Dr. Michael Morris’s Clinical Trial: Combining Taxotere + Xofigo

Dr. Michael J. Morris is a medical oncologist who specializes in prostate cancer at Memorial Sloan Kettering Cancer Center in New York City where he serves as the Prostate Cancer Section Head.

He spoke with Prostatepedia about a clinical he’s running that looks at combining Taxotere (docetazel) and Xofigo (radium-223).

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What attracted you to medicine in the first place? Why did you become a doctor?

Dr. Michael Morris: I came to medicine from a somewhat different background than many physicians. I grew up in a family that’s heavily focused on the humanities—history, culture, and literature. I inherited those genes from my family, but I also had a real scientific interest that I found to be equally compelling.

In college, I divided my time between literature and science. What attracted me to medicine was that it perfectly merged humanism and science – both patient care and research require an understanding of the history of a patient, his disease, and his treatments. The challenge of medicine is to creatively conceive how biology can be brought to bear to alter these for an individual and the field.

Have you ever had any patients over the years whose stories have changed how you view either the art of medicine or your own role?

Dr. Morris: Many people feel absolutely devastated when they get prostate cancer, which for many people can be a chronic disease. The anxiety provoked by a cancer diagnosis, and even by a detectable or rising PSA can be existential. One of my patients was a Vietnam War veteran. He had been through his share of battles before, and saw more than a few of his closest friends not live past early adulthood. For him, prostate cancer was a reminder to him of what he had survived already. He felt that he was lucky to have lived long enough to face prostate cancer as the primary threat to his life. He took his prostate cancer journey as the next opportunity to lead, to teach, and to be in charge of and help so many people through their disease. Even in our waiting room, he was guiding people and keeping everybody’s anxiety in line. That made a huge impression. People who have faced risks before can be incredibly helpful to those who are not experienced with the helplessness and fear that a cancer diagnosis provokes. We have a lot of first responders in our practice, and their experience managing risk and anxiety can be very helpful to those without those skills. They can help the care providers as much as the patients, too.

From a clinical trial standpoint, I’m struck by the selflessness of so many of our patients. They understand that their treatments are the result of the efforts of patients on studies who have preceded them, and they’re willing to volunteer so that we can learn how to best treat those patients who will follow them. They’re saying, “I’m going to give my body to a clinical trial so that the next generation of prostate cancer patients can learn from my experience.” That’s inspiring.

Talk to us about your Phase III trial combining Xofigo (radium-223) and Taxotere (docetaxel). Why this particular trial? Why now?

Dr. Morris: In general, my research focus is where nuclear medicine and medical oncology intersect. That is, looking at drugs that you can deliver systemically, that are targeted to either the prostate cancer cell itself or to the host organ of most metastatic disease which is bone. And that also means looking at combining those drugs with other drugs that can help patients either feel better or survive longer.

This trial comes out of a long history of work, trying to combine radioligand therapy, which are essentially liquid systemic radioactive drugs, with other systemic treatments, to target both the cancer cell itself and bone, which is the host organ to most metastatic disease.

Xofigo (radium-223) is a known, life-prolonging radioactive agent that targets metastatic disease to bone. Since most metastatic disease in prostate cancer is in the bones, you can really encompass most of the disease by targeting that one bony compartment. Within the bone is the cancer itself, and the chemotherapy is used to target the prostate cancer cell. It’s a concept of dual targeting, both the environment that the cancer is hosted in and the cancer itself. That’s why we’re using these two agents, one of which targets bone and the other cancer, and both of which prolong survival independently, to see if those effects can be amplified by giving them together.

What will you be doing step by step?

Dr. Morris: The first thing is, a man has got to qualify for the trial, which means that he has to have predominantly bone metastases because that is the target for the Xofigo (radium-223).

The second thing is that he can’t have a significant amount of soft tissue disease in either the lungs or the liver. He has to have progressed through standard testosterone-lowering agents, such as Zytiga (abiraterone) or Xtandi (enzalutamide). If that patient is otherwise a chemotherapy candidate, then the treatment involves giving chemotherapy once every three weeks and then the Xofigo (radium- 223) once every other chemotherapy dose, so every six weeks. They’re both IV agents. That’s the essence of the treatment of the study.

Xofigo (radium-223) is a unique radioactive drug. It emits an alpha particle, which releases a lot of energy in a very tiny distance, only a few cell-lengths deep. It has virtually no side effects, so it’s a well-tolerated, life-prolonging treatment.

Chemotherapy is standard first-line chemotherapy in the form of Taxotere (docetaxel). It’s given every three weeks. It’s life-prolonging as well, and is a member of a class of taxane-based chemotherapy.

What are the side effects like for that?

Dr. Morris: Primarily fatigue, but some patients can have tingling in their fingers and toes as well, and sometimes changes in taste. A very small number of patients can have their white blood cell counts suppressed.

How long are you going to be following these men while they’re on these two agents?

Dr. Morris: Patients receive a total of six doses of Xofigo (radium-223) and no more than ten doses of chemotherapy. After that, they’ve completed the treatment portion of the protocol, and they could go on, if they needed, to any other treatments. But we follow them for the rest of their lives.

Are there any fees associated with the trial? I’m assuming the Xofigo (radium-223) and the Taxotere (docetaxel) are provided.

Dr. Morris: The Xofigo (radium-223) is provided by the study, and the patient is responsible for the docetaxel, which is standard chemotherapy.

What else do you hope to learn from this study?

Dr. Morris: There are a whole host of innovative biomarkers and science that is built into this trial, so we learn as much as we can about each patient as they’re treated.

We’re looking at circulating tumor cells and cell-free DNA. We’re looking at the impact of the treatment using novel imaging techniques. We’re looking at quality of life. There’s a whole component of the study that will allow us to learn as much about the prostate cancer and the efficacy of the drugs as well.

Those will be covered under the trial as well, right?

Dr. Morris: Absolutely. Those are all covered by the study.

Is that information shared with the patient?

Dr. Morris: Any information we gather in real-time can be shared with the patient. Some of the scientific aspects of the trial will only be performed after the trial is done, so results from those will be delayed until after the study. But as we learn new information, we pass it on to our patients.

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Clinical Trial: Free Genetic Testing

Dr. Heather Cheng is an Assistant Professor at the University of Washington and Fred Hutchinson Cancer Research Center, and the Director of the Seattle Cancer Care Alliance Prostate Cancer Genetics Clinic.

Prostatepedia spoke with her about a clinical trial she’s running that looks at inherited genetics of men with metastatic prostate cancer.

What attracted you to medicine?

Dr. Heather Cheng: There are a couple of things I love about medicine and especially oncology. One is getting to know patients, finding out what’s most important to them as people, and using that information to help guide discussions and decisions about their treatment in a way that is true to what is most important to them. These days I guess you call this shared decision-making. That’s the most rewarding part about what I do.

Have you had any patients over the years who have changed how you see your own role or how you view the art of the medicine?

Dr. Cheng: I have a lot of patients who fit those criteria. My interest in this area started when I was a first-year Hematology and Oncology fellow. I was in the clinic and it was when we were at the beginning of this wave of new exciting drugs that prolong survival, such as Zytiga (abiraterone) and Xtandi (enzalutamide).

I met this patient who was 43 years old; he had new, aggressive metastatic prostate cancer. His disease blew through every one of the new drugs. It was extremely humbling and disappointing because we were so excited about these drugs, but they didn’t do much to slow his disease. And it was heartbreaking because he was so young. He had a family history of cancer but not prostate cancer. He had a teenaged son. We had a lot of discussions about the effect of his disease on his son. I wondered if there was something genetic, something that was making his cancer so aggressive. And then, what could this mean for his son? His memory has stuck with me.

