Jan Manarite joined the prostate cancer community in 2000 when her husband Dominic was diagnosed with advanced prostate cancer. She has gone on to become one of the most recognized advocates in the prostate cancer community today.

Prostatepedia spoke with her about questions prostate cancer patients may want to ask when considering joining a clinical trial.

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Why might a patient want to consider joining a clinical trial?

Ms. Manarite: A clinical trial decision is just another treatment option. That’s all it is. It’s still a risk versus benefit decision, just like choosing hormone therapy or surgery. That’s what it has to be.

One of the risks involved in a clinical trial is that it can take you a month to get in. You should definitely plan on it taking three weeks, though it could be longer. There’s a screening process. You have to fill out paperwork, make sure you qualify, get your medical records, check their boxes, cross their Ts, and dot their Is.

If your PSA is doubling every three weeks, and you’re metastatic, you have to factor that in: is it worth it for you to wait three weeks to see if you even qualify? That’s one of the risks. I don’t think people know it takes awhile to get into a clinical trial.

No. I don’t think they do at all.

Ms. Manarite: The other risk is the side effects. That’s always part of your treatment decision. The side effects can be tricky if you’re considering a clinical trial with a drug that we don’t know a lot about yet. However, there is a way to dig for that information. I don’t think patients realize this. If it’s in the early stages of the clinical trial, the name of the trial drug is going to be an acronym.

For examples, MDV-3100 is now Xtandi (enzalutamide), and ARN-509 was apalutamide and is now Erleada. If you Google that acronym adding the words discussion, forum, and side effects, you’ll find people who are on a clinical trial for this drug talking about the side effects in forums.

That’s a fantastic tip.

Ms. Manarite: Adding the word discussion to Google searches directs your results to discussion forums, where probably you’re going to find conversation. Data is important, but so is conversation. Honestly, if these are your peers, it’s your own peer-review. Data is never everything. Sometimes you find information through word of mouth. Sometimes you have to search discussions to dig up things to help you make your personal decision. No information is perfect, but sometimes that’s what you need.

In an early clinical trial, this can be helpful. You need a basic understanding of the side effects. Ask your doctor about them. If something happens, knowing it was a side effect for someone else is helpful.

What about the issue of a placebo? Many patients are afraid that if they join a trial, they’re just going to get the placebo.

Ms. Manarite: Great question. Placebo is another risk involved in a trial. You have to evaluate if you are willing to take that risk. But not every clinical trial has placebo. Let’s look at them by phase.

Almost every Phase III trial has placebo. However, even then, sometimes two-thirds of the patients get the drug and only one-third gets placebo. That’s kind of interesting, and right off the bat, it gives you a question to ask and clarify.

Almost all Phase II trials have no placebo. There are always exceptions, but most of them do not. That would make Phase II really interesting to me if I were a patient.

No Phase I trials have placebo (that I’ve heard of) because they’re busy doing things like giving patients the drug and kicking the dose up as high as they can to see what patients cannot tolerate. There is some risk involved in what they call dose escalation. Again, you need to be informed about what that means. That all being said, here’s another thing patients don’t realize. You can stop the clinical trial at any moment you want. You are 100% in control of whether and when you enter or exit. That makes it a little less scary.

Are there any other areas of misinformation that you feel are important to highlight?

Ms. Manarite: There are a few Phase III trials—not many, but a few—in which you may get a placebo.

If, during the trial, your disease progresses on the drug, you may be able to come out of the placebo and get treatment. That’s called a crossover provision. Unless you ask, you may not get that information up front. Again, that changes your perspective on the risk versus benefit. A great example of this is the Erleada (apalutamide) trial. They had a crossover provision in the Phase III trial so that if your disease progressed on placebo, you got free Zytiga (abiraterone). At the time, Zytiga (abiraterone) cost maybe $5,000-$7,000 a month. That is a big benefit to a patient. “I’m going to get free Zytiga (abiraterone) if I fail the trial drug or placebo. I don’t have to put it through Medicare or my insurance. That’s kind of interesting. Now I’m listening.” A crossover provision in a Phase III trial that has placebo is a great question to ask.

Do you have any thoughts or advice about the financial end of clinical trials?

Ms. Manarite: Yes. Make that a question. In most clinical trials, especially Phase III drug company driven trials, the treatment is going to be free. You may also be covered for travel, including compensation for long drives. You can’t assume you know the answer because they’re all different. The point is: ask.

Is travel frequently covered?

Ms. Manarite: Frequently, yes, but not always. You have to ask. That becomes part of your decision, your risk versus benefit. If you don’t live in a town that has a large institution or university where they’re more likely to be doing clinical trials, you may have to drive. There are exceptions. That’s another good question to ask.

