Prostate Cancer Clinical Trials

MARK SCHOLZ, MD

Clinical studies are primarily performed on men with advanced prostate cancer (the Royal Shade of Blue). Why?  The FDA.   FDA only approves new drugs when survival is proven to be prolonged compared to similar men treated with a placebo. The FDA’s insistence on a survival endpoint forces pharmaceutical companies to limit their research to men with a short life expectancy. If survival has to be the endpoint and the study participants live a long time, the cost of performing the study goes up exponentially.

Undergoing experimental therapy with a new medication is reasonable consideration when standard treatment is either no longer working or is causing unacceptable side effects.  However, it’s rare for doctors to recommend an experimental medication before other FDA-approved drugs on the market have been tried.  The commercially available treatments already proven to extend survival are Lupron, Provenge, Xtandi, Zytiga, Xofigo, Taxotere and Jevtana.

Getting Involved in a Trial Can Be Challenging

Eligibility requirements for participation can be rigorous. Trials have carefully specified pretreatment and health status criteria: Eligibility may be denied if the patient is either too sick or not sick enough, if there is too much previous treatment or not enough previous treatment. Criteria are pre-specified so that the final results of the trial are not skewed by a lack of uniformity among patients.  Other requirements designed to achieve trial uniformity include stopping all other anti-cancer medications and the use of placebos, both of which at times may be at variance with a patient’s best interest.

An additional challenge is finding the right trial that matches a patient’s need. The clinical trials landscape changes quickly.  New trials are initiated with limited fanfare and close as soon as they have met their pre-specified number of participants. Trials available at one center may not be so at another.  Another difficulty patient’s face is how to determine the effectiveness of a prospective study drug. Is it likely to work or not?  Due to a study drug’s newness, its functional characteristics are often unclear to patients and doctors alike.

There are different types of study designs to consider each with different goals.  Phase I studies, for example, are primarily designed to learn more about a drug’s side effects. Phase I studies sequentially escalate medication dosages up to determine the point of dosage intolerability. Phase II studies treat a group of patients at a fixed dosage to get a preliminary sense of a drug’s response rates. Phase III studies are the final step that leads up to FDA approval.  Phase III trials are the placebo-controlled trials.

The Business of Clinical Trials

Patients contemplating participation in a clinical trial should be aware that the clinical trial world functions like a business.  It’s funded primarily by the pharmaceutical industry. As such, doctors working in academia are highly motivated to find participants in their research.  If trials are not completed in a timely fashion funding for new trials will be harder to come by in the future.

Participating in a clinical trial has become more attractive over the last ten years as the pharmaceutical industry has made significant strides toward understanding cancer.  Now that they have access to cancer “blueprints” it’s feasible for brilliant biochemists to design “software patches,” new drugs that are far more effective and far less toxic than what has been traditionally available.  However, patients need be careful they don’t mistake a “new” drug for being an “effective” drug.  Despite the tremendous advances in research, most phase I and II drugs still fail to meet minimum standards of clinical effectiveness and never even advance to phase III testing. Sadly, many of the potential prostate drugs that have been tested in Phase III studies over the last ten years have failed to meet the FDA minimum threshold of showing a survival advantage.

Dr. Scholz is the Principal Investigator at Prostate Oncology Specialists - a list of the active trials are found at http://www.prostateoncology.com/clinical_trials

Another Milestone at Prostate Oncology, Father Joe Gets his First Apartment

BY MARK SCHOLZ, MD

Father Joe Johnson has been with Prostate OncologySpecialists since its inception. Twenty years ago, after he retired from parish work, he started pursuing his lifelong interest in medicine and computers by volunteering to do internet searches to help find new treatments for our cancer patients. Doing an internet search does not sound like a big deal today, but back in the early 1990s there was no Internet Explorer (or Netscape Navigator for that matter). Getting online required substantial computer expertise and information could only be accessed through medical libraries by payment of an annual licensing fee. Father Joe was well equipped for his radical career change out of parish work. He had previously spent a number of years as a chemistry teacher at Loyola University.

A few years later, when searching the internet became a more straight-forward proposition, Father Joe asked if he could help out in some other capacity. Our practice had a large database of early-stage prostate cancer patients who were treated with hormone therapy, but we lacked the statistical skills to analyze the results. I knew of Father Joe’s lifelong interest in mathematics, and wondered if he would consider tackling medical statistics on our behalf.

For those of you who don’t know, qualified statisticians are rarer than diamonds and far more expensive and difficult to come by. To make a very long story brief, Father Joe subsequently mastered medical statistics and has coauthored all the scientific publications at Prostate Oncology.