When I think about the work and research that I do, it’s not just for the individual patient in front of me. I’m also thinking about how we can improve things and advance the field so things can be better for the next generation. How can we make progress as quickly and with as much positive impact as possible?

I met another patient who had a great effect on me. He had just been diagnosed with high-risk prostate cancer, Gleason 9. He was planning to get radiation. As part of a research study, we offered to sequence the DNA of his cancer because he had an unusual appearance of his cancer– ductal histology. He was kind and generous enough to volunteer and participate. It wasn’t going to affect his treatment, but he agreed to help us learn more.

In his cancer, we found a mutation in the BRCA2 gene, the one that many people may have heard of because of its association with breast and ovarian cancer risk. There was suspicion that the mutation could be inherited, so we brought him back for dedicated genetic testing for inherited cancer risk. And, it turns out he did have an inherited version of that mutated BRCA2 gene. He was the first person in his family to be found to carry the mutated version of BRCA2. Neither he nor his family would have known until later if we had not looked in his tumor.

After this, some of his relatives had genetic counseling and were also tested. The sister who had breast cancer had a recurrence and was found to carry the BRCA2 mutation. This information was important for her because it offers additional treatment opportunities for her cancer that might not have otherwise been considered. His daughter was also found to carry the BRCA2 mutation and after learning of this, had a mammogram and was diagnosed with breast cancer. She’s still curable, so she’s going through treatment, but it is possible that she might not have known until much later otherwise.

The importance of test results can extend to relatives in a way that might help more than one person, not just the person that I see in the clinic, but other members of their family. I do want to be clear that these mutations are not found in most people— even those with cancer—but for the people who have these mutations, it can be life saving information for their family members.

What will you be doing, and what can men expect to happen, during your clinical trial?

Dr. Cheng: You can learn about the study from your doctor, support group, or by visiting our website, http://www.GentlemenStudy.org. There is information about the study. You can consent online, confirm that you have metastatic prostate cancer, and check that you’re interested in genetic testing for cancer risk.

There is a questionnaire that many take about 40 minutes to complete, that asks about your knowledge of genetics, basic health, family history of cancer, and demographic information about where you live.

You can upload supporting information about your diagnosis, or you can check a box saying you’d like help from the research team to gather that information on your behalf. Because there are strict privacy laws around medical records, you need to give permission to our team to get medical information for the study on your behalf.

To be eligible, you must have metastatic prostate cancer and must live in the United States. There’s one other exclusion, which is that if you have some blood disorders such as leukemia, we cannot be sure that the test results are valid.

If you meet criteria, you will be mailed a saliva kit, a medical-grade genetic test through Color Genomics, with instructions on how to provide a saliva sample. Follow the instructions carefully and then mail the kit back. Results are typically available within 4 weeks. You will have access to a genetic counselor following your results, and you are invited to follow up in person to our clinic if you live in the area. If you don’t live near us, we can direct you to resources to find a genetic counselor for in-person visit or by telehealth.

The testing for this study is not recreational testing. It is not the same as Ancestry.com or 23andMe. This is clinical, medically appropriate testing if you have metastatic prostate cancer.

Do you share this information with their doctor, or is it up to them to share the information with their doctor?

Dr. Cheng: We strongly encourage participants to share the results and information with their doctors, but our ethical board does not allow us to do this for participants without their specific consent.

Are there any fees for patients?

Dr. Cheng: There is no fee for the patient.

It sounds similar to the process for the Metastatic Prostate Cancer Project, except I don’t think they share their results.

Dr. Cheng: Yes, it is similar to that project. The difference is that the patient or the participant gets results that apply to them individually. The Metastatic Prostate Cancer Project, which is fantastic and an important and innovative study, is de-identified, and the patient doesn’t get individual-level results back.

Their goal is to amass as much data as they can for research.

Dr. Cheng: Correct, yes.

Are you also cataloging the information that you collect?

Dr. Cheng: Yes.

What will you do with the data that you collect?

Dr. Cheng: We’ll be looking at demographics, the proportion of people who have mutations (pathogenic variants), information about family history, and validated measures of knowledge, distress measures and satisfaction with testing.

If patients consent to re-contact, they will be contacted at the conclusion of the study. If there are other follow-up studies, they can opt to learn about those. There will also be an invitation for those who agree to subsequent studies, like treatment studies or PARP-inhibitor studies, for example.

We’re still learning about certain genes, such as ATM mutations and CHEK2 mutations. As we learn more, we may want to update participants on what the field has learned. There are still many important questions that the field needs to answer, and patient engagement and participation will make this happen more quickly. There will be opportunities for those downstream studies.

How many patients are you looking for, overall?

Dr. Cheng: The plan was for 2,000. We have sent kits out to over 350. We still have room for participation!

Join us to read the issue and learn how to participate in Dr. Cheng’s study.

 

Frontiers In Prostate Cancer Genomics

Dr. Felix Feng is a physician-scientist at University of California, San Francisco (UCSF) keenly interested in improving outcomes for patients with prostate cancer. His research centers on discovering prognostic/predictive biomarkers in prostate cancer and developing rational approaches to targeted treatment for therapy-resistant prostate cancer. He also sees patients through his prostate cancer clinic at UCSF.

Prostatepedia spoke with him about the state of genomics for prostate cancer today.

Not a member? Read the rest of this month’s conversations about prostate cancer genomics + prostate cancer genomics clinical trials.

What would you like prostate cancer patients to know about the state of genomics for prostate cancer today?

Dr. Feng: Genomics is becoming an important reality for patients with prostate cancer. We’ve talked about genomics for years in the context of research and possible advances for patients, but we are now reaching the era when these advances are being used in clinical practice or being assessed in clinical trials.

For patients with metastatic prostate cancer, patients with alterations and mismatch repair genes should be treated with immunotherapy (checkpoint blockade) at some point in the course of their treatment. At some point in their treatment, patients who have alterations in the BRCA1 and BRCA2 genes or other DNA repair genes should also enroll on a trial involving a PARP inhibitor.

There are many other trials testing specific biomarkers for selection for patients. For example, a few years ago, Prof. Johann de Bono presented the results of a study looking at an AKT inhibitor for patients with PTEN deleted prostate cancers. That’s currently being explored in a Phase III trial, and we’re eagerly awaiting the results of that.

In addition, the presence of androgen receptor (AR) splice variants is being used to select patients for studies. These need to be tested out. Some are molecular biomarkers rather than genomic biomarkers. But for patients with metastatic prostate cancer, we can point to definite examples where science is becoming clinical reality.

In the context of patients with localized prostate cancer or non-metastatic prostate cancer, we’re also seeing a number of advances. There are several tissue-based biomarkers that are now covered in various contexts by insurance companies, and they can be ordered as standard-of-care clinically.

In one of my roles, I chair the Genitourinary Cancer Committee for the Clinical Trials group NRG Oncology. A number of our national trials are Phase II and now also Phase III. The trials that we’re developing incorporate these genomic biomarkers for patient stratification or patient selection. When you start to see genomic markers like Decipher incorporated into NRG or PAM50 trials, it means that, sooner or later, these will become standard-of-care, assuming that the trials are positive.

Are there any open and enrolling clinical trials that either focus on prostate cancer genomics or incorporate genomics into their design that you think men reading this may either want to look into or ask their doctors about?

Dr. Feng: Two of the most promising studies are in patients who have had surgery for prostate cancer and now have a PSA recurrence. They are both actively enrolling.

The first trial that I would highlight is NRG-GU006. This study is open at hundreds of hospitals in the United States and Canada; it takes men who have a PSA recurrence after prostatectomy. We go back, we profile the prostate cancer sample from those patients, and we assess a biomarker called the PAM50 classifier, which we helped validate in prostate cancer as predicting response to hormonal therapy. Patients get stratified by this biomarker and are then randomized to standard-of-care, which is radiation alone, or to radiation plus the next-generation antiandrogen Erleada (apalutamide). They get both genomic testing with the PAM50 classifier and randomization, as well as the opportunity to be on Erleada (apalutamide).

