Take Care,
Jimmy B
Showing posts with label melanoma therapies. Show all posts
Showing posts with label melanoma therapies. Show all posts
Friday, November 20, 2009
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
Take Care,
Jimmy B
Tuesday, June 9, 2009
Educational Teleconference: Update on Immunotheraphy of Melanoma - July 15, 2009..Melanoma..Jim Breitfeller
Please save this date!!!!!
Educational Teleconference: Update on Immunotheraphy of Melanoma - July 15, 2009
The teleconference will focus on the latest information on immunotherapies of melanoma. Whether you are newly diagnosed or are years after diagnosis, this program will provide quality information about melanoma. The conference is intended for patients with melanoma or friends or family member so that you have the information you need to understand melanoma from diagnosis, to treatment, to long term follow up.
Speaker: Jedd Wolchok, M.D., Ph.D.
Moderator: Lynn Schuchter, M.D.
Join us for a free teleconference, Update on Immunotherapy of Melanoma, from 1:00 pm to 2:00 pm Eastern Standard Time (EST) on July 15, 2009. After Dr. Wolchok’s presentation, there will be time for live question and answer period.
Dr. Jedd Wolchok, is an Assistant Attending Physician at Memorial Sloan-Kettering Cancer Center. Dr. Wolchok is a member of the faculty of Memorial Sloan-Kettering Cancer Center with expertise in the treatment of metastatic melanoma. His specific research interest is novel immunologic therapies and he has been involved in the development of the DNA vaccine program at every level, from pre-clinical studies in mouse models through clinical trials. He has authored numerous articles concerning DNA vaccines and clinical care of melanoma, and he co-authored two chapters in the definite textbook, Cutaneous Melanoma. Dr. Wolchok received his advanced education at New York University where he earned an M.D. as well as a Ph.D. in microbiology.
Dr. Lynn Schuchter is a Professor of Medicine. She is the Director of the Melanoma Program at the Abramson Cancer Center of the University of Pennsylvania as well as the Director of the Clinical Research Unit at the Cancer Center. Dr. Schuchter’s research focuses on a new approach to cancer treatment for patients with melanoma known as molecularly targeted therapy. Dr. Schuchter is also involved with numerous cancer vaccine trials. She is the Co-Principal Investigator of the Skin Cancer SPORE grant at the University of Pennsylvania/Wistar Institute. Dr. Schuchter completed her oncology fellowship at the John’s Hopkins Cancer Center. She joined the faculty of the University of Pennsylvania in 1989. Dr. Schuchter is on the Melanoma Research Foundation Board and is the Chair of the Scientific Advisory Board for the MRF.
After the presentation, Dr. Wolchok will answer your questions.
source:http://www.melanoma.org/upload/2142.pdf
Take Care,
Jimmy B
Educational Teleconference: Update on Immunotheraphy of Melanoma - July 15, 2009
The teleconference will focus on the latest information on immunotherapies of melanoma. Whether you are newly diagnosed or are years after diagnosis, this program will provide quality information about melanoma. The conference is intended for patients with melanoma or friends or family member so that you have the information you need to understand melanoma from diagnosis, to treatment, to long term follow up.
Speaker: Jedd Wolchok, M.D., Ph.D.
Moderator: Lynn Schuchter, M.D.
Join us for a free teleconference, Update on Immunotherapy of Melanoma, from 1:00 pm to 2:00 pm Eastern Standard Time (EST) on July 15, 2009. After Dr. Wolchok’s presentation, there will be time for live question and answer period.
Dr. Jedd Wolchok, is an Assistant Attending Physician at Memorial Sloan-Kettering Cancer Center. Dr. Wolchok is a member of the faculty of Memorial Sloan-Kettering Cancer Center with expertise in the treatment of metastatic melanoma. His specific research interest is novel immunologic therapies and he has been involved in the development of the DNA vaccine program at every level, from pre-clinical studies in mouse models through clinical trials. He has authored numerous articles concerning DNA vaccines and clinical care of melanoma, and he co-authored two chapters in the definite textbook, Cutaneous Melanoma. Dr. Wolchok received his advanced education at New York University where he earned an M.D. as well as a Ph.D. in microbiology.
