Pearls of Wisdom: Melanoma ..Jim Breitfeller

Pearls of Wisdom: Melanoma
Reviewed by Douglas Johnson, MD and Jeffrey Sosman, MD

This entry was posted on Tuesday, January 8, 2013 at 6:33 pm Management of Advanced Disease


Metastatic melanoma historically has had a very poor prognosis with a median survival of 6-9 months. However, recent advances in molecularly targeted therapy as well as immune based therapies have provided several effective treatment options for oncologists and their patients. In 2012 there are several important issues to consider in the management of patients with newly diagnosed advanced melanoma.


Advanced Stage III/Stage IV resectable disease

• In patients with advanced stage III disease or oligometastatic disease, consultation with an experienced surgical oncologist is warranted, as patients can experience long term survival with an aggressive surgical approach. Despite the advances in systemic therapy, surgical resection is still our preferred option in most of these clinical situations. One series of 64 patients showed a >30% four year survival in patients who had completely resected metastatic disease.1

•Another option we have offered is a short course of systemic therapy for 6-12 months prior to surgery with the intent to improve the chance that rapid recurrence of disease does not occur and to define the tumor’s responsiveness to the treatment.
•Patients should be considered for clinical trials in the adjuvant setting. Studies are ongoing to assess whether ipilimumab or vemurafenib is effective in preventing recurrences in high risk patients. For stage IV (M1) disease after complete surgical treatment there is no standard of care adjuvant treatment.


•Interferon, the current standard of care for fully resected stage IIb-III disease, is also an option in the adjuvant setting.
Molecular Testing

•All patients with metastatic disease should undergo testing for BRAF V600 mutations given the availability of targeted therapy for this mutation. This should include testing for the alternate V600 mutations that make up about 20% of BRAF mutations at this codon and appear sensitive to the BRAF inhibitors such as vemurafenib and dabrafenib.2 Patients with advanced local or regional disease can also be considered for testing since there are a number of clinical trials either recently or soon to be activated with BRAF inhibitor based therapy in BRAF V600 mutated melanoma at stage IIC-IIIC. Additionally, results will be available on progression so that therapy can be rapidly initiated if needed.
•Evaluation of several KIT mutations should also be considered in at least specific clinically defined subsets of patients. Though KIT mutations are present in only ~2% of all melanomas, acral (feet and hands) and mucosal melanomas harbor KIT mutations in 15-20% of cases. KIT mutations are sensitive to imatinib in about 25% of the cases based on limited numbers of patients.3
•NRAS mutations are also present in 15-20% of patients and though no targeted therapies are yet established as standard for this subset, there are a number of studies underway specifically targeting this mutation. Furthermore, the NRAS mutation may confer a poor prognosis to the melanoma.4


Standard therapies for metastatic disease

Vemurafenib
Vemurafenib is a BRAF inhibitor approved for patients with metastatic melanoma with BRAF V600 mutations (40-50%). In phase III trial data, objective tumor shrinkage was seen in well over 50% of patients, and clinical benefit seen in nearly all patients during the initial few weeks of administration. Median progression-free survival was 6.9 months (compared to 1.6 months with dacarbazine).5 Some important points regarding vemurafenib therapy:
•Responses are often rapid and dramatic. If patients with mutated BRAF V600 melanoma are highly symptomatic, vemurafenib would be our first line therapy in nearly all such patients.
•Patients will inevitably progress or relapse, often within the first year. Strategies to prevent or delay resistance are being pursued. In fact, recently the addition of a MEK inhibitor, trametinib, demonstrated an ability to improve the frequency of objective responses and the duration of progression-free survival in those melanoma patients receiving dabrafenib (BRAF inhibitor).
•Vemurafenib has clinical activity in patients with brain metastases in small series. Prospective phase II trials are pending completion. Trials with dabrafenib have also demonstrated frequent clinical benefits in such patients.6
•Secondary squamous cell carcinomas are common in BRAF inhibitor trials (10-25%).7 Suspicious lesions should be biopsied. Additionally, secondary melanomas and CMML have been reported in the presence of vemurafenib; almost certainly the drug has played a role to accelerate the appearance and growth of these tumors.
Ipilimumab (Yervoy)


Ipilimumab is an antibody to CTLA-4 and functions as an immune checkpoint inhibitor. This “removes the brakes” on the immune system which decreases immune tolerance to the tumor but may also cause autoimmune toxicities. In phase III trials, overall survival was increased compared to a vaccine in previously treated patients (10 mos vs. 6.4 mos), and in combination with dacarbazine compared with dacarbazine alone in the first line setting (11.2 vs. 9.1 months).8,9 Some important points to consider:
•Tumor burden on exam or on imaging may transiently worsen even in patients destined to respond. We do not repeat imaging until after 12 weeks of therapy unless the patient develops concerning new or progressive symptoms.
•Since even responding patients may have tumor growth or slow shrinkage, we are hesitant to use this therapy in highly symptomatic patients, especially if there are reasonable alternatives.
•Autoimmune side effects may be severe. Colitis, hepatitis, dermatitis, neuropathy, and endocrinopathies are the most common toxicities.
•Patients should be monitored closely for colitis. Concerning symptoms (diarrhea, melena/hematochezia, abdominal pain) require rapid evaluation. Though Imodium is appropriate for mild diarrhea (grade I), grade II toxicities or worse require prompt initiation of steroids. Colonoscopy should be performed to confirm the diagnosis in patients with severe colitis. Bowel perforation and death have been reported in extreme cases almost always when initial therapy is delayed.
•Headaches, with or without vision changes and fatigue may represent hypophysitis. Evaluation of TSH, cortisol, and testosterone, and brain MRI can aid in this diagnosis.
•We monitor TSH, cortisol, and liver enzymes at every visit.

•Other rare immune mediated side effects such as Guillan Barre syndrome, myasthenia gravis, sarcoidosis, and hemophilia have also been described.
Interleukin-2 (IL-2)


IL-2 has been used for many years in treating metastatic melanoma. It is associated with 6% durable remission rate (cures) and 15-20% overall response rate.10 Its use is limited to centers familiar with the associated severe side effects. Some points to consider when treating or referring patients:


•Therapy is limited to healthy patients usually under 70 years of age with adequate cardiac, pulmonary, renal, hepatic, and hematopoietic organ function and well controlled brain metastases. Nearly all patients experience treatment associated hypotension, multi-organ dysfunction, and vascular leak syndrome

•Though newer agents exist, IL-2 has the most long term data showing durable remissions in the minority of patients. We still consider this therapy in interested, eligible patients.
•Advantages of using IL-2 compared to ipilimumab include longer duration of use and more rapid assessments of benefit (8 weeks vs. 12+ weeks). Advantages to ipilimumab include outpatient use, generally less severe side effects, and possibly higher rates of durable remissions.



Cytotoxic chemotherapy

•Dacarbazine, temazolamide, and carboplatin/paclitaxel occasionally benefit patients with metastatic disease.
•No consistent survival benefit has been demonstrated with cytotoxic chemotherapy. Response rates are typically in the 5-10% range.
•We use chemotherapy only in patients who are not eligible for other therapies.
Which therapy should be chosen as first line therapy in patients with BRAF V600E/K mutations?
•This decision should be individualized. No head to head comparisons have been done with immunotherapy in the form of ipilimumab or interleukin-2 therapy. BRAF inhibitors are associated with high response rates but inevitable progression, while immune therapies have low objective response rates but durable remissions in a minority of patients.

•In patients with rapidly progressive or highly symptomatic disease, we typically use vemurafenib. In patients with asymptomatic disease, we favor immune based therapies for interested patients. An intergroup randomized cross over trial will address this issue, where half the patients start with vemurafenib and the other half on ipilimumab.