Another trial that is actively enrolling is the NRG-GU002 trial, which takes patients who have very aggressive recurrences of their prostate cancer after surgery, and tests them using the genomic classifier Decipher. In the control arm, those with aggressive disease get randomized to radiation and hormone therapy or radiation and hormone therapy plus chemotherapy with Taxotere (docetaxel).

We and other groups have many other trials in development trying to incorporate these biomarkers, but those are the two trials that are open and accruing.

Who are the lead investigators on these two trials?

Dr. Feng: On NRG-GU006, the co-leads are Dr. Daniel Spratt from the University of Michigan and me. On the NRG-GU002 trial, the lead is Dr. Mark Hurwitz from Thomas Jefferson University.

Is there anything else that patients might want to consider?

Dr. Feng: For patients with metastatic disease, there are a number of PARP inhibitor studies in development right now. We’re looking to move PARP inhibitors into earlier and earlier disease spaces in select patients, largely based on the presence of DNA repair alterations.

This study using the Genentech AKT inhibitor is exciting to me. It’s a Phase III study for patients with PTEN alterations. Not all prostate cancers are the same, but we have traditionally put prostate cancer into one disease. But the many different cancers that comprise prostate disease could be genomically selected or stratified.

That is the future, right? Smaller and more precise categories?

Dr. Feng: Yes.

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Prostate Cancer Genomics

This issue is devoted to the genetics and genomics of prostate cancer, which is one of the most promising and exciting areas of prostate cancer research. Already, this line of investigation is having a major impact. For example, by better defining the genomics of patients entering clinical trials, there can be a marked reduction in the number of patients needed to reach statistical significance. This can potentially reduce the costs of drug development dramatically.

Research into the role of genetics and genomic alterations in the biology and treatment of prostate cancer are still at a much earlier stage than it is for breast cancer. While laboratory studies have discovered a wide range of genes that might act to determine prostate cancer behavior in the clinic, proof that these changes actually determine outcome in the clinic are rather limited. There are even fewer examples where drugs attacking these changes have been FDA-approved for the treatment of prostate cancer.

The PD-1 inhibitor, Keytruda (pembrolizumab) is at present the only example. In 2017, this drug was approved to treat cancers that show mismatch repair or microsatellite instability. These mutations are found in a small proportion of prostate cancer patients.

There are a number of mutations targeted by drugs that are in advanced testing, so this list may expand rapidly. One of the more promising targets is BRCA2. Mutations that alter the function of this gene are known to be involved in breast and ovarian cancer. Cancer cells with these BRCA2 mutations become dependent on the protein, PARP, for their survival and drugs that inhibit PARP can be effective therapy. Studies on patients with advanced prostate cancer show that altered BRCA2 is found in 10-30% of cases. PARP inhibitors have shown significant activity in early clinical trials. Randomized controlled trials needed for FDA-approval are in progress.

Genomic information can also be used to determine how likely prostate cancer is to behave aggressively. This can help identify patients who are likely to do well with active surveillance or to be at low risk for recurrence after an initial attempt at curative treatment.

While genomics promises to revolutionize the treatment of prostate cancer, this revolution requires support from the patient community. The key studies can only be done if patients elect to participate in these trials. For this reason, we made sure to provide you with information on how to become involved in this process.

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Mr. Tony Crispino: Patient + Research Advocacy

Mr. Tony Crispino found out that he had prostate cancer at age 44. In the years since his treatment, he has become an outspoken prostate cancer advocate. Today, he runs a support group for other patients in Las Vegas, Nevada and is a Patient Advocate at Southwest Oncology Group (SWOG) where he works with leaders in prostate cancer research on cutting-edge clinical trials.

He spoke with Prostatepedia about his own journey as well as ways in which you can get involved in advocacy.

How did you find out that you had prostate cancer?

Mr. Crispino: Like most, I was asymptomatic. I was 44 years old and had no reason to believe that I had cancer. I wasn’t even aware that I had a PSA test taken, and I was unaware of what PSA was. It was by chance that I’d had a diagnostic PSA, which was at 20, and then I found out that I had stage IIIB disease.

Which treatment path did you take?

Mr. Crispino: Being diagnosed in 2006, I had fewer options than patients have today. We didn’t have Zytiga (abiraterone), Xtandi (enzalutamide), or Erleada (apalutamide) then. The path I chose was not considered standard-of-care yet, but eventually, it became that for guys with locally advanced disease. I read papers from Harvard, Stanford, UCSF, UCLA, and more, and I decided that a multimodal approach was reasonable. So radiotherapy, hormonal therapy, and participation in research trials were all reasonable. Today, I would likely be offered Zytiga (abiraterone) [per STAMPEDE], six cycles of Taxotere (docetaxel) [per CHAARTED], or both. But I am fortunate to have a good outcome with what I chose. I have not been treated since 2010, and I have a durable remission.

Has the prostate cancer journey changed you in any way?

Mr. Crispino: A cancer diagnosis is a life changing experience for most. Nearly all who are diagnosed and their families have a new reality. My well-known mantra to others diagnosed is to stay positive. I followed that rule, and once I came to understand my condition, it was time to take that lemon and make lemonade. My negatives are obvious, but my positives outweigh them. I have done well with advanced disease and that helps as there are many who are not as fortunate, and it becomes more difficult for them to stay positive.

I got involved as an advocate, which has been one of the blessings in my life. I have been actively involved in support, mentoring, research, serving on guidelines panels, and lobbying, and I have authored many physician-facing documents. I would have never had those opportunities without that diagnosis, and I would never have dreamed of being a part of them.

How did you first become involved with prostate cancer patient advocacy?

Mr. Crispino: Almost immediately, I was an online surfer like never before trying to regain control of my life. It was through this method that I became educated, a support group leader, and determined to be a part of cancer treatment as more than a patient. But first I had to experience the support I received from all those who paved the way ahead of me.

What do you do with Us TOO and SWOG?

Mr. Crispino: Us TOO is education and support. I am well equipped to help in these areas, and I have run the Las Vegas chapter for over 10 years.

SWOG is a fantastic experience. There are only four such networks in the National Cancer Institute (NCI) group called the National Clinical Trials Network (NCTN). Being included in clinical trial design and evaluation is a very unique experience that very few patient representatives in this area of research get to participate in. SWOG has led me to my membership in societies like ASCO, participation in guidelines panels for ASCO, AUA, SUO, ASTRO, and being elected to the Prostate Task Force for the NCI.

Why do you continue reaching out to other men with prostate cancer?

Mr. Crispino: I have a great deal of experience across the board. It is not only helpful to the diagnosed patient but rewarding to be able to help others. Reaching out to the patient community allows me to help the physician community and vice versa. It is very fulfilling.

Do you have any advice for other men with prostate cancer?

Mr. Crispino: Get educated. I tell all those I mentor that educated decisions are always better than emotional decisions or passing the decision on to your oncologist. Shared decision making requires that you have some knowledge before a decision.

Beware of bias, as there is plenty of it in the patient and physician communities. Beware of conflicts of interest, as there is plenty of it in the physician community. Even with good intentions, biases and conflicts of interests are common.

Do you have any advice for men with prostate cancer who’d like to get involved with advocacy but aren’t sure how to go about it?

Mr. Crispino: Just do it! Many of the positions I hold are elected and have term limits. This means that someone has to grab the baton and move the effort forward when I move on. Being a part of effective advocacy requires many things.

Become educated through peer groups and reading, and by that I mean, listen to all experiences and take notes.

Lose or limit your biases. This is easier said than done. We all think that our decisions are the best and can apply to everyone in the same way. Strong bias might help in the physician and patient communities, but it’s not a good trait in research and guidelines panels. It can be harmful in support and education communities.

