Saturday, April 25, 2009

Melanoma Update: Highlights of research presented at ASCO and an update on vaccines trials.Melanoma..Jim Breitfeller

Issue Number:
Volume 17 - Issue 3 - March 2009
John Otrompke, Contributing Editor
Mixed Melanoma Trial Results Point to Need for Tailored Studies

"Effective melanoma therapies may be inching forward, with a number of the new class of potential therapeutics in the pipeline entering Phase III trials, and researchers presenting some of the first published data on other agents at this year’s annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

But with mixed results, some disappointing, some surprising, some researchers say clinicians and clinical trial designers must rethink development strategies, including patient selection, if some of the new class of biological therapeutics for melanoma are to make significant headway.

“The problem with melanoma is that, other than surgery, there really are no very good effective therapies. The chemotherapies that are out there are not curative but palliative treatments,” explains David Solit, MD, Elizabeth and Felix Rohatyn Chair and Assistant Attending Physician, Department of Medicine, Sloan-Kettering Cancer Center.

But medical science is progressing, says Dr. Solit, who spoke at the ASCO conference. “We actually know a lot of the genetic alterations that cause the cancer. In 2002 there was a mutation in a protein called BRAF that was identified, and the mutation is found in the tumor in 50% to 70% of patients with melanoma. Then there’s a protein called NRAS, which also gets mutated in 15% to 20% of melanoma patients. But when you have an NRAS mutation, you don’t have a BRAF mutation. In total, between 60% and 90% of patients have one of the two,” says Dr. Solit, who gave the presentation, “Genetic Predictors of RAF/MEK Dependence.”

But the news at ASCO was not all good for the new therapies.

Early Promise, Mixed Results

Some of the most important new strategies for treating advanced melanoma focus on the patient’s immune system.

“Two of the strategies use anti-CTLA 4 and anti-PD1 agents to take the brakes off the patient’s immune system. Both are receptors on a patient’s T-cells, which are part of the normal braking system, which is a good thing at most times, but not a good thing in regards to a cancer cell,” says Walter Urba, MD, PhD, Director of Cancer Research at the Earle A. Chiles Research Institute in Portland, Oregon.

“The other two strategies use antibodies 41BB or OX 40. At ASCO this year, we saw some late clinical trial results with the anti-CTLA 4 product, and the first published results with anti-41BB and anti-PD1,” says Dr. Urba, who also discussed very early results with his own institution’s investigational agent, OX 40.

A disappointing trial of a new potential therapeutic agent was a head-to-head trial of an agent called a MEK inhibitor, which was tested against temozolomide, a standard pre-existing chemotherapy for melanoma. There was no significant difference between the standard arm and the MEK inhibitor (AZD 6244 by Astra Zenaca), according to the trial results.

However, patient selection may be the problem. “Genetic differences are relevant, because the BRAF mutation found so often in melanoma patients, activates a protein called MEK. “If you have a RAF mutation, you may respond a lot better to a MEK inhibitor,” explains Dr. Solit, noting that in addition to the Astra Zenaca drug, another MEK inhibitor in research is a drug from Pfizer called PD 0325901. The Astra Zenaca drug, which encountered the disappointing result, is in Phase II trials, whereas the MEK inhibitor from Pfizer is only in Phase I.

“The problem with the Astra Zenaca trial is that they didn’t look for BRAF-mutated patients. It’s possible temozolomide is as good or better than AZD 6244 in unselected patients, but five of the six responders in the MEK inhibitor arm had BRAF mutations,” Dr. Solit says. “There is technology out there already to start looking for these mutations, and it has already become routine in lung cancer for other genes.”

There were some positive, surprising results presented as well, however. A Phase II trial of ipilimumab, an investigational immunomodulatory agent from Bristol Meyers Squibb, which is in late Phase III trials, was studied in a population of 115 patients in combination therapy with Budesonide, a currently existing therapy. “Our primary endpoint was to see whether in a randomized trial we could reduce the amount of diarrhea that occurs as a side effect of the Budesonide, and our primary endpoint was not successful, but ironically, the clinical results were outstanding. Our median survivals were over a year,” says Jeffrey Weber, MD, PhD, Director of the Donald A Adam Comprehensive Melanoma Research Center and Professor of Oncologic Sciences at the University of South Florida.