Promising Therapies


Therapy for metastatic melanoma is rapidly evolving. Many clinical trials are ongoing, and patients should be encouraged to participate in clinical trials for first line therapy or at progression if treated with standard therapy options. Some therapies that are likely to be approved are listed below.
•BRAF/MEK inhibitor combination therapies: Dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) have both shown benefit individually over dacarbazine in phase III trials in patients with BRAF mutant metastatic melanoma. However, interest lies especially in combination therapy to delay resistance and disease progression. In a randomized phase II trial, combination therapy was associated with an improved objective response rate (54% vs 76%) and progression free survival compared to dabrafenib alone (9.4mo vs. 5.8mo).11 Additionally, the incidence of squamous cell carcinomas was dramatically decreased with combination therapy. Trials are ongoing comparing this combination with vemurafenib in untreated patients with BRAF mutations. An additional trial is evaluating vemurafenib in combination with GDC-0973, a MEK inhibitor.



•Anti-PD-1 therapy:

Several newer checkpoint inhibitors block the interaction between PD-1 (expressed on T-cells) and PD-L1 (expressed on tumor) which activates the immune system, hopefully in a tumor specific manner. A phase I trial with nivolumab (anti-PD1 BMS) data shows a 31% response rate with fewer autoimmune side effects than ipilimumab.12 Pneumonitis was described in several patients. Trials are ongoing in patients who have progressed on ipilimumab. Early reports of another anti-PD1, MK-3475 also show a remarkable response rate in patients either following Ipilimumab or de novo in the 40-50% response range.

•Anti-PD-1 + Yervoy therapy:

By using both Checkpoint inhibitors, you and block two pathways that the melanoma can't use for immunosuppression. This allows the activated T-cells to go unchecked and keeps the immune response switch on. This clinical trial is ongoing at Sloan Kettering, and Yale. Rumor has it that they are seeing high response rates.



References

1.

Sosman JA, Moon J, Tuthill RJ, et al. A phase 2 trial of complete resection for stage IV melanoma: Results of Southwest Oncology Group Clinical Trial S9430. Cancer 2011.
2.

Lovly CM, Dahlman KB, Fohn LE, et al. Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials. PloS one 2012;7:e35309.
3.

Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA : the journal of the American Medical Association 2011;305:2327-34.
4.

Devitt B, Liu W, Salemi R, et al. Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma. Pigment cell & melanoma research 2011;24:666-72.


5.

Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. The New England journal of medicine 2011;364:2507-16.     “It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
 Take Care,
Jimmy B

A very Happy Father's Day from a stage IV Melanoma Survivor..Jim Breitfeller

I want to thank all the people that has made this day a very special Day.


As a stage IV Melanoma Survivor, I never dreamed that I would be here today to witness my children spread their wings and learn to fly. My daughter was just entering college when I was first diagnosed and my son, Chris was a sophmore in High School. Today, I am preparing to help my son relocate to Connecticut. He just landed an engineering job at an areospace company. My daughter, Jessica is globe-trotting around the world working on her dual Masters in "International Affairs" and "Natural Resources & Sustainable Development". This day, marks Dee and I as offically "Empty Nesters".

This all was made possible by entering a journey that entailed four clinical trials along with the best and internationally renowned medical team that makes climbing Mt. Everst apiece a cake. And you , My carepage friends that kept me on the "Yellow Brick Road". I have won the "lottery of life."

Many Thanks

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~

Take Care,

 Jimmy B
 

New Options in Melanoma Therapy Dr John Kirkwood Feb 2010..Jim Breitfeller

Take Care,

Jimmy B

Bristol-Myer Squibb says it will seek FDA approval for ipilimumab as a second-line treatment in advanced melanoma in 2010.Melanoma..Jim Breitfeller

Bristol-Myer Squibb says it will seek FDA approval for ipilimumab as a second-line treatment in advanced melanoma in 2010.

"Phase 3 top-line results are due from a study of ipilimumab in patients with previously untreated metastatic melanoma taking a combination of ipilimumab plus the chemotherapy dacarbazine or dacarbazine plus placebo. Concurrent with a business update to analysts and investors on Mar. 4, BMS says it will seek U.S. regulatory approval for ipilimumab as a second-line treatment in advanced melanoma in 2010, and will move the drug into Phase 3 trials in non-small cell lung cancer based on Phase 2 study data, which it would present at a major medical meeting later in 2010. The company did not provide any additional details on the data."

Source:










Bristol-Myer Squibb's Ipilimumab Can't Cure Cancer alone, It will need to be done with Combinatorial Therapy.









Take Care,

Jimmy B

What If you combine Therapies? Response from Dr. Keith Flaherty..Melanoma ..Jim Breitfeller

What If you combine Therapies? Response from Dr. Keith Flaherty

Jim,


Thanks for the note.




"It is actually critical “patient advocates” which obviously includes patients, as well as those who are motivated to advocate on behalf of patients get involved in this process. One of the very reasons why I thought that a consortium was important to form, so that there could at least a body of researchers to point to as a group jointly focused on this direction. You see, companies find it very easy to say no to individual investigators when it comes to “difficult” requests. We need to make it harder for them when it involves losing time that our patients don’t have."



A very obvious combination that we are trying to move forward now is PLX4032 with ipilimumab. There is unanimity among the academic researchers that this must be investigated. Both companies see the logic, but are reluctant with neither of their drugs yet being FDA approved. As you know ipilimumab (and tremelimumab) have not overwhelmed the FDA yet as they were told to show a response rate greater than 10% and neither drug could do so. Most melanoma researchers believe that there are additional patients who get real and long-term benefit without having their tumors shrink significantly in size, but the randomized trials are needed to show that. The worrying sign is the outcome of the tremelimumab randomized trial. So, now we are down to waiting for the results of the dacarbazine vs. dacarbazine plus ipilimumab phase III trial. If this is negative, we are in trouble as ipilimumab will have no clear path forward with the FDA. If it’s positive, then the idea of moving ahead with combinations becomes much, much easier. But, even it that trial is negative, we know that CTLA-4 blockade can induce phenomenal responses in some. So, in that case, we have to figure out (1) who those patients are and, (2) how to make those responses happen in more patients. The other way of thinking of #2 is that PLX4032 doesn’t work for as long as we would like and that making those responses more durable would be desirable.

The companies need to hear it from patients and all patient-advocates that fairly obvious directions need to be pursued to find multiplicative effects. For the first time in melanoma, we have the building blocks in front of us and scientific rationale to guide us for the next steps.


Best regards, Keith

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
Keith,


Base on my research, Ipi doesn’t work well is because it is lacking the tumor-specific antigens. DTIC+ Patrin-2, Irradiation, Oblimersen and others. We need the tumors to shed antigenic protein. To get the immune response into motion.


By using PLX-4032, my guess it will shed the protein needed. Then Anti-CTLA-4 Blockage comes in. It leaves the cd4+ T-cell activated and at the same time suppresses the Treg function allowing the CD8+ T-cells to get crossed primed and have them break though the tumor microenvironment. The HD IL-2 is added at the peak expansion of the CD8+ T-cells ( 50 days after Ipi is introduced into the host.). IL-2 is essential in the survival and function of the CTLs.


The above is my take on this combinatorial therapy. If you want, I can send you all the supporting papers of this theory.


Also, Can I get your permission to post your reply on my Blog?