Define the area in which you think you can be the best advocate. Being an advocate is a broad role. You can lobby and participate in the political side, which I did but I found it wasn’t my niche. You can be a research advocate, a support advocate, a patient-physician liaison, or even an online poster.

Partake in physician-patient group meetings. Whether it’s attending an ASCO, AUA, ASTRO, or coalition meeting, be there. You will see what it’s about and whether it’s for you. This is not always easy as these types of group meetings can require travel. If you cannot do that, you can still be an effective support advocate in various ways. For example, you could advocate online or by attending support groups meetings.

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How You Can Participate in Genomic Research

Dr. Eliezer Van Allen, Assistant Professor of Medicine at Harvard Medical School, a clinician at Dana-Farber/Partners Cancer Care, and an Associate Member at the Broad Institute of MIT and Harvard, focuses on computational cancer genomics, using new technology in precision medicine, and resistance to targeted prostate cancer therapies.

Prostatepedia spoke with him about how even those of you in remote areas can participate in nationwide genomic research study for men with advanced or metastatic prostate cancer.

What is it about medicine and caring for patients that keeps you interested and engaged?

Dr. Eliezer Van Allen: There are two answers to that question. One, the scientific answer, is that it’s been so remarkable to see how quickly advances that we’ve learned from studying patients with cancer have immediately translated into the clinic and have impacted my patients’ lives. It’s impacted people I don’t know, and that cycle of innovation is becoming quicker. It’s so exciting. It’s a privilege to be part of that from a professional level.

The other answer is more of a humanistic thing. I went into medicine because of my experiences at Camp Kesem, which is a camp for kids whose parents had cancer. It was a life-changing experience to be involved with that and to help drive it from the beginning. Whether or not any individual therapy works for any of my advanced cancer patients, there’s a human element to this job that’s very profound. That is also a privilege, to be involved with that day-to-day, no matter what.

Camp Kesem is still around, right?

Dr. Van Allen: Yes, it’s growing amazingly. There are over 100 camps now around the country, and thousands of families are involved. It’s wonderful.

Have you had any patients who changed either how you view the art of medicine or your own role?

Dr. Van Allen: Absolutely. At some level, every single patient both challenges and reinforces aspects of what it means to be a doctor and deliver care. Each in their own way has changed the way I think about things. There are obviously some stories that stand out and some experiences.

Some of the patients who’ve had the most catastrophic outcomes and succumbed to the disease in rapid form have taught me the most about what it means to live your life to the fullest, whatever that means to you. I have a lot of respect for them.

It’s a special thing to care for people at the particular moment, when they face big life questions.

Dr. Van Allen: About eight or nine years ago, I wrote a piece for the Journal of Clinical Oncology’s Art of Oncology series. It was about this one patient I had as a first-year fellow who had this positive thinking attitude in the wake of the most potentially catastrophic scenarios up until he passed away. It was such a surreal thing. In that case, it was rare, but I think it teaches you a lot about what it means to be human and how hard this disease is.

What is the goal of the Metastatic Prostate Cancer Project?

Dr. Van Allen: The Metastatic Prostate Cancer Project is a patient-driven research project whereby, rather than expecting the patients to come to us to join and participate in advanced research, we bring the project to their doorstep, and we engage with patients in new ways. We give patients an opportunity to share information about themselves and share their tumor specimens for us to do genetic testing. The goal is building the largest genomic registry of prostate cancer that we can learn from, and in so doing, accelerate that discovery to translation cycle even more.

Can you give us some updates on how the project has been going since you launched?

Dr. Van Allen: We launched this project in January 2018 in a patient population that is known not to talk about their disease in any venue, under any circumstances, to anyone. There’s no social media presence for this disease space, or at least on the surface, and frankly, we would’ve been thrilled had ten people signed up. Our sister project, the Metastatic Breast Cancer Project, has a loud and overt presence of women taking selfies with their saliva kits, so we weren’t sure how this was going to work.

We’re a little past a year from launch and over 700 men have engaged in research, given us consent to access their samples, filled out the patient-reported survey, and joined this Count Me In movement. It’s remarkable, but not only have these 700 men signed up, we’re already at the other end of the cycle of this project now, and we’ve generated complete data sets for the initial wave of these men. By complete data set, I mean genetic, clinical, and patient-reported data, and we’ve put that data out to the entire community in the research setting to learn from.

This proves the principle that we mean what we say when we’re generating data for the community. We’re not trying to build a silo here. This is patient-demanded, and therefore patient-driven, from day one. From every aspect across the board, it’s been remarkable and exciting to see how we’ve done so far.

We are 150% absolutely still looking for patients. We’ll always be looking for patients. Anyone who’s interested should feel comfortable to go to MPCProject.org and click Count Me In.

What kinds of patients should join? Anyone with prostate cancer?

Dr. Van Allen: This project is for advanced or metastatic prostate cancer, which means prostate cancer that’s left the gland. That could be folks with local, regional prostate cancer involved in the lymph nodes, folks with biochemical recurrence only (only PSA detected in the blood), and all the way to patients with heavily pretreated, advanced disease that’s spread to bone, liver, or wherever. Anyone in that spectrum is considered advanced or metastatic from our perspective.

The project is basically unending, right?

Dr. Van Allen: That’s the goal, releasing it as fast as we can.

Do you just release the data, or are you also forming collaborations with other institutions or projects?

Dr. Van Allen: We’ll release the data. We’re obviously going to try to learn from it ourselves and use it to come up with perhaps new drug targets, biomarkers, and whatnot, but also we would like to connect with other efforts that are spiritually aligned in any way that’s feasible.

One of the best outcomes would be that some researcher who is in no way affiliated with our project finds our data useful and uses it for their research to inform what they do. We’re already starting to see that happen with our sister projects where there are scientists and labs that we are not affiliated with who are using the data to inform how they think about their research and their projects. All of those outcomes are on the table, and we’re excited to pursue all of them.

Is there anything else you want patients to know about how the project is doing, about further studies you’re doing, or other studies you think people may find interesting?

Dr. Van Allen: This is a patient-driven project. Some of the patients who’ve given us feedback on their experiences so far have also prompted questions that we can ask that we, in our little academic bubble, probably would’ve never thought of. That’s how we’re starting to dive into things that are driven by patient experiences or that we’re observing in the patients who have signed up, down to questions that might seem curious but are illuminating, ones that we hadn’t intended initially.

For example, in the first patient data release, when asked if they had surgery for their prostate, almost half the patients marked: “unknown.” We can compare that to their medical record and sort that out, but it provides a window into something that wasn’t the initial intent of the project. That feedback opened up a lot of interesting questions and opportunities for research that we hadn’t necessarily anticipated up to that point.

Men didn’t know if they’d had prostate cancer surgery or not?

Dr. Van Allen: It may have been the way we asked the question. It may have been that patients were interpreting what they were supposed to answer. We don’t know. The point is that this is not something we initially set out to do, but it is an early example of how patients can guide where the research needs to go.

I just presented this project at the American Urologic Association meeting, and a gentleman came up to me afterwards. He’s had metastatic prostate cancer for four years and a complete response to cancer immunotherapy, and he wanted to know if he was eligible for this project. Not only is he eligible, but he’s an extraordinary case. We want to understand why. This patient is not within 500 miles of an academic medical center, and he would otherwise never be approachable or available to engage in research. We exchanged information, and he’s going to sign up.

Patients may not realize: they have the power to drive this field forward in this unique way. It’s not something that medicine is used to doing. We want to get the message out that this is all starting with patients and their ability to contribute. That will determine how far this goes.

It’s easy for them to participate: go to the website, fill out the forms, and give a blood sample?