Dr. Lynn Schuchter is a Professor of Medicine. She is the Director of the Melanoma Program at the Abramson Cancer Center of the University of Pennsylvania as well as the Director of the Clinical Research Unit at the Cancer Center. Dr. Schuchter’s research focuses on a new approach to cancer treatment for patients with melanoma known as molecularly targeted therapy. Dr. Schuchter is also involved with numerous cancer vaccine trials. She is the Co-Principal Investigator of the Skin Cancer SPORE grant at the University of Pennsylvania/Wistar Institute. Dr. Schuchter completed her oncology fellowship at the John’s Hopkins Cancer Center. She joined the faculty of the University of Pennsylvania in 1989. Dr. Schuchter is on the Melanoma Research Foundation Board and is the Chair of the Scientific Advisory Board for the MRF.
After the presentation, Dr. Wolchok will answer your questions.
source:http://www.melanoma.org/upload/2142.pdf
Take Care,
Jimmy B
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
author:
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."
source: http://www.skinandaging.com/content/melanoma-update-highlights-research-presented-asco-and-update-vaccines-trials
Melanoma Update: Highlights of research presented at ASCO and an update on vaccines trials
Take care
Jimmy B
Volume 17 - Issue 3 - March 2009
author:
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."
source: http://www.skinandaging.com/content/melanoma-update-highlights-research-presented-asco-and-update-vaccines-trials
Melanoma Update: Highlights of research presented at ASCO and an update on vaccines trials
Take care
Jimmy B
Wednesday, March 18, 2009
A Review of Treatments for Patients with Metastatic Melanoma..Jim Breitfeller
The educational objectives of this activity are:
1.)Describe existing standard treatments for metastatic melanoma
2.)Clarify the mechanisms of action of monoclonal antibodies
3.)Discuss recent clinical trial outcomes of Ipilimumab and Tremelimumab based treatments in metastatic melanoma
4.)Describe the side-effects of Ipilimumab and Tremelimumab as well as other treatments in patients with metastatic melanoma
Describe appropriate nursing management of patients receiving Ipilimumab and Tremelimumab
Disclosures of significant relationships for author and planning committee and sponsorship :
The author, Suzanne McGettigan, MSN, CRNP, is a speaker for the Amgen, Inc. speaker’s bureaus. Carolyn Vachani, MSN, AOCN and Margaret Hampshire, BSN, OCN (planning committee members) have no financial relationships to disclose. This activity is supported through an unrestricted educational grant from Bristol Myers Squibb.
Source:http://www.oncolink.org/resources/article.cfm?c=16&s=59&ss=224&id=972
A Review of Treatments for Patients with Metastatic Melanoma
Take care
Jimmy B
1.)Describe existing standard treatments for metastatic melanoma
2.)Clarify the mechanisms of action of monoclonal antibodies
3.)Discuss recent clinical trial outcomes of Ipilimumab and Tremelimumab based treatments in metastatic melanoma
4.)Describe the side-effects of Ipilimumab and Tremelimumab as well as other treatments in patients with metastatic melanoma
Describe appropriate nursing management of patients receiving Ipilimumab and Tremelimumab
Disclosures of significant relationships for author and planning committee and sponsorship :
The author, Suzanne McGettigan, MSN, CRNP, is a speaker for the Amgen, Inc. speaker’s bureaus. Carolyn Vachani, MSN, AOCN and Margaret Hampshire, BSN, OCN (planning committee members) have no financial relationships to disclose. This activity is supported through an unrestricted educational grant from Bristol Myers Squibb.
Source:http://www.oncolink.org/resources/article.cfm?c=16&s=59&ss=224&id=972
A Review of Treatments for Patients with Metastatic Melanoma
Take care
Jimmy B
Tuesday, February 3, 2009
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.
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.