Best Regards

Jim

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

What If you Combine three Therapies? PLX-4032 after remission, to let the tumor burden be low, Than add one dose of Anti-CTLA-4 Blockage. Wait 50 days so the CD8 T-cells would be at their maximum expansion. Then add two cycles of HD IL-2 to help grow and differentiate the CD8 T-cells into Cytotoxic T Lymphocytes (CTL's). You use the PLX-4032 to lower the tumor burden and shed the antigenic protein from the tumor.



For the patients that have the Braf mutation, use PLX-4032 to shed the antigenic protein and lower the tumor burden.

If you don't have the mutation, use radiation, chemo DTIC+ Patrin-2, Oblimersen and other small molecules to shed the antigenic protein.







Take Care,

Jimmy B

Tremelimumab Shows Low But Durable Response Rate in Advanced Melanoma..Jim Breitfeller

Tremelimumab shows low but durable response rate in advanced melanoma
FEBRUARY 18, 2010

"NEW YORK (Reuters Health) - In a phase II trial in patients with advanced refractory or relapsed melanoma, tremelimumab (CP-675,206) showed a 6.6% objective response rate, with these responses lasting more than six months, a multinational group of researchers report in the February 1 issue of Clinical Cancer Research."

Source:http://www.curetoday.com/index.cfm/fuseaction/news.showNewsArticle/id/13/news_id/2350

Tremelimumab shows low but durable response rate in advanced melanoma


As you can see, the response rate is low as a monothrapy, but if you can get the tumors to shed antigentic proteins by combining with chemotherapy, irradiation and other molecules to stop the repair of the tumor Cell DNA, then you have antigens to present on the the (APCs) Antigen Presenting Cells. Interluekin-2 can be added at the end of the T-cell expansion to help grow and maintain the (CTLs) Cytotoxic T Lymphocytes.





adapted from Henry Stewart Talks by Jim Allison



Take care

Jimmy B

Melanoma_Missionary


"Today might be the worst day of your life...but tomorrow could be the best. You just have to get there."
~Unknown~

The Orchestration of an Immune Response Unrehearsed! Melanoma..Jim Breitfeller

February 4 is World Cancer Day—a global day of awareness created by the International Union Against Cancer. With cancer set to become the #1 killer in the world this year, the day brings us together to highlight the growing personal and economic impact of the disease. On this day it’s critical that each organization—and each individual—share responsibility for sending a powerful message about cancer prevention.





















Melanoma And the Magic Bullet (monoclonal Antibodies



Take Care,

Jimmy B

A Review of Treatments for Patients with Metastatic Melanoma | OncoLink Cancer Resources

A Review of Treatments for Patients with Metastatic Melanoma | OncoLink Cancer Resources

Take Care,

Jimmy B

The Top 5 Most Promising Upcoming Drugs for Melanoma..Jim Breitfeller

New Phase III Clinical Trials for the Treatment of Melanoma
From Timothy DiChiara, Ph.D., for About.com
Created: May 21, 2009

About.com Health's Disease and Condition content is reviewed by the Medical Review Board


Treatment of advanced (stage III and IV) melanoma is in desperate need of some good news. Although the incidence of melanoma is increasing by a whopping 3 to 5% per year in the United States, current therapies don't significantly increase survival in most patients and no new first-line medicines have been approved in over 10 years.
Clinical trials are the best hope for a long-lasting reduction or elimination of metastatic melanoma (called a "durable response" or "complete response" by doctors). The US National Institutes of Health lists 27 late-stage (phase III) clinical trials currently recruiting patients with melanoma. Many of the trials are testing new combinations of existing drugs, new ways to administer them, or new surgical procedures, but some are investigating brand new drugs. The most promising are the following:

Allovectin-7 - This novel gene therapy is injected directly into the tumors of patients with stage III or IV disease, which then alerts the body's own immune system to attack the tumor. Earlier trials of Allovectin alone showed that tumors in 4% to 9% of patients responded to the therapy. The new trial is comparing Allovectin-7 to the standard chemotherapy treatment, either dacarbazine or temzolomide. Made by Vical. Find out if you may qualify for the AIMM trial of Allovectin-7.

oblimersen (Genasense) - Genasense is a unique inhibitor of Bcl-2, a protein made by cancer cells that is thought to block chemotherapy-induced cell death (called "apoptosis"). So by reducing the amount of Bcl-2 in cancer cells, Genasense may enhance the effectiveness of current anticancer treatment. Previous studies demonstrated that Genasense combined with the chemotherapy drug dacarbazine tripled response rate and significantly increased overall survival compared to dacarbazine alone. Made by Genta. Find out more about the AGENDA trial of oblimersen.

MVax - MVax is a melanoma vaccine prepared from the patient's own cancer cells. Several studies have shown that MVax followed by interleukin-2 can lead to a complete response in up to 13% of patients, double that of interleukin-2 alone. MVax is also effective in patients with stage III melanoma when given post-surgery: it doubled the 5-year survival rate compared to surgery alone. Made by AVAX Technologies. Find out more about the MVALDI trial for MVax.

ipilimumab (MDX-010, MDX-101, or BMS-734016) - Ipilimumab is an antibody that activates the body's immune system to fight melanoma by inhibiting the CTLA-4 molecule. Three previous phase II clinical trials have shown that treatment with ipilimumab results in a one-year survival rate of 47% to 51% for people with stage III or IV melanoma, which is almost double the average. The current trial is comparing ipilimumab to a dummy treatment (placebo) in patients with stage III melanoma who have already undergone surgery. Made by Medarex and Bristol-Myers Squibb. Find out more about the EORTC 18071 trial for ipilimumab.

OncoVEXGM-CSF - OncoVEXGM-CSF is a vaccine that works by spreading within tumors and causing the death of cancer cells while stimulating the immune system to destroy metastatic tumors. Previous results from 50 patients with inoperable stage IIIc/IV melanoma demonstrated that 28% of patients responded, including 12% with a complete response. The new trial is enrolling patients with previously treated but inoperable stage IIIb, IIIc or IV melanoma and is designed to compare OncoVEXGM-CSF to a naturally-occurring substance in the body called a "granulocyte monocyte colony stimulating factor" (GM-CSF), which increases white blood cells. Made by BioVex. Find out more about the trial for OncoVEXGM-CSF.

Why Participate in Clinical Trials

Those who take part in clinical trials get access to the latest treatments that are often not available anywhere else. These treatments may be better than the standard of care and may offer the only hope for those with advanced disease. Simply put, participation in clinical trials by patients like you is the only way research will advance toward an eventual cure for melanoma.

Talk about the possibilities with your doctor!

Source:

ClinicalTrials.gov. US National Institutes of Health. 10 February 2009.

Take Care,

Jimmy B

As I Continue my Quest, I have come to another Windmill..Melanoma..Jim Breitfeller

As I Continue my Quest, I have come to another Windmill.

Anti-CTLA-4 Blockage maybe coming back to compassionate care or better yet,may be getting ready to seek FDA approval.

I have stumble upon another Review Article by Dr. Kim Margolin from 2008.

"Moving forward with immunotherapy: the rationale for anti-CTLA-4 therapy in melanoma."

Source:http://www.communityoncology.net/journal/articles/0507367.pdf
Moving forward with immunotherapy: the rationale for anti-CTLA-4 therapy in melanoma

If you look closely at the tables, you know why Brisol-Meyer Squibb aquired Medarex for their "String of Pearls".

This is the quote I like the Best:

"The preliminary results of these trials are encouraging, considering most patients were previously treated for advanced melanoma. The possibility that anti-CTLA-4 antibodies, used as single agents, will be superior to proven therapies, ie, dacarbazine or IL-2, will be tested in phase III trials. Of greater promise may be the combination of these agents in carefully timed sequence with cytotoxic or other immunotherapeutic strategies."