Dr. Van Allen: Yes. You don’t even have to do the blood sample if you don’t want to. It’s exactly what you described. Go to the website, click a few buttons. There’s a very simple online consent form. We’ll send you a saliva kit and a blood biopsy kit and take it from there.

Can you still participate even if you’re in a remote area?

Dr. Van Allen: Yes, anywhere in the United States and Canada. For the blood biopsy, we send you a kit, and you bring it to your next lab draw, PSA test, or whatever, and there are instructions in the kit for the phlebotomist. In some cases, phlebotomists have not been willing or able to participate, so we can provide vouchers to patients to do it at a Quest Diagnostics lab or somewhere convenient to them. The intent here is that the patient bears no financial burden in participating.

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NRG Oncology’s Clinical Trials

Dr. Mark Hurwitz, a widely recognized leader in the fields of thermal medicine and genitourinary oncology, is the Vice-Chair for Quality, Safety and Performance Excellence and Director of Thermal Oncology for the Department of Radiation Oncology at The Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, Pennsylvania.

Dr. Hurwitz talked to Prostatepedia about NRG Oncology and a trial he’s running with them that looks at anti-androgen therapy and radiation therapy with or without Taxotere (docetaxel) in treating patients with prostate cancer that has been removed by surgery.

Why did you become a doctor?

Dr. Hurwitz: Medicine is an extraordinarily rewarding career in regards to being able to help people at important and often critical junctures in their lives. It’s extremely humbling to see strangers walk into my office and put their trust in me to help them through a difficult time in their lives.

It’s an enormous responsibility.

Dr. Hurwitz: It is, but one that comes with many years of training and preparation for a physician to get to the point when we enter practice.

What is NRG Oncology? What has been your involvement with the group?

Dr. Hurwitz: Several years ago, the National Cancer Institute (NCI) mandated the merging of cooperative cancer research groups into fewer but larger groups. One of these groups NRG Oncology, was the result of the merging of the Radiation Therapy Oncology Group (RTOG) with the Gynecologic Oncology Group and the National Surgical Adjuvant Breast and Bowel Project (NSABBP). This dynamic new large cooperative research group is primarily supported by the NCI. It’s been exciting and rewarding to be a part of this new larger group putting all our resources together to bring trials to patients.

I’ve been involved with NRG Oncology since its inception. Predating that, I was involved with both RTOG, as well as the Cancer and Leukemia Group B (CALGB) during my years at Harvard Medical School.

What kinds of trials does NRG oncology run?

Dr. Hurwitz: The focus of cooperative groups, including NRG Oncology, is on conduction of clinical trials to answer important questions that are best addressed by getting multiple centers involved. These tend to be Phase II or Phase III trials involving hundreds, and sometimes thousands of patients, to answer a critical question that experts in a given field see as being one of the most impactful issues to address for a given set of patients.

NRG is also involved in translational science as well. Almost all of our clinical trials have an incorporated translational aspect to them to answer leading-edge questions in regards to some of the pertinent science behind advancing treatment for our patients.

Are the participating institutions limited to within the US?

Dr. Hurwitz: There are international participants. The group does have a North American focus. Therefore, the United States, as well as many Canadian institutions, are very active in NRG, but NRG has branched out to include international institutions outside of North America as well.

Is it difficult to enroll patients in trials?

Dr. Hurwitz: We all in academic medicine seek to engage more patients with involvement in clinical trials. Only a small percentage of patients nationally participate in clinical trials, so there’s a real opportunity to match patients and their needs with the clinical trials that will help advance the field, as well as their own personal care.

Some of the challenges include having appropriate trials available for patients seen within a practice, as well as the time commitment both in terms of the extra time that the physician needs to take to explain trials as well as the resources needed to support the conduction of clinical trials at a given site.

There is also the issue of awareness both on the patient and provider sides as to opportunities for clinical trial participation.

Why should patients consider joining the clinical trial?

Dr. Hurwitz: There are several reasons for patients to consider trials. A trial often provides patients access to leading-edge therapeutic strategies that may not be available off clinical trials.

It also will help provide additional information that will benefit future patients, although our focus is always on the patient who is sitting in front of us.

Also, interestingly enough, there are multiple studies that have looked at the impact of clinical trial participation on patient outcomes, with very consistent findings that patients on clinical trials tend to have better outcomes including survival outcomes than patients not on clinical trials. This is likely due to a number of factors, including the rigorous monitoring of patients on clinical trials as well the follow up after treatment that is done. These patients are followed very closely. There are state-of-the-art treatment guidelines that must be followed on clinical trials to help reduce undesirable variability in patient care. These aspects of clinical trials help to improve outcomes regardless of the particulars of any clinical trial.

Are there certain stages along the cancer journey when a patient should consider a trial?

Dr. Hurwitz: There are clinical trials that are suitable for patients across the whole spectrum of disease severity. In the case of prostate cancer, there are trials for patients with very favorable risk disease for which active surveillance is an option to trials for patients who are on second or third line interventions for metastatic prostate cancer. And everything in between. It’s not a matter of whether a patient has a certain stage of disease. There are questions to be answered at each stage of a given disease for which clinical trials may provide benefit.

Are there any considerations patients should keep in mind as they evaluate trials?

Dr. Hurwitz: People have to gauge the particulars of a trial much like the particulars of any proposed treatment for malignancy in regards to what makes them most or least comfortable with the options before them.

Let’s say a patient participates in an NRG trial. Are they informed of the results once the trial is completed?

Dr. Hurwitz: There have been increased efforts in recent years to disseminate outcomes of trials to patients. It’s a particular challenge in some diseases like prostate cancer where the results may come a decade or more after trial participation.

That’s true.

Dr. Hurwitz: There is an effort regardless of the outcome of the trial to make not just practitioners but patients aware of the results.

Are there interesting NRG prostate cancer clinical trials that you’d like to highlight?

Dr. Hurwitz: I’m happy to highlight NRG-GU002, for which I am privileged to serve as the principle investigator. This trial builds on a prior Phase II single-arm RTOG trial, RTOG-0621, which I led that revealed very promising outcomes with the addition of Taxotere (docetaxel) and hormonal therapy to radiation for patients with adverse risk factors post-prostatectomy. NRG-GU002 builds upon the single-arm Phase II trial as a randomized Phase II into Phase III trial exploring the use of radiation and hormonal therapy with or without Taxotere (docetaxel) in men who fail to achieve a PSA nadir of less than 0.2 nanograms per milliliter after prostatectomy. This is a particularly high-risk group of patients in regards to risk of subsequent treatment failure. We have been very encouraged by the efficacy of Taxotere (docetaxel) in treating prostate cancer. Taxotere (docetaxel) has been shown initially in metastatic prostate cancer and subsequently in locally advanced disease to have a survival advantage—as opposed to using radiation or hormonal therapy alone in the primary treatment setting. Therefore, there is a lot of interest in exploring its utility in the post-prostatectomy setting for high-risk patients.

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Reporting Clinical Trial Results

Ms. Merith Basey is the Executive Director of Universities Allied For Essential Medicines (UAEM) North America, a global network of university students who believe that their universities have an opportunity and a responsibility to improve access to publicly funded medicine developed on their campuses.

Prostatepedia spoke to her about UAEM’s transparency campaign to get universities to report the results of the clinical trials they run and how prostate cancer patients can help.

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How did you get involved with health advocacy?

Ms. Merith Basey: A little bit by accident. My interest in public health and health advocacy stemmed from my undergraduate degree in modern languages and my interest in Latin America.

In 2004, I volunteered with an organization in Ecuador called AYUDA in conjunction with a local diabetes foundation that worked with children with Type 1 diabetes and their families. We worked together to provide diabetes education to children with Type 1 and their families so that they could learn how to better manage their condition and increase access to resources.