Updated survival data of three Phase 2 studies of ipilimumab in patients with metastatic melanoma (Stage III or IV) who had previously been treated were presented at the European Society for Medical Oncology in Stockholm. Study results show that approximately half of patients who received ipilimumab (10 mg/kg) remained alive beyond 1 year. The results are based on follow-up of the patient population from studies 008, 022 and 007 treated with 10 mg/kg of ipilimumab (induction and maintenance) and show a consistent 1-year survival rate between 47% and 51%.

Combination Therapies of the Future, Today

Another promising strategy offering hope to advanced melanoma patients is to stimulate the patient’s immune system, by mimicking signal’s sent naturally by the body.

“We have learned from studying patients with melanoma just how powerful the immune system can be, but we need to supplement the response, and free it from some of its limitations,” says Robert H. Vonderheide, MD, Assistant Professor of Medicine at Abramson Cancer Center at the University of Pennsylvania.

The immune response in melanoma patients can be so pronounced that in rare cases, tumors even shrink in the face of it, says Dr. Vonderheide.

Dr. Urba agreed. “The immune response in melanoma is different from other cancers,” he explains. “One of the thoughts is that melanoma tumors are more immunogenic. Sometimes the response occurs after disease progression. In a couple percent of every patient population, the patient comes in and looks for all the world like they’re having tumor progression, and they end up having the tumor go away in response. The rationale is, that maybe it takes time for an immune response to build up and eliminate tumor cells following these investigational therapies,” he says, noting that these delayed responses can occur 8 or 12 weeks following therapy.

To attempt to take advantage of melanoma’s unique immunogenicity, Pfizer has developed an investigational agent that acts on an immune receptor called CD40, according to Dr. Vonderheide. “This is an antibody that binds to CD40 and mimics the signal sent to activate the immune system.”

The CD40 agonist has been tested by itself and in conjunction with standard chemotherapy drugs carboplatin and paclitaxel. The first clinical trial with the agent started about 4 years ago, and was reported 2 years ago at ASCO. Though the drug is only in Phase I trials, “taking it to Phase II is definitely warranted,” notes Dr. Vonderheide. “In the second study, we saw clinical activity: one patient has regressed, and remained in remission for years.”

In another study, the CD40 agonist will be given, along with chemotherapy, every 3 weeks, and the trial is enrolling as many as 30 patients, according to Dr. Vonderheide.

With some of the therapies, lack of experience in testing them may lead to unpredictable future results; in others, the sheer longevity of their period in trials can lead to skepticism.

“Anti-CTLA 4, an anti-inhibitory drug, has probably been in clinical trials for about 7 years, whereas anti-PD1, which is also an anti-inhibitory drug, has probably not been in trials for much more than a year,” says Dr. Urba, noting that the 41BB has also been in trials for 2 years.

For some drugs, clinical trials have enrolled hundreds of patients over the years, while other novel agents have only been tested in a few dozen humans. “The delayed response phenomenon, for example, has not been seen with other agents besides ipilimumab and tremilimumab, but with the other agents, the number of patients who have been treated is so small I’m not sure if we would have seen it,” he adds.

Still, the novel agents, whether young or old, often offer the only hope for advanced melanoma patients to hold onto.

“Nonetheless, it’s probably going to be a long series of trials to figure out which are the patients who are going to benefit. It’s a targeted therapy, and it doesn’t work for everybody. But we have insight into who it would work in, and we need to incorporate that information into our clinical trial design,” Dr. Solit says."


Melanoma Update: Highlights of research presented at ASCO and an update on vaccines trials

Take care
Jimmy B

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Greetings to One and All

This Blog is dedicated My Brother Kenny B. who passed away in the late 1970's with Cancer before the Internet.

It was he, who showed me How to live and give back. He was wise beyond his years.