See , I believe that the combination therapies Hold the greatest Promise.
I can vouch for that. NED FOR OVER 25 MONTHS AND STILL COUNTING!!!!!

Please seek out this therapy if you need it. It could extend or even save your life.



Take Care,

Jimmy B

Followup of the Anti-CTLA-4 Shortage Story..Melanoma..Jim Breitfeller

Base on this Clinical trial which is not active yet, It looks like Bristol Meyer Squibb/Medarex is trying different processes.

Comparison of Ipilimumab Manufactured by Two Different Processes in Patients With Advanced Melanoma

This study is not yet open for participant recruitment.

Verified by Bristol-Myers Squibb, June 2009
First Received: June 9, 2009 Last Updated: June 12, 2009 History of Changes
Sponsors and Collaborators: Bristol-Myers Squibb
Medarex

Information provided by: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00920907

Purpose
The purpose of this clinical research study is to compare pharmacokinetics of ipilimumab manufactured by two different processes.


Condition Intervention Phase
Advanced Melanoma
Biological: Ipilimumab
Phase I

I wish they would just come out and tell the world so we would stop the speculations.

This was posted on MPIP:

"Jim! I don't believe that Medarex involve anthing to the shortage of drug in its compassionate trial.

Medarex is just a research company... not a drug manufacturing... it does not have any capacity to scale up the drug. That's a reason why they partner up with Bristol Myers for MDX-010. Because BMS is the big drug company, which already has production plans/manufacture facilities.

I do believe BMS actually ran into a shortage of production due to unexpected demands. Right now they are working on the other process production plan, which called plan B vs plan C. But the FDA still requires them to run a trial for it. See my link..

http://www.clinicaltrial.gov/ct2/show/NCT00920907?term=ipilimumab&rank=13
Comparison of Ipilimumab Manufactured by Two Different Processes


If anyone to blame for.. it's the FDA.. From the recent ASCO data, MDX-010 proves that it doubles 1 year overall survival rate, it doubles 2 years survival rate.. when compares to the history data of DTIC. But that is still not good enough to let the company market the drug? Why the FDA want to sacrifice more human lives in order to prove the drug is efficacy? The history data of DTIC, which has been studied for 30 years.. which including very recent studies ... but still not convince them. What they want.. is another trial.. 300 human lives or more in DTIC arm, and another 300 human lives in MDX-010 arm.. then to seen if 300 human lives or more in DTIC arm die sooner?

30 years since DTIC approved, NO single drug has improve overall survive.. and now the only MDX-010 has proved it.."

Thanks John for your perspective on the situation


Take Care,

Jimmy B

Drug Czars ..FDA Dragging It's Feet!!Melanoma..Jim Breitfeller

Drug Czars

By STEVEN WALKER
published 2007

The Food and Drug Administration recently argued in the D.C. Court of Appeals that it has the power to ban meat and vegetables without violating anyone's fundamental rights. The agency chose this bizarre position in an attempt to counter arguments made by patients and their advocates in Abigail Alliance v. von Eschenbach. This groundbreaking case challenges the agency's refusal to grant access to investigational drugs, even as a last resort for terminally ill patients.

Last year, a three-judge panel decided that the FDA is violating the due- process rights of terminally ill patients by denying them access to promising investigational drugs. In response the FDA moved for a rehearing by the full court, hoping to prevent a lower court-supervised examination of whether its draconian policies actually serve a narrowly tailored compelling governmental interest. In layman's terms, this means the FDA would have to show its policies toward terminal patients are so critical to the well-being of society that they supersede (in broad and highly imperfect fashion) the fundamental right of an individual to pursue life free of undue government interference. The FDA knows their policies will not survive this test, and doesn't want the question asked.

Consider the FDA's handling of Genasense, a new drug for melanoma and chronic lymphocytic leukemia (CLL), two often terminal forms of cancer. The drug is being developed by Genta, a small, innovative company with only one approved drug and limited financial resources. Despite compelling evidence that Genasense is making progress in fighting both diseases, the FDA appears determined to kill the drug.

.In the case of the melanoma application, instead of reviewing the clinical-trial data in accordance with usual methods (which showed positive results), the FDA chose a nonstandard statistical approach aimed at discrediting the results. The agency used this analysis in its briefing to its advisory committee, claiming that the drug might not be effective. The committee then relied on that information to vote against approval.

Now, Genta has found a serious mathematical error in the FDA's analysis, rendering its results meaningless. Genta is filing a complaint under the Federal Data Quality Act to correct the record. But in the meantime, the drug remains unapproved and melanoma patients continue to wait.

Genasense was also shown in a well-run, randomized clinical trial (the FDA's gold standard) to cause a complete disappearance of disease in 17% of patients with advanced CLL when combined with two older drugs. Just 7% of patients in a control group who received only the older drugs experienced similar benefit. The responders to Genasense have seen their relief last an average of 36 months, while those using other drugs saw their cancer return, on average, in 22 months.

Following these results, the Director of the FDA's cancer division, Dr. Richard Pazdur, again convened a public meeting of his advisory committee. After an agency presentation designed to elicit a negative outcome, the panel voted 7 to 3 against approval, triggering an immediate reaction of surprise and dismay among many CLL experts.

But the committee vote is less surprising if one knows that the FDA appointed several voting consultants to the committee (none of them CLL experts), and recused from the meeting the only sitting member of the committee who is an expert in CLL. Perhaps even more troubling, two of the voting committee members worked behind the scenes as undisclosed consultants for the FDA on Genasense, then without disclosure voted in the open meeting.

A shocked Genta quickly requested a meeting with the FDA to seek clarity on the agency's position, and to present additional information from patient follow-up. On the referral of an eminent leukemia expert, Genta asked if we would attend the meeting as witnesses in our capacity as patient advocates. No compensation was offered, requested or received.

Most of the meeting was consumed by getting the FDA to admit the obvious: The long-lasting, complete disappearance of CLL and its symptoms constituted "clinical benefit." Making these arguments were two cancer-medicine professors at M.D. Anderson Cancer Center, the recused ODAC member and an immediate past president of the American Society of Hematology -- all experts in CLL. None were employees of Genta and collectively represented a far more qualified advisory committee than the one that the FDA had convened.

The FDA's inane answer to the CLL experts was that the long-lasting disappearance of disease in patients taking Genasense was a "theoretical construct" and not grounds for approval.

The experts explained to the FDA that complete responses in advanced CLL patients are the medical equivalent of the Holy Grail. The FDA finally agreed, but was unimpressed with emerging data showing responders to Genasense living longer than responders in the control group.

The experts were unanimous in advising that Genasense should be approved, but the FDA was unmoved. The agency's Dr. Pazdur suggested that Genta could make the drug available as an unapproved treatment through an expanded access program -- this from a regulator fond of stating that the best way to get a drug to patients in need is through approval! In this case the agency was saying to Genta: We are not going to approve your drug, but any patient who needs it can have it so long as you give it away.

Genta responded that nonapproval would be a denial of patient access to Genasense because they could not afford to give it away in an expanded access program. Twice, Dr. Pazdur referred to that logic as a "business decision."

Less than 48 hours later, the FDA rejected Genasense. Within days Genta made a "business decision," laying off a third of its staff in a cost cutting move aimed at keeping the doors open long enough to appeal the FDA's decision. The appeal was filed in early April. Genta's announcement of the filing included a statement from one of the expert physicians: "It is puzzling that they would deny approval to a drug that met its primary and key secondary endpoint, especially since these findings were observed in the only randomized controlled trial that has ever been conducted in patients with relapsed CLL."