I drove my husband to Miami once every two weeks for a Phase II Xinlay (atrasentan) trial. He got sick of it. He really didn’t want to do it, but I wanted him to do it. He didn’t feel good enough to get in a car, travel for two hours, sit in the clinic for an hour, and drive back for two hours. We did it for a while, but then he’d had enough, and he pulled out.

Another question to ask is if the clinical trial requires a CAT scan, bone scan, or blood test to qualify. They almost always do, but they aren’t always covered by the trial. Some are covered by your insurance, but if you don’t have insurance, will you have to pay? Again, this is a good question to ask. For someone who does not have insurance, accessing a clinical trial with potentially free treatment can be a huge benefit considering the risk/ benefit profile.

Especially for the imaging. That comes up a lot.

Ms. Manarite: That’s why you have to ask if imaging is covered.

What about finding trials? Do you recommend patients go to clinicaltrials.gov and look through there?

Ms. Manarite: You can definitely search http://www.clinicaltrials.gov. It has the largest selection. And they recently made their website a little more user-friendly.

But it’s not easy.

Here’s an example. I just went on clinicaltrials.gov and searched prostate cancer in Florida. Because I chose recruiting and not other criteria, I got 66 studies that are recruiting. Then I can filter down from there. That’s definitely better than it used to be.

They also have an 800-number you can try, which is new. I’m not sure if it’s general help or disease-specific.

Do you think if someone had a specific trial they were curious about, their experience might be different rather than just calling up and asking what’s available?

Ms. Manarite: Yes. That may be a better question. I would try (800) 4-Cancer.

My feeling is that most people find out about trials through their doctors, if at all.

Ms. Manarite: Most of the time. I think that’s fair. You’re right about that.

This happens all the time: people will call me, and they’ll say, “My doctor wants to put me in a clinical trial. I’m not sure if it makes sense, but he seems to like it. I’m going to try it.” I’ll ask them for more information on the trial—what it’s even called—and they’ll have no idea.

So, if your doctor’s talking to you about a clinical trial, walk out of there with a paper about it. Don’t leave without some kind of paper that has the name of the drug, the name of the trial, or something because you’ll never be able to research it when you get home. Walk out of there with a paper.

At least the name of the trial so you can go home and Google it.

Ms. Manarite: They should give you a 1-page printout at least. Also, if you’re going into a clinical trial, you will probably meet a new medical professional, such as a clinical trial nurse or the research nurse. It’s a whole new person. If you develop a relationship with them in the beginning, it might help expedite your enrollment. One of the tips I always tell people is: hand the clinical trial nurse your medical records. They won’t have to look for your information because you’ve given them your file already. It might speed things up.

Aren’t most medical records electronic right now, or are you suggesting people keep a print copy?

Mr. Manarite: Either or. Whatever works for you. If you’re going into a clinic for a doctor’s appointment, and you have this specific question, having a printed medical record on you that you can ask about is exactly what you need to be doing. There’s a time and a place for both types of medical records (online and printed) depending on what you’re doing.

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Ms. Marie Vastola is a Clinical Research Assistant in Radiation Oncology at Dana-Farber/Brigham and Women’s Cancer Center. She works on Dana-Farber-led and international clinical trials that accrue men with multiple stages of prostate cancer. She is an author on six research articles focusing on prostate cancer and has presented her research at a national conference.

Dr. Paul Nguyen is an internationally recognized expert in prostate cancer clinical care and research. He has published over 250 original research articles and has various national leadership roles and is the Dana-Farber Cancer Center Genitourinary Clinical Center Director for Radiation Oncology, Vice-Chair for Clinical Research in the Department of Radiation Oncology, and Associate Professor at Harvard Medical School.

Prostatepedia spoke with them about how eligibility requirements for prostate cancer clinical trials may unfairly exclude African American men.

How have black men been underrepresented historically in prostate clinical trials? What are some of the prevailing theories or ideas about why that might be?

Dr. Nguyen: It’s multifactorial, and that was something that our research aimed to get at. Because of the historical experiences like the Tuskegee experiment, some African- Americans may have been more leery of engaging in clinical trials. Because trials require certain costs and extra time away from work, this can be more difficult on certain populations. Or it could be from the doctor side. Some doctors may not be as willing to engage African-American patients to enroll them on trials. There are multiple factors, so it’s hard to know exactly what is the main driver.

Ms. Vastola: We have patients come from long distances to Dana-Farber, and they do that because they know that Dana-Farber is a good place for them to get treated. Many patients, especially ones who travel long distances, either have connections in the medical field and that’s how they found out about this, or they’re highly educated and they have the resources to look into research and potential treatments themselves. These are tools that only people who are a little more privileged have.

Why did you zero in on eligibility criteria? What were you looking at?

Ms. Vastola: Actually, a patient is what started this research project. I had been screening an African-American patient for one of our open trials, and filling out the paperwork to determine if he was eligible. Most of this paperwork is related to the cancer, to make sure that patients have the type of cancer that we’re studying. But other sections of the checklist establish that the patient is otherwise healthy. We wouldn’t want to give an experimental treatment to a patient who wasn’t healthy for their sake and for the research’s integrity. He didn’t meet the criteria for one of those health checks.