Throughout all the years of unsung service volunteering in our office—which as you probably know, focuses exclusively on the treatment of prostate cancer—Father Joe has been a constant and immovable rock of steadfast optimism and hope, visiting with patients and keeping them company while the doctors and nurses rush around trying to stay on schedule. Sure, after entering an exam room and introducing himself as a Catholic Priest he has to good-naturedly endure innumerable bad jokes about his being there to give last rites. But almost invariably people quickly warm up to his friendly presence. I strongly suspect that some of our long-term patients are only willing to suffer the terrible Marina del Rey traffic because of the pleasure of visiting with Father Joe.

Perhaps it’s reasonable to expect patients to put up with the terrible traffic since they only have to endure it on a periodic basis. But what about me? Back when I lived in Long Beach I used to suffer the traffic daily. Being a problem solver by nature, I began considering the purchase of a limousine. My plan was to black out all the passenger windows and don a cap every morning so that I could pretend I was chauffeuring a passenger and drive in the diamond lane. However, it was Father Joe who rescued me from my law-breaking soul.

One evening, after a long day at the office while bemoaning my own tiresome commute home, I discovered that Father Joe was on the lookout for a new place to live. Once our mutual need was discovered it led to a quick solution. Father Joe had lived in trailers off and on throughout his life. And my home in Long Beach had a huge, unused backyard easily accessible through an alley behind the property. After a quick search of the classified ads, we made a phone call. That same evening we purchased Father Joe’s new home and had it delivered to my back yard. For the next five years Father Joe’s calm and loving presence helped me fight the good fight on the 405 freeway morning and evening.

The privilege of taking the diamond lane was definitely a huge improvement. But in 2003 I got the opportunity to purchase a home ten minutes from the office. The problem was that the backyard of the new house was a hillside, with no place for a trailer. What about Father Joe? My initial calls around the Marina were very discouraging: all I was encountered were ten-year wait lists. But the problem was solved when we found out that a relative of one of our patients owned the marina across the street from the office. Father Joe has been living happily in a boat ever since. Clearly he has friends in high places.

Father Joe’s odyssey of volunteering at Prostate Oncology began twenty years ago when he was a young man. But now at age 82, what the heck is he doing living on a boat? Thank God he has not slipped on the wet dock or fallen into the water off his rocking boat. Last night I showed him a new apartment located a mere three-minute walk from the office but he ended up asking me to take him back to sleep on his beloved boat. After a lifetime spent in the small spaces of boat and trailers, to Father Joe, the one-bedroom apartment is gargantuan. I’ll take another run at getting him to stay at the apartment tonight. If that doesn’t succeed I may have to sink the boat.

Hormone Blockade for Early-Stage Prostate Cancer

MARK SCHOLZ, MD

Being medical oncologists rather than surgeons—and being more impressed by the toxicity of surgery than by its effectiveness—my partners and I hypothesized back in the early 1990s that since testosterone inactivating pharmaceuticals (TIP) are powerful enough to reverse metastatic disease, they should be even more effective against early-stage disease.

Clinical Experience with TIP for Early Stage
In 2011, we published a scientific article in the Clinical Genitourinary Cancer detailing the twelve-year outcome for 73 men who embarked on TIP as primary therapy. In this group of men the average PSA was 9 and the average Gleason score was 7 (intermediate grade). Most of the men had tumors in their prostate large enough to be felt by digital rectal examination. Twenty-one of them maintained a low PSA indefinitely with a single course of TIP—they never needed a second cycle.

Another group of 24 men required periodic repeat cycles of TIP to keep their PSA less than five. In the remaining 28 men, after one or more cycles of TIP, the decision was made to undergo treatment with surgery, seeds or radiation.  However, the average time to treatment was 6.2 years after the first cycle of TIP. Only three of those 28 men ever relapsed after treatment. In summary, this study showed that initial remissions with TIP were universal and that even if the remission was not permanent, treatment with more radical therapy was delayed many years.

In 2012, we published another scientific study in The Prostate, in which we evaluated the effect of 12 months of TIP in 102 men. Twenty-two men were in the Low-Risk category, 30 were Intermediate-Risk and 50 were High-Risk. The median PSA was 7.8 and the median Gleason score was 3 + 4 = 7. The attainment of a clear biopsy after TIP followed by a sustained 7- year remission occurred in forty-five men. The likelihood of durable remission was dependent on the risk category: 82% of Low-Risk, 47% of Intermediate-Risk and 25% of men with High-Risk required no further treatment.

Monitoring TIP’s Effectiveness
One of the beauties of TIP is how easily its anti-cancer effects can be monitored with PSA. Although there is much debate about using PSA for cancer screening, PSA is an amazingly accurate tool for monitoring treatment response. In a study we published in Urology in 2007, we showed that more than 95% of men with newly-diagnosed disease drop their PSA to less than 0.05 within eight months of starting therapy. It’s a rare for cancers to continue producing PSAs above a threshold of 0.05 after six months of TIP therapy.  However, when these rare cancers occur, i.e. when an elevated PSA nadir occurs, it is a flashing sign that aggressive multi-modality therapy should be instituted.