The FDA's handling of Genasense lays bare the all too common, aggressive incompetence of the FDA's cancer-drug division and should lead to an immediate examination of its policies and leadership, followed by swift corrective action.

As for the FDA's belief that their power to control us and even deny us the pursuit of life itself is unlimited under the Constitution, we can only hope the appeals court disagrees. An agency that blocks progress against deadly diseases -- while arguing that its power to do so is above challenge -- is in dire need of a court supervised review.

Sourcre:http://online.wsj.com/article/SB117824324837591782-search.html

Printed in The Wall Street Journal, page A15

Mr. Walker is co-founder and chief adviser for the Abigail Alliance for Better Access to Developmental Drugs . He receives no compensation for his work as an advocate, nor has he ever received compensation from any private or public-sector entity involved in drug development, approval or marketing

This drug plus Dacarbazine seems to shed the right antigen-Tumor-specific Peptide

We need every patient and caregiver and family member to write to their Congressperson and Legislators.

This is not right!!!!!!

Bristol Meyer Squibb is violating the due- process rights of terminally ill patients by denying them access to promising investigational drugs. The Anti-CTLA-4 monoclonal antibody.

I am asking you to standup for your Rights and contact your congress person.
Your life might depend on it.

Take Care,

Jimmy B

First, how did I get the right antigen to be presented on the Antigen Presenting Cell (APC)?

There are three types of Antigen Presenting Cells:
• Macrophages
• Dendritic Cells
• B Cells

We will focus our attention on the Dendritic cells (DCs ) because I postulate that these cells played a major roll in help generating an immune response. Induced Dendritic cells go through a developental program call maturation, which transforms them into efficient antigen-presenting cells (APCs) and T-cell activators. They are the most potent of the three APCs.

So what really happened? Well, Dr. Kirkwood started me out on Dacarbazine with PaTrin-2. Dacarbazine is a chemotherapy agent, approved by the FDA for fighting Melanoma. Dacarbazine alkylates and cross-links DNA during the phases of the cell cycle, resulting in disruption of DNA function, causing cell cycle arrest, and apoptosis.17 The only problem is that the Melanoma Cells overexpresses this enzyme called MGMT.

Proteins known as DNA repair enzymes are present in cells to target damaged DNA and reverse the modifications caused by alkylating agents. One such enzyme is methylguanine methyltransferase (MGMT). MGMT directly reverses the chemical modification guanine, one of the four building blocks of DNA, allowing normal replication to take place.

The DNA-repair enzyme MGMT is a key factor in resistance to alkylating agents. This is one reason why the Dacarbazine therapy doesn’t have a very successful response rate. The MGMT enzyme repairs what the dacarbazine cross-links. So, PaTrin-2 was added to the trial. This drug is known to inactivate the MGMT activity. By inactivating the MGMT enzyme, it makes the tumors cells more susceptible to the chemotherapy.

This therapy was able to get the tumors cells to shed some antigenic Protein which I theorize and was used as the presenting antigen. This made the antigen “tumor-specific.”




Base on a paper by Dr. Olivera J.Finn called Cancer Immunology published in the New England Journal of Medicine in June 19, 2008, there are three ways for self antigens to become Tumor Antigens:


1. Mutation
2. over expression
3. Post-translational Modification

I postulate that some failure of the tumor cells to repair the DNA damage cause by the Dacarbazine in the present of PaTrin-2 resulted in a mutation causing the cancer cells to shed an antigenic peptide.


Well there is also anther protein that is overexpress in the cancer cells. It is the Bcl-2 protein. Bcl-2 has been implicated in disease resistance.


There is now a drug called Genasense®. Based on the clinical results. It also helps shed the right antigen. (The tumor-specific antigen)


Genasense®


If I am reading the data correctly, it is telling us that it to can be used with (DTIC) Dacarbazine to shed some antigenic protein. So If you combine the two, you are most likely will have the right antigen to present.


source:http://mct.aacrjournals.org/content/3/10/1215.abstract?ck=nck
Molecular Cancer Therapeutics



Take Care,

Jimmy B

First, how did I get the right antigen to be presented on the Antigen Presenting Cell (APC)? Melanoma..Jim Breitfeller

drI am so excited I could not stay away!!!!!!

So now we know what had transpired with the therapy, we need to know how and why it happened. I will try to decipher and or postulate each step of the therapy.

First, how did I get the right antigen to be presented on the Antigen Presenting Cell (APC)?

There are three types of Antigen Presenting Cells:
• Macrophages
• Dendritic Cells
• B Cells

We will focus our attention on the Dendritic cells (DCs ) because I postulate that these cells played a major roll in help generating an immune response. Induced Dendritic cells go through a developental program call maturation, which transforms them into efficient antigen-presenting cells (APCs) and T-cell activators. They are the most potent of the three APCs.
So what really happened? Well, Dr. Kirkwood started me out on Dacarbazine with PaTrin-2. Dacarbazine is a chemotherapy agent, approved by the FDA for fighting Melanoma. Dacarbazine alkylates and cross-links DNA during the phases of the cell cycle, resulting in disruption of DNA function, causing cell cycle arrest, and apoptosis.17 The only problem is that the Melanoma Cells overexpresses this enzyme called MGMT.
Proteins known as DNA repair enzymes are present in cells to target damaged DNA and reverse the modifications caused by alkylating agents. One such enzyme is methylguanine methyltransferase (MGMT). MGMT directly reverses the chemical modification guanine, one of the four building blocks of DNA, allowing normal replication to take place.

The DNA-repair enzyme MGMT is a key factor in resistance to alkylating agents. This is one reason why the Dacarbazine therapy doesn’t have a very successful response rate. The MGMT enzyme repairs what the dacarbazine cross-links. So, PaTrin-2 was added to the trial. This drug is known to inactivate the MGMT activity. By inactivating the MGMT enzyme, it makes the tumors cells more susceptible to the chemotherapy.

This therapy was able to get the tumors cells to shed some antigenic Protein which I theorize and was used as the presenting antigen. This made the antigen “tumor-specific.”

Base on a paper by Dr. Olivera J.Finn called Cancer Immunology published in the New England Journal of Medicine in June 19, 2008, there are three ways for self antigens to become Tumor Antigens:

1. Mutation
2. over expression
3. Post-translational Modification

I postulate that some failure of the tumor cells to repair the DNA damage cause by the Dacarbazine in the present of PaTrin-2 resulted in a mutation causing the cancer cells to shed an antigenic peptide. But I was still missing a signal or signals to activate my immune system.




I am still here plugging away.



Take Care,

Jimmy B

You have questions for Me? Why DTIC & PaTrin-2?..Melanoma..Jim Breitfeller

Remember I went to United Kingdom virtually to scour the research papers Last year?

Introduction:

"Temozolomide is an alkylating agent that mediates its cytotoxic effect by forming O6-methylguanine (O6-meG) DNA adducts, which during DNA replication pair preferentially with thymidine. These O6-meG:T mispairs
can result in a G-to-A point mutation during a subsequent round of DNA replication but are also substrates for the postreplication mismatch repair pathway, which after a further round of DNA replication leads to apoptosis (1). O6-meG DNA adducts can be repaired by the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT), which removes adducts from the O6 position of guanine by accepting them onto a cysteine residue within its active site. Furthermore, fibroblasts and
bone marrow cells of MGMT knockout mice are significantly more sensitive to the toxic effects of temozolomide than those from MGMT wild-type mice (2).

The protective role of MGMT against the cytotoxic effect of temozolomide has been shown in human cell lines (3) and human xenograft models (4).