Friday, January 30, 2009
Lessons From Three Decades of Clinical Trials in Metastatic Melanoma..Jim Breitfeller
Vernon K. Sondak, MD
Chief, Division of Cutaneous Oncology
Director, Surgical Education
H. Lee Moffitt Cancer Center & Research Institute
Professor
Departments of Interdisciplinary Oncology and Surgery
University of South Florida College of Medicine
Tampa, FL
Fifth International Symposium on Melanoma
and Other Cutaneous Malignancies
New York, New York
March 7, 2008
LESSON 1
There has been no significant improvement in overall
survival for metastatic melanoma in the past 30 years
This Is a Hard Lesson to Swallow!!!!!!!!!!!!!!!!
Please don't shoot the messenger!!!!!!
The good news is the 1971 to 2001!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
So this is the new begining with targeted therapy I believe!!!!!!!
Lessons From Three Decades of Clinical Trials in Metastatic Melanoma
Chief, Division of Cutaneous Oncology
Director, Surgical Education
H. Lee Moffitt Cancer Center & Research Institute
Professor
Departments of Interdisciplinary Oncology and Surgery
University of South Florida College of Medicine
Tampa, FL
Fifth International Symposium on Melanoma
and Other Cutaneous Malignancies
New York, New York
March 7, 2008
LESSON 1
There has been no significant improvement in overall
survival for metastatic melanoma in the past 30 years
This Is a Hard Lesson to Swallow!!!!!!!!!!!!!!!!
Please don't shoot the messenger!!!!!!
The good news is the 1971 to 2001!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
So this is the new begining with targeted therapy I believe!!!!!!!
Lessons From Three Decades of Clinical Trials in Metastatic Melanoma
Wednesday, January 14, 2009
A Reply back from DR. Markovic, Svetomir N., M.D., Ph.D. ON Emerging Therapies for Melanoma ..Jim Breitfeller
Emerging Therapies for Melanoma
Rajini Katipamula; Svetomir N Markovic
Expert Rev Anticancer Ther. 2008;8(4):553-560.
Posted 07/09/2008
Dear Mr. Breitfeller,
Thank you for your note.
I just got back from a trip and am catching up with e-mail. I must say, I really enjoyed reading your message.
Our thoughts on the matter (as summarized in my brief article you noted) are basically that there are 3 elements to the puzzle that need to be addressed:
(1) the tumor; (2) its vascular supply; and (3) the body's immune system.
Addressing each one of these alone, will only gain little benefits for most, transient benefits for some and awesome results in a lucky few patients. So, why not look at the problem in the context of the patient.
And, that is basically where we are right now. We are crafting therapies that will engage all 3 elements; we measure the impact on all 3 and gain insights into what's working, what's not, and what we need to do next.
The first study we did using this approach was just published in Cancer this month. And, we did reasonably well for the majority of patients (best progression free survival result in a single arm phase II study done by the US cooperative groups in patients with metastatic melanoma).
What was most interesting is that we learned that the drugs we used may have worked in a completely different mechanism... The combination of chemotherapy and an inhibitor of angiogenesis may have yielded the good clinical outcomes via an immunological mechanism (paper in preparation).
I think that there may be something to this, and we'll keep plugging on this path. Hopefully we will be able to lend some insights that may be helpful to our patients and colleagues.
Take care,
Svetomir
--------------------------------------------------------------------------------
From: dbreitfe [mailto:dbreitfe@rochester.rr.com]
Sent: Monday, January 05, 2009 8:28 AM
To: Markovic, Svetomir N., M.D., Ph.D.
Subject: permission to post on Carepages "Emerging Therapies for Melanoma"
Svetomir, I am a cancer patient under the care of John M Kirkwood at the Hillman Cancer Center. I think you paper is very fascinating. Let me give you a little back ground of my dealings with Melanoma:
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. I asked my wife to take a look at it. It was just a mole. So I decide to go to the dermatologist. To make the log story short, it was cancer. It took about a month and a half to get it biopsied . (Sept. 26 2005) I contacted a surgical oncologist and on October 27 2005 I had a wide incision to remove the tumor off my back. I also had a PET scan and a sentinel lymph node biopsy done and it showed no cancer except the localized one on my back. 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. They all recommended to start with Interferon treatment. In the meantime, my back got infected and it took until Feb. 14 2006 to heal. On March 6 2006, I started the High Dose Interferon treatment that was to last 4 weeks with daily infusions. The treatment lasted only 2 ½ weeks because my blood sugar went completely out of control. I also have type 2 diabetes.
