at least 1 prior therapy (eg, chemotherapy) and whose cancer cannot be surgically removed. (

-targeted therapies are in various stages of investigation. One of them, infigratinib, has recently been granted priority review status by the United States Food and Drug Administration (FDA). This means that the FDA has agreed to reduce the amount of time they will require to review the data on the drug and decide whether to approve it. This decision was based on impact that this treatment would have for patients if approved. Clinical trials with infigratinib are enrolling patients so they can gather data the FDA needs to make their decision.

Clinical trials are rigorous scientific research studies of potential new treatments. They are conducted using approved methods and are closely monitored to make sure that the proper procedures are followed and that no unexpected safety issues emerge. The FDA requires data from clinical trials when deciding whether to approve or reject a new drug. We would not have the treatments we do today without past clinical trials and the patients who made them possible. Although there is no guarantee, the patients who participate may benefit from the study drug, which would otherwise be unavailable to them. They also have more frequent contact with medical staff who monitor their progress.

Participating in a clinical trial is also an opportunity to contribute to science and help future patients. Two large surveys have shown that contributing to science to help future patients is the most common reason that patients enroll in clinical trials. In 1 survey, 67% of patients said they would recommend participating in a clinical trial for a loved one or friend. (

) There is an urgent need for patients to participate in cancer clinical trials. A recent study found that only 8% of cancer patients in the United States participate in clinical trials, and most cancer trials can’t enroll enough patients to complete the trial. (

Clinical trials are conducted in 3 main phases. Each phase is designed to answer a different question about the study drug(s) or treatments. Phase 1 trials are designed to test the drug’s (or combination of drugs’) safety in a small number of patients. These trials do not evaluate whether the drug will help to control or cure a disease. If the drug is considered safe, it will move into Phase 2 testing. Phase 2 evaluates the drug’s safety and efficacy (how well it works) in a larger number of patients. If Phase 2 trials show that the drug works, it will move on to Phase 3 testing. (

Phase 3 clinical trials generate the data that the FDA reviews when deciding whether to approve a new treatment. These trials compare the safety and efficacy of the study drug to that of the drug(s) currently used to treat the condition. Phase 3 typically enrolls hundreds of patients and assigns each patient to 1 of the treatment groups randomly. Randomization ensures that each treatment group is similar in every way possible except for the treatment they are given. Each patient has a 50/50 chance of being assigned to the study drug, so treatment groups should have roughly the same percentage of women vs men, old vs young, Black vs White vs Latinx, etc. If the results show that 1 drug is better than the other, researchers can then be sure it is truly related to the drug and not to some unexpected or unknown influence of gender, age, race, etc.

Phase 3 trials also use double-blind procedures. Double-blind means that neither the patient nor the study doctor knows which treatment someone has been assigned to until the study is complete. This technique is important to negate bias and expectations from influencing patient or physician ratings of drug side effects or efficacy. For example, even patients receiving a placebo—a sugar pill with no active drug—report treatment benefit and/or side effects if they believe they are receiving the active drug. In the same way, patients and doctors may view symptoms or side effects differently if they know which medication a patient has been assigned to vs if they do not.

Patients who enroll in clinical trials need to understand that, in most cases, there is no guarantee that they will get the study drug or that the study drug is better than the standard-of-care drug. The clinical trial team is in frequent contact with enrolled patients to monitor their response to treatment, as well as any side effects or concerns. Participation in a trial is always voluntary, and patients can decide to withdraw from the trial at any time without penalty. It is also important to understand that clinical trials are conducted according to predetermined methods, and every patient will be treated according to those methods. The study doctor is not acting as your personal doctor but can share your test results with your personal doctor if you provide permission.

Enroll in a clinical trial and become part of the team that helps to bring new treatment options to patients with CCA.

For more information about infigratinib clinical trials near you, call QED Therapeutics at 1-877-280-5655, or visit www.clinicaltrials@QEDTx.com, or go to www.clinicaltrials.gov.

Articles

There are multiple treatment patients for patients with cholangiocarcinoma, here's what you need to know about them. 

Cholangiocarcinoma: Understanding Potential Paths For Treatment

Cholangiocarcinoma is a rare cancer of the bile ducts that is often diagnosed in later stages. For patients who are not candidates for surgery or perhaps have failed other treatment interventions, clinical trials may offer a treatment path for patients who are eligible for investigational therapies that have not yet been approved by the Food and Drug Administration (FDA). For instance, patients with FGFR2 gene fusions/translocations, may be eligible to join the PROOF trial, a study investigating an oral agent specifically designed for patients matching that profile.

Many patients with cancer may not be familiar with what goes into being enrolled into a clinical trial. It is important to have a conversation with your physician about eligibility for clinical trials, so that you can learn about the risks and benefits of clinical trials, and why clinical trials represent opportunities not only potentially for you, but for other patients with this condition.

®, Daniel Pennington, a clinical research coordinator at the University of Arizona Cancer Center, discusses how patients with cholangiocarcinoma can get involved in clinical trials, what patients who are enrolled onto the phase 3 PROOF trial can anticipate, and what they should know once they are enrolled on the trial.

CURE: What are some ways patients with cholangiocarcinoma can join a clinical trial, particularly the PROOF trial?