One of the ways we determine that a patient is otherwise healthy is to look at their immune function, and his white blood cell count was too low. I hadn’t seen that before, and we ran his blood test again. His medical oncologist said the patient had benign ethnic neutropenia, which I had never heard of it until then. Because of that he couldn’t go on the trial that we had. It wasn’t a trial that we were running out of this hospital, but we talked to the sponsors. And as with many big trials, they don’t allow exceptions, no matter what.

He didn’t get the opportunity to be on a trial that was designed for men just like him, and that was really frustrating. Everyone involved with his treatment was frustrated with that, and so we looked into if that could be happening to other men. We also looked at creatinine. It’s well known in the medical field that black patients have a higher serum creatinine, and so you have to use a special formula that accounts for race when you’re looking at their kidney function. We looked at benign ethnic neutropenia because that’s what started it, and it was something that people seemed unaware of.

Dr. Nguyen: In a research group, the ideas usually come from the lab principal investigator (PI), and then the junior people carry it out. In this case, Marie actually came up with this idea herself because of a patient experience that she had, seeing an African-American patient not be able to get on one of our trials. It’s what led to this Journal of the American Medical Association Oncology paper, which is impressive.

That is. What did you look at?

Ms. Vastola: We wanted to know how often this happens. Was this a fluke, or does this happen to other African-American men? The best way to find out was to look at the eligibility criteria of other trials. Every trial records when people don’t meet the criteria. They don’t often record why though, so we couldn’t just look at the internal records of our trials. The website clinicaltrials.gov lists all trials available to patients in the United States and also a lot of international trials, and it usually lists the eligibility criteria. Not all the trials go into detailed criteria, but many do. We went through 401 trials that had endpoints that we thought meant that they had the potential to reach large audiences and change practice. We looked at all of them and pulled the eligibility criteria to see how many of them had this white blood cell criterion.

We expected some would have it. We did not expect that almost 50% of trials would have either of these two criteria. We were also surprised that the serum creatinine criterion was so common that a quarter of the trials have it.

People are aware of this, and they know to calculate kidney function accounting for race. A lot of trials would use serum creatinine, which is just the blood test, but then they would also say that if a patient meets formula criteria (based on race), then they’re okay, which is what we want to see. Not all trials do that, and that’s the issue. Every single lab result you look at that measures creatinine says at the bottom that if the patient is African-American, apply this formula. But over 25% of these trials weren’t including that formula.

What else did you find?

Ms. Vastola: Those were the two criteria that we looked at. We also broke it down by year, size of the trial, the phase, and toxicity of the therapy. We were glad to see that, over time, people are using the serum creatinine eligibility criteria less and less, which may mean that more people are aware of it. That’s not the case for the white blood cell criterion though.

Dr. Nguyen: We looked only at trials that have survival as an endpoint, so these are trials looking to make people live longer. We think it’s especially important that all patients have equal access to these kinds of trials. There are a few consequences of not having African-Americans on these trials. Patients who go on trials can sometimes get access to new drugs, so it’s a problem if African-American patients aren’t getting on trials. We also don’t get to learn enough about whether certain drugs perform particularly well in African-Americans, and so we don’t get to learn about the specific benefits or lack of benefit of certain agents for African-American patients. We wind up extrapolating from the larger patient pool, which probably works most of the time, but perhaps there’s something special that we can learn from having African-American patients on trials so that we could find better cures that can be tailored for African-American patients.

Ms. Vastola: Exactly. Not having access to these clinical trials hurts the individual because they don’t have access to treatment that could potentially help them. But the lack of access also hurts the whole population.

It also skews your results, so that what you’re learning about isn’t really prostate cancer in all men, just prostate cancer in a subset of men.

Ms. Vastola: Exactly.

What do you hope this will mean for clinical trial design and eligibility recruitments?

Ms. Vastola: We presented this research letter at the Prostate Cancer Symposium of the American Society for Clinical Oncology in poster form. We got a lot of feedback from academic investigators, people who devote their lives to this. Their papers define the field. They said they’d never thought of this, and that some didn’t know benign ethnic neutropenia existed. This section of the eligibility criteria—the part that defines whether a patient is healthy—is just carried over from trial to trial because it’s so standard. It’s not something people think about when they design trials because it’s so standard.

It’s textbook. We hope that, as more people understand this, they will consider it when they design their trials.

Dr. Nguyen: We were guilty of it in our own trials, and that’s how this all came about. We just used standard entry criteria copied over from previous studies. We were surprised to learn that this could disproportionally disadvantage African-American patients from being able to enroll in our trials. Given all the barriers that African-American patients face in getting on clinical trials in the first place, the last thing that we need is yet another barrier.

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