It changed my life. I ended up working for that organization for a number of years in a number of different settings. However, during that time, I began to see that, in some of the countries in which we worked, access to insulin was an ongoing challenge, and for many families, the price of insulin was simply too high. The lack of action at that time spurred me and a small group of advocates to launch the 100 Campaign for access to insulin back in 2012. Today, one in two people who need access to insulin still don’t have regular access, a challenge that is increasingly apparent in the United States and in many countries around the world. It was through this lens that I ended up in health advocacy.

What is Universities Allied for Essential Medicine?

Ms. Basey: Universities Allied for Essential Medicine (UAEM) was founded in 2001 at the height of the HIV/AIDS epidemic. A drug called d4T, or stavudine, had been developed at Yale University with public funds and was being used as part of a cocktail of drugs, at least in the United States, to treat people living with HIV.

At the time, Doctors Without Borders/Medecins sans Frontiers (MSF) was looking to treat people living with HIV in South Africa where the burden of disease was highest. They realized that the price of this one drug was too high for them to be able to treat the millions who were in need of access to treatment. However, a young student and activist who started Yale law school that year decided to take action. She organized, with other students in conjunction with MSF and Civil Society, with the goal of lobbying her university and the company Bristol-Myers Squibb (who had purchased the rights to the drug) to change the license between them to allow for the legal generic importation of this drug into South Africa. The campaign was a success; it led to a 90 percent reduction in the price of that drug in that region, allowing MSF to treat people living with HIV for the first time.

That’s the founding story of UAEM and is at the heart of our work, primarily based on university campuses in the United States and today in over 20 countries around the globe. A simplified vision of our work is that we believe no one should be poor because they’re sick or sick because they’re poor.

We understand the role that universities have in the drug development pipeline and believe that they should be critical partners and leaders in ensuring access to affordable medicine, especially when it is developed with taxpayer funds. Also, in particular, we work to urge universities to increase their research into neglected diseases since most research in the current system tends to go into drugs or treatments for wealthier and historically whiter populations. A lot of other drugs for diseases that predominantly impact the poor are left behind until there’s an urgent demand like there was for Zika and Ebola. It is estimated that 90 percent of the research dollars go to just 10 percent of the global burden of disease.

Do you focus on universities because that is where some of this initial research is done or because you’re trying to activate younger students on campus?

Ms. Basey: I think it’s both in part. Initially, it was inspired by that success story at Yale, but it was also about understanding where students have power. Students are key stakeholders in university systems, and while they are actively enrolled, they have unique power and access to faculty and other decision-makers. They have the right to be able to meet with the administration, ask them about their policies, and urge them to address historic inequities or errors.

Secondly, universities are the key drivers of much of our most innovative biomedical research. In the United States, for example, every year $37 billion of taxpayer money goes in the form of grants from the National Institutes of Health (NIH) to universities across every state and in a number of countries around the world to do biomedical research and clinical trials.

Given this massive public investment into researching and developing new compounds and medical innovations, it is also an opportunity to influence the way that those drugs are patented and eventually licensed into the hands of pharmaceutical corporations down the line. We also believe that the public should have a return on that investment and that the product of that investment should be accessible and affordable to the people who paid for them in the first place: the public.

Yes, the National Cancer Institute (NCI) and the National Institute of Health (NIH) fund quite a number of clinical trials. Most of the people reading this are familiar with trials as potential participants. But what happens when a trial is completed?

Ms. Basey: It depends on who is leading the trial. In the United States, for example, when a university is responsible for leading a clinical trial and it is completed, the results should be reported onto a public database within a period of 12 months. (There are of course exceptions based on a number of different criteria). A significant portion of NIH funding is invested into clinical trials. It’s estimated that in 2017, at least about 38 percent of that $37 billion figure that goes to universities actually goes directly into funding for university-driven clinical trials, clinical research, and other activities related to clinical trials.

On average, however, it has been estimated that only about 50 percent of clinical trials are registered and reported. This obviously has impact. I can’t speak for the specific motivations that certain individuals might have for entering a trial, but in general, people participate to help find out more about the effects of specific treatments on a particular disease whether that be in the hope of helping improve their own health or the health of others. Knowing that, it’s unethical that this data goes unpublished.

Why is this data not reported?

Ms. Basey: A couple of things are happening. Obviously, that 50 percent is a global figure so it is a global problem. In the United States, however, even though the FDA Amendments Act makes it required by law for certain trials to be posted, according to UAEM’s recent report (www.altreroute.com/ clinialtrials) 31 percent of trials that are due are still missing results on the public registry with performance varying strongly between the top 40 institutions reviewed. Why are they not reporting? In some cases, they don’t report because they haven’t been required to, because it takes time, and because often the results are not favorable to the people funding the trials. Trials with negative results are two times as likely to go unreported as trials with more positive results. Publications typically like to report favorable outcomes rather than negative outcomes. If you are a private pharmaceutical corporation funding a trial for a drug you intend to produce and the initial results are not in your favor (due to limited effects on health outcomes or number of adverse effects) or if there isn’t a legal obligation to report, you may choose not to publish data. Obviously, this is entirely unethical but the evidence suggests it happens.

Best practices are set out to say that all clinical trials should be posted because, without all the data it’s going to skew data in a manner that is ultimately harmful. It’s going to skew the results. It’s going to skew the information that doctors are going to have in terms of deciding which drug is safer than another. The system is flawed in that sense. Failing to publish trial results means the decisions-makers with regards to medical treatments won’t have full information about the benefits or risks of treatments.

Just to clarify for patients, how are the results of clinical trials usually reported?

Ms. Basey: In the United States, a trial would first have to register on clinicaltrials.gov when the trial starts. (Although not all studies are required to be registered, e.g. observational studies or trials that do not study a drug, biologic, or device). Clinicaltrials.gov is a United States government database that has all that information for both federally and privately funded trials conducted under investigational new drug applications to test effectiveness of experimental drugs for serious or life-threatening diseases or conditions. Because of this FDAAA Final Rule, specific trials that involve patients will need to register or report their data within 12 months on that same database. At UAEM, in conjunction with TranspariMED, we just looked at the top 40 United States universities driving a lot of this biomedical innovation via clinical trials. Even though the law required that they register and report data within 12 months, about a third of these university-driven trials were unreported.

Essentially, they’re breaking the law. For every day that they hadn’t reported, the FDA could fine them $10,000. There’s quite a large incentive (beyond the ethical one) for them to report, but the FDA so far hasn’t collected any fees. We need to be making sure that all data and all trials are ultimately registered and reported so that there is full transparency and full information for everybody in terms of open data. It really comes down to making sure that data isn’t hidden.

So you’re running an awareness campaign?

Ms. Basey: For us, it’s very clear that, as receivers of public funds and given their social missions, universities should be leading the way in terms of registering and reporting of their own clinical trials. The campaign that we’re running is not only to urge universities to register and report but to go a step further. The World Health Organization (WHO) developed a joint statement on public disclosure of results from clinical trials. This was first signed in May 2017 by 21 key funders of clinical trials around the world including the Wellcome Trust, the Gates Foundation, MSF, the Indian Council of Medical Research and the Drugs for Neglected Diseases Initiative, just to name a few. They agreed, that if they fund clinical trials they will require investigators to register and publicly report the results in a timely manner. We go little bit further because we are also asking those universities or institutions to come up with a policy to hold themselves and others accountable. We have students in over 50 universities in North America and in 20 different countries around the world organizing on their campuses to urge their universities to make sure that they’re registering and reporting their own clinical trials and thinking about signing this WHO joint statement on clinical trial transparency.

Is there anything that my readers can do to help?