Most patients with cholangiocarcinoma end up having some kind of symptom — weight loss, abdominal pain, nausea, whatever it may be — and they end up in the hospital. Scans and images then may show they might have a mass or lesion and then they have a biopsy that shows that it may be cholangiocarcinoma. Pretty quickly after that, especially with cholangiocarcinoma, and in this trial, patients get referred to oncologists pretty quickly, because ultimately, the main goal is to get started on treatment as soon as possible. When they arrive in clinic, that's more when someone like me comes into play.

The patient is seen by an oncologist, who then comes to someone like myself and says, “I think this patient would benefit from this trial.” Especially with cholangiocarcinoma, anywhere between 10% to 15% of patients can have an FGFR2 fusion, which is what this specific treatment targets in the PROOF trial. And so, we then send patients off for molecular testing and get a baseline and make sure that they are eligible for the study.

At that point, I would come down, talk to the patient about the trial, and tell them the next steps that are going to happen. For example, we always have what they call a screening phase to make sure that they would be eligible for the trial on which, specifically for this trial, we'll be collecting tissue for the purpose of conducting genomic tests, we'll get some imaging assessments, go over all of their medical history, laboratory studies, EKG. And then another extra one in this instance is an echocardiogram, and then an ophthalmology assessment just to make sure that we get an accurate baseline for the patients. 

We would wait for the genomic test to come back to see if there is an FGFR2 fusion in patients, and the PROOF trial has kind of expedited that because typically, it'll take three to four weeks. However, for this study we can expect results within 7 days from tissue receipt, depending on the lab used. So, they've really expedited that process to really allow the patients to have a better chance at enrolling in targeted clinical trials.

In the beginning, when they're on the trial, they come in for more frequent assessments because we're always trying to evaluate for safety and make sure that everything's going well. They do have repeat echocardiograms and repeat ophthalmology assessments. After the first couple of months, the assessments slow down a lot. After a while, we end up seeing them once every month, which is better than the required 2 out of every 3 weeks if patients were to be randomized to the chemotherapy arm.

If patients are randomized to receive the investigational oral treatment, then they can take the oral drug at home for three weeks on and one week off, and then we assess them for safety and then we check scans every eight weeks to really see if the drug is working, if the patient's disease is stable and what is going on. The real benefit from this study is that patients are randomized two to one, which means they have a 66% chance of getting the oral pill, and a 33% chance of getting randomized to the chemotherapy.

But what's cool is that if unfortunately, they've progressed while on chemotherapy in the trial, they have the opportunity to cross over and still get that oral drug. So that's a huge benefit that if the patient is willing to wait that little amount of time that it takes for us to get the FGFR2 fusion report back from the Mayo Clinic, then they'll at least, at some point in time on study, they may get the oral drug, whereas in most other clinical trials, it's this or this and that's it.

What are some of the inclusion and exclusion criteria patients should be aware of when determining if they want to be a part of a trial like the PROOF trial?

The biggest factor of this study is it is a frontline trial. So, patients can’t have had any treatment beforehand. In every trial there’s always time points where we must wait. For example, some patients might have had a resection.

Or, if you have had adjuvant therapy or chemotherapy, a certain amount of time has had to pass before they've had progression before they can qualify for the study.

For any clinical trial, is there an application process to get on the trial?

So, patients don’t have to apply for anything specifically. Each institution has its own consent form, which is varied a little with differing verbiage. When they consent, that allows us to get everything going. But they don’t have to go online and apply for something like this. Most of the time, someone like myself approaches the patient and says the doctor thinks they would qualify for this trial. And, that we’re going to complete everything to make sure they do qualify for a trial.

Patients can also search the internet for clinical trial information, including visiting clinicaltrials.gov for a whole list of trials (

https://clinicaltrials.gov/ct2/show/NCT03773302

). Or, patients can visit a portal that the Sponsor of PROOF has put together with more information on the trial (

In terms of timing, what should a patient be prepared for when they hear they’re eligible to participate in a trial?

With any trial, it takes a little bit of time. For this trial, the main struggle is obtaining the tumor tissue from patients, getting that submitted and approved. So, the first thing we must do is collect it; if they're with our institution, typically it's a little bit faster, but realistically, I personally will plan everything around when that anticipated result would come in.

I don't want to collect unnecessary assessments and things if it's not required, [especially] if the patient wouldn't be eligible in the end. [Therefore], we try to collect everything within a very short time span. From timing of consent, it can take a couple days to get the actual tumor tissue to get the result, then these screening assessments [take time, as well]. 

Once a patient becomes an active participant in a trial, what are some things they should be aware of to ensure that things are going as smoothly as possible?

The best thing I can recommend is close contact. At least with myself, I'm always in contact with my patients throughout the week, and if they have any problems they call me right away and if there's a red flag or something that doesn't seem right, we can bring them in pretty quickly the day of, and I can get close contact with a physician that's in charge of them and address their concerns right away. Because with any clinical trial, we must keep a close eye on any symptom that might arise because it could be something that's coming, we don't know. So just close communication is probably the number one thing.

A clinical research coordinator discusses how patients with cholangiocarcinoma can get involved in clinical trials, such as the phase 3 PROOF trial, as well as what they should know once they are enrolled. 

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Marialice’s Story with Chronic Lymphocytic Leukemia (CLL)

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What Patients with Cholangiocarcinoma Should Be Prepared for When Joining a Trial

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