What about Side Effects?
So what is the catch?  To this point TIP sounds like a very logical way to initiate treatment. Even if the disease is not arrested altogether, it delays progression for many years. And men who select TIP as initial therapy can always “jump ship” and undergo radiation or surgery. Delaying surgery or radiation with their potentially irreversible side effects makes sense considering the acclerating pace of medical progress. In this rapidly changing environment, postponing irreversible treatment for even five years is unquestionably an attractive proposition.

The catch is that while TIP side-effects are manageable, they are not trivial. Without attention to diet, notable weight gain occurs. Without regular resistance training and weight lifting, significant muscle weakness will ensue. While on treatment, the majority men lose their sex drive. A loss of sex drive is, however, different than impotence. With medications such as Viagra and Cialis most men on TIP can have erections sufficient for intercourse. Sex can be enjoyed, but it is not sought after with the usual male verve. There is also the potential for additional side effects such as breast enlargement, osteoporosis and hot flashes. As dire as these sound, they are preventable with common medications such as Femara, Prolia and progesterone. However, the side effects are cumulative and become more prominent the longer TIP treatment is continued.

Final Thoughts
Some men are concerned that their cancer will progress if “real treatment” like surgery or radiation is delayed. They forget that surgery and radiation only eradicate the “friendly types” of prostate cancer, the ones that remain contained in the gland. The real danger lies in the possibility of microscopic metastasis. Radiation and surgery have no effect whatsoever on cancer that has already spread. Only TIP circulates throughout the entire body attacking early-stage micro-metastasis in the lymph nodes or bones.

In my next blog, I will be discussing a new, more powerful type of TIP that has recently been approved by the FDA. The enhanced effectiveness of this new drug may enable a shorter course of treatment. And since testosterone levels in the blood remain normal throughout, the risk of lingering side effects should be eliminated.   

Combination Immune Therapy—A Major Breakthrough

BY MARK SCHOLZ, MD

Normally it’s a rule for me in these blogs to avoid straying away from the theme of prostate cancer. I want my efforts to have a practical application for those struggling with this condition.  After all, prostate cancer is my specialty.

 

However, I am going to make a rare exception and break with my usual policy because of a stunning medical breakthrough in the treatment of advanced metastatic melanoma, a very deadly condition that until recently has been totally resistant to all forms of treatment.  The only exception has been a newly FDA-approved immunotherapy called Yervoy.

 

A month ago I wrote about the high hopes we have for immune therapy for prostate cancer.  I also wrote about a clinical trial we are conducting at Prostate Oncology Specialists that evaluates the combination of two different types of immune treatment, Provenge and Yervoy (see my blogs from March and April of this year for further details).

 

Immune therapy has tremendous potential for treating cancer since the immune system has unlimited potential to adapt to any cancer scenario.  As more and more new types of immune therapy are being discovered, it’s only logical to conduct clinical trials that combine them to see if the simultaneous use of two immune treatments will further enhance the anticancer effect.

 

The report I am so excited about was just published in the New England Journal ofMedicine (NEJM). Doctors from Memorial Sloan Kettering and from Yale evaluated the combination of two types of immune therapy in advanced melanoma—Ipilimumab (Yervoy) and Nivolumab.  In my previous blog I explained how Yervoy functions by taking the “brakes” off the immune system.  Nivolumab works in a similar fashion, but works on a different set of brakes.  (It turns out that the immune system has two separate brake systems).

 

While Yervoy by itself has already been shown to be effective for treating melanoma and is FDA approved for this purpose, Nivolumab is still going through clinical trials. Twelve weeks after the researchers administered Yervoy and Nivolumab simultaneously, one third of the patients had more than an 80% regression of all known tumors.

 

Furthermore, the side effects of giving the medicines in combination were no more severe than those encountered when either of the drugs was used by itself.

 

This report from the NEJM is very exciting because it provides proof for the concept that combining immune treatments will lead to enhanced anticancer effects. Moreover, another report of success using a combination of immune treatments was just released at the annual meeting of the American Society of Clinical Oncology (ASCO). Two-hundred and forty-five men with melanoma were treated either with Yervoy alone or with a combination of Yervoy plus Leukine.  The men treated with the combination of Yervoy plus Leukine lived 30% longer!