Kenny B

Jimmy and Dee

Carepage: Jimmybreitfeller
Jimmy Breitfeller

My Profile as of 2009

My photo
Last July (2005)I was riding my bicycle to work at the Eastman Kodak Research Labs about 3 miles from home. I was wearing a knapsack to carry my things to and from the labs. I started noticing an ache on my back. So I decide to go to the dermatologist. To make the long story short, it was cancer. I knew from my research that I would be needing adjuvant therapy. So I started communicating with Sloan Kettering, University of Pittsburgh Cancer Center, and a couple of others including the Wilmot Cancer Center at Strong. I realized that by telling my story, I might help someone else out there in a similar situation. So to all who are linked by diagnosis or by relation to someone with melanoma, I wish you well. Stay positive, read as much as you can (information helps to eliminate the fear associated with the unknown), and live for today, as no one can predict what tomorrow may bring. Jimmy B. posted 12/15/08


The information contained within this Blog is not meant to replace the examination or advice of your Oncologist or Medical Team. The educational material that is covered here or Linked to, does not cover every detail of each disorder discussed.

Only your physician/Oncologist can make medical decisions and treatment plans that are appropriate for you. But, An Educated Consumer is a Smart consumer.

As Dr. Casey Culberson Said:

"The BEST melanoma patient is an ACTIVE PARTICIPANT in his or her treatment

Melanoma and the “Magic Bullet” (Monoclonal Antibodies)

Just to let you know I posted the first draft of the Melanoma and the “Magic Bullet” (Monoclonal Antibodies). on Melanoma Missionary In the Shared File Section. you can download it for 19.95 (Only kidding) it is Free for the taking.

It is 33 pages long and may help you in your quest for the Yellow Brick Broad. Just to let you know it is only the first draft. Revisions are sure to come. I wanted to get it to the people that need it the most, the Melanoma Patients.


So, where does Interluekin-2 (IL-2) come into play? According to Byung-Scok et al and recent reports, IL-2 is not needed for developmental CD4+ CD25+ Treg cells in the thymus but does play an important role in the maintenance and function in the peripheral.18 Peripheral is defines as secondary system outside the bone marrow and thymus. It entails the site of antigen, immune system interaction. IL-2 is required for the peripheral generation of Tregs based Abbas’s and colleagues research.19

IL-2 prevents the spontaneous apoptosis of the CD4+ CD25+ Treg cells. It has been reported that patients with multiple advance-stage tumors have elevated levels of Tregs within the tumor microenviroment.20 Interluekin-2 is the survival factor for CD4+ CD25+ Treg cells.21 If the addition of IL-2 is on or before the maximum propagation of the CD4+ T cells, the Tregs population can increase 5-fold in a 96 hour period based on certain growth mediums.

By controlling the addition of the endogenous IL-2, one has a knob to turn and can lead to the control of the expansion of the Tregs. When you combined this control with the anti-CTLA-4 blockage, you can shift the balance of the immune response.

Now here is the catch. The maintenance and function of the CD8+ T-cells require CD4+ cells which secrete IL-2. So we don’t want to deplete the CD4+ cells, we want to control the expansion of the Tregs which are a subset of the CD4+ cells. It has been postulated by some researchers that the Anti-CTLA-4 blockage also suppresses the Treg function in a different mechanism. By using IL-2 as the rate limiting factor, we can suppress the CD4+ CD25+ Treg cell expansion by controlling the concentration and timing of the Inerluekin-2 at the tumor microenvironment.

The Interluekin-2 plays another role in this Melanoma Maze. In a study by Janas et al, Il-2 increases the expressions of the perforin and granzyme A, B and C genes in the CD8+ T-cells. This increase expression causes the CD8+ T-cells to mature into Cytoxic T Lymphocytes (CTLs). The exogenous IL-2 is required for the granzyme proteins. As stated previously, CTLs have cytoplasmic granules that contain the proteins perforin and granzymes. A dozen or more perforin molecules insert themselves into the plasma membrane of target cells forming a pore that enables granzymes to enter the cell. Once in the tumor cell, these enzymes are able to breakup (lyse) the cell and destroy it. This is the beginning of the end for the cancer cells. The tumors begin to shrink and the rest is history,

On the other hand, prolong therapy with Il-2 can result in causing apoptotic death of the tumor- specific CD8+ T-cells.23

Clearly in a clinical setting, timing, dose, and exposure to these drugs play a major roll in the immunotherapy, and can have dramatic effects on the outcome.