Ms. Basey: If you’ve had the privilege of going to a university, call or email your alma mater to ask them about their policy or their performance if they are listed in our report. Let them know that this is something you support and you’d like them to take action. We know that universities respond to pressure from their alumni. You could also financially support UAEM’s grassroots campaign directly via http://www.UAEM.org

At UAEM we will continue to urge universities to step up to their commitments. They are, ultimately, morally bound to be transparent with their research outcomes since most of these trials are publically funded. We’re really proud to see that the universities that are 100 percent reporting are actually beginning to mobilize and think about moving forward with signing onto the WHO statement. But we still have a long way to go. Every pressure and encouragement is recommended.

Clinical trial transparency helps accelerate medical progress for new treatments and improve our understanding of treatment efficiency and safety, ultimately contributing to improved access to medicines and better health outcomes for us all.

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Jake Vinson + The Prostate Cancer Clinical Trials Consortium

Mr. Jake Vinson is the CEO of the Prostate Cancer Clinical Trials Consortium (PCCTC), a multicenter clinical research organization that specializes in trailblazing prostate cancer research.

Prostatepedia spoke with him about clinical trials for prostate cancer and the pioneering work of PCCTC.

How did you get involved with clinical research administration and patient advocacy?

Mr. Jake Vinson: My involvement in clinical research dates back to college years. My part-time job was working in a clinical research organization, and I really enjoyed that environment and the work that was a being done. I progressed through college and graduate school and subsequently was able to run a number of clinical research organizations. That process brought me to New York about ten years ago to be involved in the Prostate Cancer Clinical Trials Consortium.

As far as patient advocacy, I’ve grown to distinguish two threads of advocacy, one being patient advocacy and the other being research advocacy. My path in working through drug development and clinical trials has really been geared more toward research advocacy than patient advocacy.

Patient advocacy considers needs at the individual patient level —ensuring they’re getting to the right appointments and having the right tests and seeing the right experts. Research advocacy makes certain research is funded appropriately. It ensures that research is being watched over in the right way and that it intersects with the patient advocate component. It’s an interesting distinction, but one that I think is important.

What has kept you engaged over the years?

Mr. Vinson: I’ve always found the organizations that I’ve worked with and have run sit in a very interesting and unique spot in the continuum of cancer research in that they connect academic investigators who are the subject matter experts; they think about new ways to develop drugs and treat patients; and they connect them with the pharmaceutical and biotech companies who are developing drugs aligned with the scientific programs of investigators. And finally, there is the part that we talked about—the advocacy component. Making sure that patients at the clinical sites where they’re being cared for have access to these research studies.

What’s kept me involved is being in the middle of that triangle. Not necessarily working in a hospital or in an academic research center. Not necessarily working in a pharmaceutical company. And not necessarily working at a clinic site or a doctor’s office, but really creating an infrastructure that connects all of those things. That to me has been exciting.

What is the Prostate Cancer Clinical Trials Consortium?

Mr. Vinson: The Prostate Cancer Clinical Trials Consortium (PCCTC) is an organization that has been around for going on 20 years now. It was originally created by the Prostate Cancer Foundation (PCF), which is the world’s most significant philanthropic prostate cancer research-focused organization. They recognized that there were obstacles in the collaboration of what were considered the top prostate cancer academic programs around the United States. They worked to put some funding in each of those centers with the sole goal to eliminate barriers to working together on clinical trials. This was some time ago.

That idea was subsequently leveraged into an initiative through the Department of Defense [DoD], which here in the United States has the Congressionally Directed Medical Research Program. Within that program is the DoD Prostate Cancer Research Program (PCRP).

Fifteen or so years ago, the PCRP put in place an offering for a Clinical Consortium Award. This was a formalizing effort to PCF’s idea. Memorial Sloan Kettering Cancer Center (MSK) applied for and became the coordinating center for this Consortium Award. Eight other centers were selected as participating sites. This created the coordinating center site model, or a consortium, to bring together and understand what clinical trials everyone was working on, where the intersects were, and where the collaborations across sites could happen efficiently and effectively. The aim was to shape and understand the landscape of prostate cancer drug development to take out those preconceived notions of competition and show areas where cooperation could happen.

MSK still holds that Clinical Consortium Award. We’ve had a number of sites come in and out over the last fifteen years.

A number of years ago we identified that to really be effective and to scale our infrastructure to support all kinds of prostate cancer research we needed to have a better business-operating model than something based solely on a grant from the from the DoD.

So, just over five years ago we spun off a business, which is now the operating company for the PCCTC. That business exists to conduct multicenter clinical trials so that all of our participating sites around the world now can work together on selected clinical trials. We let the investigators do what they do best, which is develop the ideas and ways to study the drugs. We let the clinical research sites and the clinics do what they do best, which is treat their patients and manage them on a study. This in turn lets us handle the regulatory, data, and biospecimen management—all of the things that go on behind the scenes of a clinical trial that investigators and sites aren’t specifically suited to address. Through contracts with our pharmaceutical partners we are able to get access to their drugs that are developed by the pharmaceutical companies and then put those into the clinical trials that our investigators are developing. That is how our model works.

That’s a unique model, isn’t it?

Mr. Vinson: It is fairly unique. It has attributes from a number of different businesses in this space. It in and of itself functions in a fairly unique way.

What kinds of clinical trials do you run?

Mr. Vinson: The organization was originally established as an early phase drug development group, so our intention is to identify new drugs, new classes of drugs, or new targeted drugs to treat prostate cancer patients of all stages. We do very early studies with patients who are newly diagnosed or often times we do studies with very late stage patients who maybe have seen a number of lines of treatment already.

We really look at the continuum of disease states from very early diagnosis to very advanced disease. We identify which studies would be most reasonable to put in place in all of those spaces so that we’re not necessarily constantly overlapping. We want to have studies distributed fairly evenly so that patients of all different disease states or manifestations within states would have an opportunity to be in a clinical trial if treated at one of our sites.

We have traditionally focused in Phase I and Phase II development. Because we’ve been fairly successful in that, we have now opened our first Phase III study, which is a much larger trial. A Phase I or a Phase II trial has from 30 to 100 patients. A Phase III study can have as many as 800 to 1000 patients.

I’ve heard that it’s difficult to enroll patients in trials and that frequently trials don’t get the number of patients they were originally seeking. Why do you think this is?

Mr. Vinson: There is data that shows this is absolutely true. What we know is that, in the United States, 3 to 5 percent of cancer patients go on to clinical trials, which is obviously not very many. Even within the number of eligible patients, only 25 percent actually do enroll in a clinical study.

I should also add that because of the way the science has taken us, we are now looking to enroll patients with specific molecular characteristics. These molecular characteristics are biomarkers, or gene signatures that we see in tumor tissues or blood, which can often be found only in a very small percentage of patients. A particular marker that we think a drug works in may only appear in 10 or 15 percent of patients. A fairly small group of patients go onto studies to begin with; molecular inclusion criteria makes this number smaller.

This is creating a conundrum whereby we have to cast a much wider net, meaning we have to have more sites collaborating to identify patients eligible for enrollment based on their unique molecular characteristics. These are interesting challenges. The science to be able to do this is incredibly significant and will be impactful to patients, but filling those clinical trials is difficult. We would think we would want to include more patients in studies, but because we’ll be able to parse the patients into much smaller groups with specific molecular characteristics, it is becoming more challenging.

You need to cast an even wider net to find these patients?

Mr. Vinson: That’s exactly right. We originally worked with eight centers. We now have 14 centers that are formally part of our group with another 50 sites in the United States who are affiliate participants. Those centers have gone through our qualification process; we know they have quality research programs at their clinical sites and have the opportunity to open studies that we’re developing as well. That is one of our strategies, to circumvent that conundrum of great science that then doesn’t enroll the patients we planned.

There are some regulatory implications here: there has to be great caution in doing clinical research. We would offer that, when you’re using drugs in a very early development space, meaning this is often the first time that the drug has been used in patients, you want to make sure that the patients are appropriate to be treated with those drugs. What you can’t do is just flood your study with patients because you might miss a safety signal, or you might miss a dosing change. There are too many variables happening at the same time. We know that is part of the issue.