MGMT can be inactivated by free guanine base derivatives that have alkyl groups at the O6 position, which act as ‘‘pseudosubstrates.’’ O6-benzylguanine (5) and O6-(4-bromothenyl) guanine (PaTrin-2, Patrin, Lomeguatrib, KuDOS, Cambridge, United Kingdom; ref. 6) have been identified as the most promising MGMT inactivators. Compared with temozolomide used as a single agent, the combination PaTrin-2-temozolomide has been shown to significantly increase tumor growth inhibition in human melanoma
xenografts (7)."


Source:http://mct.aacrjournals.org/content/3/10/1215.full.pdf

Sensitization of a human ovarian cancer cell line totemozolomide by simultaneous attenuation of the Bcl-2 antiapoptotic protein and DNA repair by O6-alkylguanine-DNA alkyltransferase


That is why, and I forgot to tell you that I did a trial with Patrin and DTIC Prior to CTLA-4 Blockage Therapy.

Take Care

Have a Great Weekend!!!!!

Jimmy B

ASCO summary By Dr. Eric Whitman.. Melanoma ..Jim breitfeller

ASCO Summary
Posted on June 1, 2009 by dr Eric Whitman

"I have been going to ASCO for years and I’m still waiting for that “a-hah!” moment when somebody presents something for melanoma that is so revolutionary and effective that we all have something tangible and exciting to come home with and build on in the future. I feel like we are getting closer as a “melanoma community.” I know that in my own clinical experience and current practice, I am able much more frequently to walk into someone’s exam room and tell them, congratulations, the tumors are shrinking. Honestly, there were many years where that **never** happened.

However, for all the hopes extended each year towards ASCO as the ultimate cancer meeting, I honestly can say that there was nothing presented over the last few days that will immediately change therapy or even holds out hope for some drug or combination of drugs posterizing DTIC or Temodar. (Posterizing somebody is a reference to pro basketball, when you savagely dunk the basketball over an opponent with such force and superiority that it becomes an instant classic athletic poster. Like the Michael Jordan slam dunk contest when he still had hair, took off from the foul-line, and the open mouth, wide-eyed stares of the sideline onlookers were forever captured.)

The closest we came in my career was the early data from about 2004 on Sorafenib/Nexavar, but that has melted away with larger scale, multicenter studies and is just a footnote at this point.

I will provide more detailed updates in other posts, but unfortunately there are no new treatments that show undeniable improvement over existing treatments. There are a few things that suggest the potential for improved therapy, but these are best described as “hypothesis-generating” or in other words, deserving of further, large scale, testing.

I know that this is frustrating to the melanoma patient community also; we’re just not there yet. We have new drugs coming down the road and they do have promising early results but the emphasis has to be on the word, promising.

The two take home words this year from the ASCO melanoma presentations were “Biomarkers” and “Targeted therapy”. In that regard, I don’t think the melanoma talks were that different from other disease areas. Biomarkers are things that can be measured, either in the blood or tumor tissue (or even in normal tissue) that classify an individual’s cancer by its behavior or potential to resp0nd to specific therapies. A biomarker could also monitor a patient’s response to therapy. A good example of this is the PSA level for prostate cancer. Finally, biomarkers could also identify patients either at risk for bad outcomes or those likely to respond to specifc treatments.

Targeted therapy refers to drugs that alter cellular biochemical pathways that are believed to influence a cancer cell’s ability to survive, grow, and/or resist therapy. Presumably, targeted therapy would have fewer side effects that standard chemotherapy but this exaggerates our true knowledge about these various pathways and their role in normal, non-cancerous, tissue. The other caveat about targeted therapy is that many of the ones that look most promising (to me) act by increasing cancer cells’ responsiveness to standard chemotherapy. As a result, these targeted agents often have no effect by themselves (ie monotherapy) and require simultaneous (concurrent is the medical word) chemotherapy drugs which obviously cause a range of side effects.

As you read my other summaries of ASCO papers and posters, keep biomarker and targeted therapy in the back of your mind; they came up over and over again"


WE NEED TO FIND THE “a-hah!” MOMENT!!!

I personally think we are getting closer.

The first step is to initiate the immune response

As our fellow carepage friend Jen has said, " DON'T STOP BELIEVING!!!!"

Take care

Jimmy B

Treatment options for metastatic melanoma. A systematic review..Melanoma ..Jim Breitfeller

Received: 12 January 2009; Revised: 9 March 2009
Accepted: 13 March 2009; electronically published: April 2009


Summary

"Metastatic melanoma is considered to be one of the most resistant tumors to standard chemotherapy approaches nowadays. Old anti-cancer treatments like dacarbacin (DTIC) or interleukin-2 (IL-2) continue to be the only approved treatments by the main worldwide health authorities. Up to now, no combination or new anti-targeted agent has shown an improvement in overall survival when compared to either of these two drugs alone. In fact, more than a dozen phase III randomized trials have tried to go beyond these old approaches, without meeting any success. Despite the fact that the median overall survival of patients diagnosed with metastatic melanoma is lower than 9 months, melanoma emerges as a challenging disease for testing new drugs and implementing the deeper knowledge in the molecular biology underlying this tumor. New immunotherapeutic targets have appeared recently trying to modulate the host immune response against the tumor. Furthermore, in the last three years, new targeted agents have changed the standard of care of other solid tumor types like renal cancer. We wonder if these new agents will be incorporated in the standard management of advanced melanoma patients in the coming years."

Source:http://www.cancer-therapy.org/CT7A/HTML/26._Blesa_et_al,_190-201.html

Treatment options for metastatic melanoma. A systematic review


Take care

Jimmy B

Tremelimumab dose selected for further testing due to favorable Safety, Tumor Response in Melanoma ..JimBreitfeller

Posted February 25, 2009
Tremelimumab given at two dosing regimens afforded durable tumor responses in patients with metastatic melanoma, according to data from a phase-1/2 trial.

Researchers conducted a phase-1/2 trial to assess the safety of tremelimumab in multiple doses and to examine the efficacy of the agent and the appropriate dosing regimen.

To determine the recommended phase-2 dose, phase-1 IV infusions of tremelimumab at 3 mg/kg, 6 mg/kg or 10 mg/kg were given to 28 patients with metastatic melanoma for up to one year. During phase 2, 89 patients received tremelimumab 10 mg/kg once each month or 15 mg/kg every three months.

The researchers reported no dose-limiting toxicity during phase 1. Eighty-four patients were assessable for response during phase 2 at which time 10% reached objective antitumor responses; one complete response and three partial responses in each dosing regimen comprised the best overall objective response.

Most responses ranged from three to 30 or more months and the most common adverse events were diarrhea, rash and pruritus. Grade-3/4 adverse events had a frequency of 13% in the 15 mg/kg arm and 27% in the 10 mg/kg arm. Frequency of serious adverse events was 9% in the 15 mg/kg arm vs. 23% in the 10 mg/kg arm.