All it takes is that one magic bullet to start the immune reaction..

Melanoma And The Magic Bullet (Monoclonal Antibodies)

Public Service Announcement

A call for Melanoma Patients by Dr. Steven A Rosenberg

"We continue to see a high rate of clinical responses in our cell transfer immunotherapy treatments for patients with metastatic melanoma", Dr. Rosenberg said.

"We are actively seeking patients for these trials and any note of that on a patient-directed web site would be appreciated."

If you would like to apply for his trials, here is the website and information.

Dr. Rosenberg's information

Dr. Rosenberg's Clinical Trials

For the Warriors

The Melanoma Research Alliance has partnered with Bruce Springsteen, the E Street Band, and the Federici family to alleviate suffering and death from melanoma. Please view Bruce Springsteen’s public service announcement inspired by Danny Federici. Danny was the E Street Band’s organist and keyboard player. He died on April 17, 2008 at Memorial Sloan-Kettering Cancer Center in New York City after a three year battle with melanoma.

Source Fastcures blog

Join the Relay for Life!!!


Dear Family and Friends,

I’ve decided to take a stand and fight back against cancer by participating in the American Cancer Society Relay For Life® event right here in my community! Please support me in this important cause by making a secure, tax-deductible donation online using the link below.

To donate on line now, click here to visit my personal page.
Jimmy B AKA Melanoma_Missionary

Relay For Life® is a life-changing event that brings together more than 3.5 million people worldwide to:

CELEBRATE the lives of those who have battled cancer. The strength of survivors inspires others to continue to fight.

REMEMBER loved ones lost to the disease. At Relay, people who have walked alongside people battling cancer can grieve and find healing.

FIGHT BACK. We Relay because we have been touched by cancer and desperately want to put an end to the disease.

Whatever you can give will help - it all adds up! I greatly appreciate your support and will keep you posted on my progress.

Keep the Fire Burning!!!



Jimmy Breitfeller
Turn off Music before you "Click to Play"
Signs of Melanoma Carcinoma Skin Cancer

How Skin Cancer Develops by " : Dermatology"

Call for Patients with Unresectable Liver Metastases Due to Melanoma

Delcath Systems Granted Orphan-Drug Designations for Cutaneous and Ocular Melanoma

Delcath is actively enrolling patients in a Phase III clinical trial testing its proprietary drug delivery system, known as Percutaneous Hepatic Perfusion (“PHP”), with melphalan for the treatment of ocular and cutaneous melanoma metastatic to the liver.

This NCI-led trial is enrolling patients at leading cancer centers throughout the United States. Commenting on these orphan-drug designations, Richard L. Taney, President and CEO of Delcath, stated, “These favorable designations are important steps in our efforts to secure Delcath’s commercial position upon conclusion of our pivotal Phase III trial for metastatic melanoma. We remain steadfast in our commitment to become the leader in the regional treatment of liver cancers and we continue to enroll patients in this study, and advance our technology and the promise that it offers to patients with these deadly forms of melanoma and other cancers of the liver, all with limited treatment options.”

Orphan drug designation, when granted by the FDA’s Office of Orphan Products Development, allows for up to seven years of market exclusivity upon FDA approval, as well as clinical study incentives, study design assistance, waivers of certain FDA user fees, and potential tax credits.

Current Trial Centers

Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using
Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancies

James F. Pingpank, Jr., MD, FACS
Associate Professor of Surgery
Division of Surgical Oncology
Suite 406, UPMC Cancer Pavillion
5150 Centre Avenue
Pittsburgh, PA 15232
412-692-2852 (Office)
412-692-2520 (Fax)

Blog Archive

Call For Melanoma Patients!!!!

Call For Melanoma Patients!!!!

Dr. Rosenberg Has a New Clinical Trial.

Our latest treatment has a 72% objective response rate with 36% complete responses.

We are currently recruiting patients for our latest trial.

Is there some way to post this “Call for Patients” on the web site?

Steve Rosenberg

Dr. Rosenberg's Clinical Trials

(For a copy of the research paper.. see My Shared files)

The news headlines shown above for Melanoma / Skin Cancer are provided courtesy of Medical News Today.