 

Leukine is an immune system stimulating medication that the FDA approved years ago for increasing white blood cell counts in patients treated with chemotherapy.  However, Leukine is also known to have anticancer effects as well. For example, it is used as an integral component in Provenge.  In addition, at the ASCO meeting in 2011, we published results from a trial we did in Marina del Rey in prostate cancer patients showing that Leukine plus low-dose cyclophosphamide (another immune-modulating drug) delays prostate cancer progression.

 

My dear friends and patients, I am amazed at how rapidly immunotherapy is progressing.  Not only are new and exciting medications being discovered,  innovative research evaluating combinations of these new powerful new medicines is leading to stunning cancer reversals in cases that as recently as a couple years ago were deemed totally hopeless.

 

Let me leave you with this final and encouraging thought.  The immune system is very egalitarian. Great results achieved in one type of cancer will inevitably translate into effective treatments for other types of cancer as well, including, of course, prostate cancer. The achievement of unprecedented anticancer effects with combination immune therapy in a stubborn and deadly cancer like melanoma bodes very well for significant breakthroughs to occur for prostate cancer as well. 

A New Immune Treatment Combination

BY MARK SCHOLZ, MD

In my last blog I contended that of all the different ways to treat cancer—hormone therapy, chemotherapy, radiation or surgery for example—immune therapy has the greatest potential to save lives: Only the immune system, by its very nature, has the ability to adapt to the many thousands of varieties of cancer.  Also, new breakthroughs in understanding how it works have led to real progress inharnessing the immune system to fight cancer. 

One discovery—that the immune system uses a specific type of immune cell called the “dendritic cell” to detect cancercells—led researchers at a company called Dendreon to develop a five-step process for enhancing dendritic cell function.

First the dendritic cells are filtered out of the blood for processing in the lab. Second, the dendritic cells are exposed to prostatic acid phosphatase (PAP), a protein that can be identified on the surface of almost all prostate cancer cells. Third, the dendritic cells are incubated with granulocyte macrophage cell stimulating factor (GM-CSF) which converts the dendritic cells from their dormant state into an activated form. Fourth, the activated dendritic cells are infused back into the patient’s blood. Fifth, once back in the body, the activated dendritic cells recruit the killer cells of the immune system, the T-cells, to attack the cancer cells, which are identified by having PAP on their surface.

This five-step process, called “Provenge,” is an elegant and clever way to enhance immune function. Two prospective, double-blind, placebo-controlled trials have proved the efficacy of Provenge.  However, one cannot help but wonder why—since Provenge is simply an enhancement of the immune system’s normal function—is all this artificial stimulation in the lab necessary?  Why aren’t the dendritic cells in the cancer patient’s immune system detecting the cancer cells spontaneously and recruiting T-cells to attack it?

Another breakthrough has been the discovery that a normally functioning immune system, like all the systems in our body, is tightly organized by a variety of controlling hormones. Obviously, both underactivity and over activity of any system, be it the heart, the pancreas or the immune system, can be dangerous.  Now, new research reveals that malignant cells actually manufacture and release excess amounts of controlling hormones that trick the immune system into remaining dormant.  Thus the natural process of immune system detection is directly inhibited by the cancer.

Provenge partially circumvents this problem by activating the dendritic cells outside the body in the lab. But the dendritic cells still face a hostile inhibitory environment after they are re-infused. The question arises, “Wouldn’t Provenge work even better if the immune environment in the cancer patient could be rendered more “friendly"?”

In this era of rapid technological advancement it is not surprising that amedicine designed for this specific purpose is already on the market! Yervoy, a monoclonal antibody from Bristol-Myers Squib, was FDA approved to treat malignant melanoma in 2011.   Yervoy enhances immune function by counteracting the excess amounts of suppressive hormones being released by the cancer. I heard one researcher characterize Yervoy as the most powerful method available for “taking the brakes off” the immune system.

Provenge and Yervoy used together are so attractive conceptually that the only question remaining is about the optimal method of delivery.  Yervoy, unlike Provenge, can have serious side effects.  In excess amounts it can induce the immune system to run wild and start attacking the organs in the body like the liver, thyroid and intestines. Caution dictates beginning with a small initial dosage of Yervoy.

In the study we will be conducting at Prostate Oncology Specialists in Marina del Rey the first three patients we treat will be given one-twelfth of a normal dose of Yervoy one week after the Provenge is completed.  The second group of three patients will receive a one-sixth dose of Yervoy.  The third group of three patients will get three-twelfths of a Yervoy dose. All patients will receive full-dose Provenge and will be closely monitored for disease response, immune function and for possible side effects.

Provenge and Yervoy are just two of the many exciting new methods being studied for harnessing the immune system to fight cancer.  However, to my knowledge, we at Prostate Oncology Specialists are privileged to be the first to test the effectiveness of these two exciting treatments in combination.  Our first patient is scheduled to start on trial this month.