“Both phase-2 regimens generated durable tumor responses,” the researchers wrote. “Based on its more favorable safety profile, 15 mg/kg every three months was selected for further clinical testing.” – by Stacey L. Adams

J Clin Oncol. 2009;doi:10.1200/JCO.2008.19.2435

The phase-3 data from ASCO, in terms of survival, show that tremelimumab given at 15 mg/kg every three months is a bit better than for the control arm of dacarbazine (DTIC-Dome, Bayer Healthcare) or temozolomide (Temodar, Schering). But, the difference was not statistically significant; median survival was a month better, but this is less than we were looking for. So we must ask: What is the real difference between clinical responses to tremelimumab and dacarbazine? In the recently published study of Camacho et al reporting the phase-1/2 experience and the larger phase-2 multicenter study I presented to ESMO and ASCO in 2008, as well as in the phase-3 experience that Toni Ribas presented to ASCO, there are very profound differences between the type of responses seen with anti-CTLA4-blocking antibodies and with conventional chemotherapy. About 8% to 10% of patients with melanoma have objective response to this modality and the majority of these have a very durable response. For example, in the phase-2 trial results I reported to ASCO and ESMO, 15 of 16 patients who had objective response with tremelimumab response was durable past six months -a very different pattern than we see for dacarbazine and temozolomide. Tremelimumab and ipilimumab are active agents in a fraction that is roughly the same as interleukin-2, interferon-alfa, and dacarbazine or temozolomide. In the largest trial of temozolomide ever conducted - results recently presented at ESMO by Patel et al.- response rates were 10% for dacarbazine vs. 14.8% for temozolomide, but there was no difference in the overall survival or the progression-free interval between these regimens. Dacarbazine and temozolomide responses do not seem to confer survival benefit in part because these responses are rarely durable. The 10% of patients who responded to the anti-CTLA4-blocking antibodies exhibit characteristically and qualitatively different kinds of responses in metastatic stage-4 disease.

When looking at the difference between the phase-3 and phase-1/2 trials, the phase-1/2 results clearly show that for tremelimumab there are very durable, high-quality responses--and the same can be said for ipilimumab. But the problem is, when you conduct a conventional trial in advanced metastatic melanoma to look at median survival, the survival median provides a different readout than the readout of durable responses. The quality of responses to tremelimumab and ipilimumab are still worthy of pursuit. The fact that the phase-3 trial of tremelimumab shows a little better outcome than dacarbazine in terms of median survival does not reflect these high-quality responses that go out well past six months, and will take different follow-up to document. So that is what is going on now: the long-term follow-up of those patients to make a qualitative assessment of the kind of response that they exhibited is really what we need.

Looking at the data from the phase-3 presentation by Ribas, the one thing that may have weighed differentially in favor of tremelimumab in the forest plot of the data was higher lactate dehydrogenase (LDH). This is curious when you think about it. It may or may not be real, but if patients who have higher LDH (perhaps worse disease) benefit more from tremelimumab than from dacarbazine or temozolomide, the study was designed in a way that may have disfavored the anti-CTLA4-blocking antibody. The protocol excluded those people who had higher than twofold elevated LDH – so, by the design of the trial, curiously the outcome may have been slanted in favor of temozolomide or dacarbazine.

Finally, it remains to test the role of anti-CTLA4 blocking antibodies in the disease setting where we have found the greatest relative benefit for other immunotherapy, such as IFN alpha. The adjuvant exploration of anti-CTLA4 blocking antibodies may show even greater relative benefit and warrants phase-3 study in relationto IFN alpha.

– John Kirkwood, MD

Source:http://www.hemonctoday.com/article.aspx?rid=36459

Tremelimumab dose selected for further testing due to favorable safety, tumor response in melanoma


Jimmy B

A Stage IV Malignant Melanoma Drug That Increases Overall Survival Would Earn a Higher Patient Share in the U.S. Than in Europe..Jim Breitfeller

Ipilimumab Will Earn Decision Resources' Clinical Gold Standard for stage IV Malignant melanoma in 2012, According to a New Report from Decision Resources

Ipilimumab is a fully human antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), a molecule on T-cells that plays a critical role in regulating natural immune responses. The absence or presence of CTLA- 4 can augment or suppress the immune system's T-cell response in fighting disease. Ipilimumab is designed to block the activity of CTLA-4, thereby sustaining an active immune response in its attack on cancer cells.


WALTHAM, Mass., Jan. 19 /PRNewswire/ -- Decision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that a drug for treating stage IV malignant melanoma that can increase median overall survival when compared with standard of care dacarbazine (Bedford Laboratories' DTIC-Dome, generics) would earn a higher patient share in the U.S. (60 percent) than in Europe (40 percent), according to surveyed U.S. and European oncologists.


The new report entitled Malignant melanoma (Stage IV): Emerging Therapies Must Increase Overall Survival over Dacarbazine to Attain High Patient Share finds that clinical data and the opinions of interviewed thought leaders indicate that Bristol-Myers Squibb/Medarex's ipilimumab has advantages over dacarbazine in the attribute of median overall survival. Following its approval in 2010 for the indication, ipilimumab will earn Decision Resources' proprietary clinical gold standard for stage IV malignant melanoma from 2012 to 2017.


"Ipilimumab has competitive advantages in efficacy and has been shown, in combination with dacarbazine, to almost double median overall survival when compared to Schering-Plough's Temodar, our clinical gold standard in 2008 for stage IV malignant melanoma," said Decision Resources Analyst Karen Pomeranz, Ph.D. "According to oncologists we surveyed, overall survival is the highest-weighted end point for stage IV malignant melanoma, which further stresses the significance of ipilimumab's achievement in increasing overall survival."

http://www.bio-medicine.org/medicine-news-1/A-Stage-IV-Malignant-Melanoma-Drug-That-Increases-Overall-Survival-Would-Earn-a-Higher-Patient-Share-in-the-U-S--Than-in-Europe-34223-1/

A Stage IV Malignant Melanoma Drug That Increases Overall Survival Would Earn a Higher Patient Share in the U.S. Than in Europe


Like I said CTLA-4 therapy with another additive therapy

Jimmy B

Trends in Melanoma -----Sanjiv. S. Aqarwala, MD January 29, 2009 Jim Breitfeller

Trends in Melanoma

Sanjiv. S. Aqarwala, MD
January 29, 2009

Sunbelt Melanoma Trial: Final Results
The Sunbelt Melanoma Trial, a multicenter prospective randomized trial, assessed high-dose interferon alfa-2b (IFN) or completion lymph node dissection (CLND) in the treatment of melanoma staged by sentinel lymph node (SLN) biopsy.

Eligible patients 18 to 70 years of age who had primary melanoma with Breslow thickness Ž1.0 mm underwent SLN biopsy and were assigned to one of two protocols. In protocol A, patients with a single positive lymph node after SLN biopsy and CLND were randomized to observation vs high-dose IFN (20 MU/m2/day IV 2 4 weeks followed by 10 MU/m2 /three times per week SC 2 48 weeks). Protocol B included patients with negative SLN determined by standard histopathology and immunohistochemistry. To detect melanoma-specific mRNA, these patients underwent molecular staging of the SLN by RT-PCR. Patients with RT-PCR–positive SLN were randomized to observation vs CLND vs CLND plus IFN (20 MU/m2/day IV 2 4 weeks only).

Randomization was stratified for Breslow thickness and ulceration. The primary end points were disease-free survival (DFS) and overall survival (OS). Intent-to-treat (ITT) and efficacy analyses were performed by Kaplan-Meier and Cox proportional hazards models, and the Data Safety and Monitoring Committee (DSMC) approved the final analysis.

Patients were enrolled between June 24, 1997, and October 31, 2003; median follow-up was 64 months. In the protocol A ITT analysis, there were no significant differences in DFS (HR 0.82; 95% CI, 0.47-1.40; P=0.46) or OS (HR 1.07; CI 0.65-1.78; P=0.79) for patients randomized to IFN (n=112) vs observation (n=106). In protocol B, there were no significant differences in DFS or OS among patients randomized to CLND (n=192; DFS: HR 0.72; CI 0.42-1.23; P=0.23; OS: HR 0.94; CI 0.55-1.59; P=0.81) or CLND plus IFN (n=184; DFS: HR 0.90; CI 0.54-1.50; P=0.69; OS: HR 0.96; CI 0.56-1.63; P=0.88) vs observation (n=180). The efficacy analysis did not demonstrate significant differences in DFS or OS.