About 2 weeks after the interferon treatments, I noticed my right lymph node growing to golf ball size and they were aching. I had them biopsied (April 4 2006) and 9 out of 11 nodes were cancerous. On April 24th , I had my lump nodes removed under my right arm. This had move me from a stage 3 to a stage 4. The cancer was spreading quite rapidly. Strong did not have any specialists in the field of malignant melanoma. So, I was in contact with Dr. John Kirkwood in Pittsburgh. So with my oncologist approval, my wife and I went down to Pittsburgh and had a consultation with Dr. Kirkwood (June 12, 2006) Kirkwood wanted another PET scan (June 16 2006) to see if the cancer was contained to my lymph nodes. The results showed 4 tumors on my back, one under my right arm, and two spots, one in each lobe of my lungs. It wasn’t good.
So, On July 10, 2006, I started my clinical trial of Dicarbazine and Patrin cycle 1. Each cycle is 21 days. On day 3, I am injected with dicarbazine at the Hillman Cancer Center in Pittsburgh. On the 11th day I go back to have a check up. Twice a month I traveled to Pittsburgh at least with this trial. I started my 2nd cycle on July 31 2006. On August 17 I had a CT scan and the report showed new tumors in my lungs so they stopped the Dicarbazine trial.
On September 6th, I had another CT scan and MRI for the next trial which was Anti-CTLA-4. On September 13 I had my first infusion. On October 8, 2006 My wife noticed two new growths on my back. It was confirmed on October 11th it was new tumors.
Dr. John Kirkwood has decided that IL 2 Interlukin 2 would be next course of action. I have completed another round of tests (CT scan, Pulmonary Function, and a Nuclear Stress Test). The CT scans shows 40+ nodules in my lungs ranging from 15mm to less than 5mm.
I am slated to be High dosage IL-2 on November 1st 2006.
I am presently washed out an IL-2 clinical trial that started in November 1, 2006. On the fourth cycle I had a heart attack and the doctors determined to abort the IL-2 on February 2, 2007. On August 23 2007 there was no change to the tumors in my back or lungs but also no growth. In October 24 2007 I got the word that the tumors and the lung nodules were shrinking. In April 14, 2008, the 40 + nodules in my lungs decrease to 2. In July 2008, the nodules in my lungs were undetectable and the ones on my back were all but one gone. Presently, CT and MRI
In November 2008 show no signs cancerous activity. I am stabilized for the time being.
As you can see I did the CTLA-4, one dose and then went on to IL-2 until I had a heart attack. Base on your 5 year View, in my case, my overall survival rate has doubled so far.
“Five-year View”
“Several advances are being made in the field of immunological and targeted therapies. In our opinion, the agents of most interest in the next 5 years would be the anti-CTLA-4 antibodies and angiogenesis inhibitors combined with cytotoxic therapy. While most of these novel agents may not have significant single-agent activity, combining them with systemic chemotherapy might be the key to clinical success in melanoma. Ultimately, rational combination therapeutics of multimodal targeting agents (immunotherapeutics, cytotoxic therapy, angiogenesis inhibitors) will likely lead to substantive clinical benefit in this patient population. Our hope is that this massive clinical research endeavor will soon yield the long sought after improvement in the overall survival of patients with advanced melanoma.”
Being a researcher myself, I came up with a theory.
11/06/08 This is my Theory
Posted Nov 6, 2008 9:59am
11/06/08 This is my Theory
The Interlukin-2
IL-2, which works by stimulating killer T-cells to attack melanoma. In some cases with the right body chemistry, helps communicate that message to the killer T-cells and the body begins to fight off the Beast.