From the other end, it’s a lot of work for the clinical sites to participate in the studies. We do our best to fund our sites appropriately, but there are so many pressures on our clinicians in terms of how they’re managing their electronic medical records and how many patients are expected to be seen by their clinics and their sites. Their additional bandwidth to enroll patients under clinical trials is finite. You have to consider all of the safety and regulatory requirements for the studies themselves and the external factors for the investigators working on the studies.

Finally, we and others have been working for a long time on research and patient advocacy.

When a patient comes in and they’re approached about a clinical trial, we don’t want that to be the first time they’ve ever heard about clinical research. That’s an entire other discussion that requires a full education to make folks comfortable with clinical trials. Those are the three angles that we try to work on in alleviating those barriers.

Why should patients consider joining a trial? What are some of the benefits?

Mr. Vinson: Depending on the study, the potential for benefit can vary. There are potential advantages to getting access to a new drug, which could in theory have great benefit to them, but again, this is called research. We don’t know exactly what the outcome will be, but there is the opportunity to get access to more cutting-edge treatment that could have an upside.

The other lens to think about is that research is advancing the field for the men who will follow. If we didn’t have the clinical trials that we did 25 years ago, we wouldn’t have the drugs that are now proven to extend life . There were men who joined clinical trials to get those drugs approved and tested as safe and efficacious or that worked in controlling cancer. We would offer that there’s great opportunity to, in a safe way, contribute to the advancement of treatments for future generations of men. We think that’s important.

Is there a certain time point when a man should start looking for clinical trials?

Mr. Vinson: Ideally patients should learn about the clinical research process at the point of diagnosis so they understand the advantages and risks of trial participation. Men should feel comfortable asking their healthcare providers about clinical research opportunities at any point in their care.

From a drug development perspective we traditionally evaluate therapies earlier in the disease continuum only after establishing efficacy in more advanced disease. We think there is potential for a cure in very early disease and are now designing trials of drugs that gave benefit in very advanced disease in this space. We really feel like there needs to be clinical research participation from very early on while we continue to look to control disease that has spread and become more advanced. In short, there are opportunities to participate in clinical trials starting at all points of care.

I suppose if you start a conversation early on with your doctor, even if there’s nothing appropriate for you at that time, if something does come up, she is more likely to bring it to your attention.

Mr. Vinson: Absolutely. Opportunities are continually turning over: new studies are opening and prior studies are closing. We know patients from all over the country who have been on multiple clinical trials. Many do very well. We think it’s exciting that they’re open to that.

Do you have any suggestions that you think patients should keep in mind as they evaluate trials?

Mr. Vinson: There are so many different types of studies out there. I think a Phase I study may have requirements in it for some additional testing or additional visits because the endpoints of that kind of study are to evaluate at very specific timepoints how a drug is being received and metabolized or processed by a patient.

The bigger and later stage Phase II or Phase III studies are designed to be as continuous with standard of care as possible so that it is not a burden or inconvenience to the patient. All of those things have to be taken into consideration. An honest discussion with your healthcare provider, healthcare team, and the research coordinator or research nurses, is really the best way to figure out which situation is going to be best.

How the results of your trials are reported? Are all trials reported? Are patients who participate in trials informed of the results?

Mr. Vinson: We publish and present all the results from our research studies. We ensure that we have the right to do that with our partners —our research sites and our pharmaceutical and biotechnology partners as well as the groups that own the drugs that we work on. We have contracts with them that are very clear in that we have the ability to put the data together, to put the outcomes together, and present them to the public. That’s done through a number of different methods— meetings where abstracts are presented to manuscripts submitted to professional journals.

Your point is a good one about returning results to patients. Many sites have programs to distribute the outcomes to those patients. This is done at the site level. The challenge for us is that we don’t get, in almost all cases, direct contact information for patients. When a patient goes on a trial, the local treating clinicians certainly know that patient well. But we give that patient what we call a subject identifier. This is a random number that is created so that we can then track that patient without having any personal information about the patient directly. We have their health outcomes data, but we certainly don’t know where they live, or what their phone number is, or how to email them. Returning those results directly to a patient from the entire study as you can imagine, is something that would be challenging.

Informed consent forms reflect the growing number of molecular testing and sequencing performed in trials. Before patients participate on a trial they are clearly notified on of which test results would be returned to them personally. This can vary from study to study.

But to your point, we think it’s important when we’re doing research tests that could have implications for a patient or their families, especially when we’re talking about genetic testing, that we have a mechanism to inform them if there are findings that need to be followed up. As you can imagine, there are implications for family members as well in genetic research. That happens through the informed consent process, and again, at the site level where the patient’s being treated.

I guess if you’re going to make a call for men to join trials for altruism’s sake and for the furtherment of science, they might want to know if the research actually did advance our understanding of prostate cancer.

Mr. Vinson: There are sites that do that: when outcomes are published, they distribute them to patients who are interested. In addition, publications can be searched for independently or requested from the clinical investigator.

It takes a long time for some of these studies, though. If you’re the first man to go into a particular study and it’s going to be a 100-patient trial that takes over a year, you’re already taking about 18 months to enroll that study. Then we do all the follow up, which could be another two years. Then we do all of the data analysis, which could be another six months. It could be three to five years from the original patient enrolled to publication. It can certainly be a long process.

Are any particular PCCTC trials looking for patients that you’d like to highlight for my readers?

Mr. Vinson: We’re doing a study called IRONMAN. IRONMAN is an international registry for men with advanced prostate cancer. We’re working with eleven countries around the world in collaboration with the Movember Foundation. (Movember is the Australian-based organization that grows mustaches and raises money every November for men’s health and awareness.) One of their core programs is a prostate cancer program, and one of their key projects is the IRONMAN project.

The PCCTC is the global coordinating center for IRONMAN. The study does not have a specific drug treatment requirement and instead tracks patients receiving standard of care therapy. Participants will be recruited across academic and community practices from around the world to facilitate a better understanding of variations in prostate cancer treatment. Patients who enroll are followed prospectively over several years. We collect data on what treatments their physicians have given them as well as some high-level clinical outcomes data from those treatments and track how treatments are sequenced or given in combination around the world.

The second part of the trial examines patient reported outcomes. We have particular surveys that study participants complete every three months that examine their quality of life and how they’re feeling across a number of domains. Then thirdly, we have a biology component, in which we collect blood samples when patients join the study and then again each time they change their treatment. This helps us understand, to the point I was making earlier, what changes are happening at the molecular level and what’s changing in the biology of the patient. Then finally, we’re asking their physicians to answer a brief survey telling us why they recommended changes in treatment, which will give us insight into the variations in prostate cancer treatment across different centers and countries. By collecting blood samples, patient reported outcomes, clinical data, and physician surveys, we can tie together the biology of the patient’s disease with the patient’s reported experience on a given treatment with the clinical data on their response to treatment. Putting all of those things together with 5,000 men around the world in eleven countries is going to give us an incredibly rich dataset to be able to mine and understand what treatment patterns may be best for particular patients. What’s unique about IRONMAN is that we are not just collecting information on how patients do clinically, but also how the patients themselves report they do. Through IRONMAN, we will also understand the biology of those patients and how it changes over time, and we will be able to tie those outcomes to the clinical outcomes to develop tests that can potentially let us predict how patients will do on a specific treatment.

IRONMAN is an exciting study. Centers around the world are now open and actively participating in the study. We have nearly 700 patients accrued from 7 countries, with 4 more coming on board soon. It’s an exciting project, and something that is very different than a standard Phase I or Phase II clinical trial, but it’s certainly something that we think is going to result in an incredibly powerful dataset for investigators to use into the future.

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