This study failed to demonstrate a benefit for adjuvant high-dose IFN for patients with a single positive SLN. In addition, there was no significant benefit to CLND or CLND plus IFN among patients with melanoma cells detected in the SLN by RT-PCR analysis.

Combination Thalidomide Plus Temozolomide in a Phase II Trial in Metastatic Malignant Melanoma (MMM): SWOG S0508
After response rates up to 32% were achieved in single-institution phase II studies of thalidomide plus temozolomide as combination therapy in MMM, some clinicians have used thalidomide plus temozolomide as a standard therapy. This large multicenter phase II trial evaluated the clinical efficacy of this
therapy and the immune modulatory effects of thalidomide when combined with temozolomide in patients with MMM.

Eligible patients had cutaneous MMM proven by biopsy, no active brain metastases, Zubrod PS 0-1, no more than 1 prior systemic therapy for melanoma (excluding thalidomide, temozolomide, or dacarbazine), and adequate organ function. Six-month progression-free survival (PFS) was the primary end point; per study design, if the 6-month PFS rate was 10%, the regimen would not be of interest; if PFS was Ž25%, further study would be warranted. Response rate, OS, toxicities, and assessment of the relationship between immunologic biomarkers and clinical outcomes were secondary end points.

Patients received thalidomide (200 mg/day escalated to 400 mg/day for patients younger than 70 years, or 100 mg/day escalated to 250 mg/day for patients 70 years of age or older) plus concomitant temozolomide (75 mg/m2/day 2 6 weeks with a 2-week rest between cycles). Anticoagulation agents were not required. Treatment was continued until toxicity became unacceptable or disease progressed.

Of the 64 patients enrolled, 2 were ineligible, and 2 refused treatment. The 6-month PFS was 15% (95% CI, 6%-24%), and 1-year OS was 36% (95% CI, 24%-49%). Fifty-one patients had measurable disease by RECIST and were evaluable for response. All responses were partial, at a rate of 14% (95% CI, 6%-26%). One treatment-related death occurred due to MI. Three grade 4 events occurred: one case each of PE, neutropenia, and CNS ischemia; fatigue was the most common of 21 grade 3 events. Immunologic biomarkers were obtained at baseline and at 5, 9, and 13 weeks, including PBMC as a percentage and as an absolute count of CD4+/CD25+/CD69+ and CD16+/CD56+ cells, and ELISPOT reactivity to a recall pool of antigens.

Thalidomide plus temozolomide has little additional clinically meaningful activity compared with temozolomide alone in MMM. In a meta-analysis of systemic therapy for MMM, thalidomide plus temozolomide compared poorly. This regimen should not be considered a standard treatment for MMM.
Clark J, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 9007

Unresectable Metastatic Melanoma: A Phase II Clinical Trial With a Second-Generation GM-CSF–
Encoding Oncolytic Herpesvirus
OncoVEX (GM-CSF) is a second-generation oncolytic herpes simplex virus that encodes granulocyte-macrophage colony-stimulating factor (GM-CSF). In a phase I trial, it was well tolerated in patients with several types of tumors, and antitumor effects were seen in both injected and uninjected tumors.
Patients eligible for this phase II trial had unresectable stage IIIc/IV melanoma with Ž1 injectable tumor (ultrasound allowed) and had failed prior therapy. Patients with clinically active brain, liver, or bone metastases were excluded. Fewer than 10 lesions were to be injected, and more than 1 lesion was to be left uninjected. The dosing schedule consisted of one injection of 4 mL of 106 plaque forming units (pfu)/mL split between target tumors, followed 3 weeks later by 24 injections of 108 pfu/mL every 2 weeks. The study was designed to assess single-arm monotherapy in up to 50 evaluable patients, and more than one RECIST response among the first 24 patients was required to continue the trial. Response rate was the primary end point; safety, response kinetics, and survival were secondary end points.

At the time of this report, the study had enrolled 40 patients, 31 of whom were evaluable. Patients had up to 18 injection cycles. By 2 months on therapy, injected tumors routinely responded, often with local complete response (CR); often, palliative benefit was also achieved. Systemic responses included: 3 patients with CR, 3 with partial response (PR), 4 with durable stable disease (SD), and 2 with mixed response (ŽPR of existing disease and ŽPR of lesions, which later became measurable); 2 patients had posttreatment objective responses. Patients with both stage IIIc and IV disease achieved systemic responses, including resolution of visceral disease. Systemic responses are delayed since injected tumor responses take up to 10 months to fully develop. All objective responses have been maintained to date at 4 to 23 months after the first dose, with those patients not achieving CR still on therapy. Side effects have been grade 1 flu-like symptoms.

Data show that 32% of patients achieved CR, PR, or durable SD. Other patients also experienced clinical benefit: 2 patients had response in tumors that were first noted during therapy; 2 patients responded after leaving the study due to progressive disease; additional patients experienced local palliative benefit in otherwise difficult-to-treat tumors. The rate and durability of response is considered impressive compared with other treatments for advanced melanoma, particularly in the second-line/salvage therapy setting, and further evaluation is therefore warranted.

Tremelimumab and Temozolomide or Dacarbazine: A Phase III, Open-Label, Randomized, Comparative Study in Patients With Advanced Melanoma
This phase III study compared OS achieved with tremelimumab, a fully human anticytotoxic T lymphocyte–associated antigen 4 monoclonal antibody, with OS achieved with standard, single-agent chemotherapy.
Eligible patients had unresectable stage IIIc/IV melanoma without brain metastasis, LDH below 2 2 ULN, and no prior systemic treatment for advanced melanoma. Patients were randomized 1:1 to either tremelimumab 15 mg/kg IV every 90 days, or physician's choice of temozolomide 200 mg/m2 po on days 1-5 every 28 days or dacarbazine 1000 mg/m2 IV every 21 days (chemotherapy arm). Primary end point was OS, and secondary end points included response, durable tumor response, 6-month PFS, and safety. Two equally spaced interim analyses were planned based on the group sequential design using the Lan-DeMets alpha and beta spending approach to an O'Brien-Fleming boundary.

Between March 2006 and July 2007, 655 patients enrolled, with 328 patients randomized to tremelimumab (324 treated) and 327 to chemotherapy (319 treated). Significant imbalances were not noted in age, sex, LDH, or disease stage (5% stage IIIc, 15% M1a, 22% M1b, 58% M1c). The most common treatment-related adverse events in the tremelimumab arm were diarrhea (43% overall, 14% grade 3/4), pruritus (25%), and rash (23%). Pituitary or adrenal gland toxicities occurred in 3% of patients, and thyroid toxicities in 4%. There were three treatment-related deaths in the tremelimumab arm but none in the chemotherapy arm.

The independent DSMC advised researchers to end the study on March 28, 2008, because the log-rank test-statistic (P=0.729) had crossed the O'Brien-Fleming futility boundary based on a protocol-specified second interim analysis that reported 340 deaths. The ITT median OS was 11.8 months (95% CI, 10.4-13.9) in the tremelimumab arm and 10.7 months (95% CI, 9.3-12.0) in the chemotherapy arm, with a HR (chemotherapy over tremelimumab) of 1.04 (95% CI, 0.84-1.28).

Tremelimumab as a single agent failed to demonstrate an improvement in OS as a first-line treatment in patients with metastatic melanoma when compared with standard chemotherapy. Analysis of the secondary end points may yield additional information.

Ribas A, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract LBA9011.