In other cases, your body chemistry is different than mine and may lack some sort protein/? or what ever. So in this case, the communication is lost like a drop signal from your cell phone. What you need is another Cell Tower to transmit that signal. That is where CTLA-4 coming in to play. It builds the tower to help with the communication. I may be over simplifying the biochemistry but I am not in the lab to do the right experiments. So, I have to take an educated guess.
So, I did a little online research
As you can see, Dr. Kirkwood and I wanted to induce tumor regression by using my own immune system. If we could get my immune system to recognize the tumors as foreign, then we might have a fighting chance.
So we decide to try the CTLA-4 Therapy, Antitumor response with prolonged time to progression has been seen in patients with melanoma who have received either of the CTLA-4 antibodies and durable antitumor responses have been observed with ipilimumab in patients with melanoma ovarian cancer, prostate cancer, and renal cell carcinoma It has been seen, antitumor responses may be characterized by short-term progression followed by delayed regression.
An important, possibly unique, clinical characteristic of anti-CTLA-4 antibodies is that the duration of clinical response -- and even stable disease -- is often quite prolonged.
This is what I believe is going on in my case but I have no proof.
So lets combine the two clinical trials and that was done by Dr. Rosenberg at the National Cancer Institute. This did not yield the Better outcome.
I think it is because doing the therapy at the same time my be jamming the signals or changing the micro-chemical in the cell and surrounding environment so that it is not inductive to passing on the communication cell to cell.. protein to protein .
But since there was a lag between my two therapies, My cells began to communicate and jump started my immune system. Do I think is a one off, NO!!!!! I have been in touch with another patient that did IL-2 then, CTLA-4 and got the same response. The trick is to get the timing and the dose right!!!!!
So I took it apon myself to to a little research and this is what I came up with. I believe it all makes sense. I still may be over simplifying the actual process but I am not a biochemist. So Here goes:
Dendritic cells (DCs) are immune cells and form part of the our immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system, thus functioning as Antigen-Presenting Cells (APC).
The dendritic cells are constantly in communication with other cells in the body. This communication can take the form of direct cell-to-cell contact based on the interaction of cell-surface proteins. An example of this includes the interaction of the receptor B7 of the dendritic cell with CD28 present on the lymphocyte. However, the cell-cell interaction can also take place at a distance via cytokines. These components of the immune system communicate with one another by exchanging chemical messengers. These proteins are secreted by cells and act on other cells to coordinate an appropriate immune response.
Cytokines include a diverse assortment of interleukins, interferons, and growth factors.One cytokine, interleukin 2 (IL-2), triggers the immune system to produce T cells. IL-2’s immunity-boosting properties have traditionally made it a promising treatment for several illnesses which include Hepatitis C and Melanoma.
There are several steps to activation of the immune system against a foreign molecule. The T cell receptor must first interact with the MHC molecule. The T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells) that is, in general, responsible for recognizing antigens bound to Major Histocompatibility Complex (MHC) molecules. MHC the most gene-dense region of the Human genome and plays an important role in the immune system, autoimmunity.
This first interaction involves the CD4 or CD8 proteins which form a complex with the CD3 protein to bind to the MHC molecule of the (APC). Antigen-presenting cell This is also called "Signal 1" and its main purpose is T cell activation.
However, this is insufficient for producing a T cell response by itself. In fact, lack of further stimulatory signals sends the T cell into anergy. Anergy is a term in immunobiology that describes a lack of reaction by the body's defense mechanisms to foreign substances.
The Second costimulatory signal necessary to continue the immune response can come from B7-CD28 and CD40-CD40L interactions. The primary role of the B7 proteins is to give a second signal to the T cell. The B7 protein/receptor is present on the Antigen-presenting cell and is able to interact with the CD28 receptor on the T cell surface; this is also known as "Signal 2". There are other activation signals which play a role in immune responses.
On these T cells there is are family receptors whose job is downregulate the T cell activation so the immune system maintains metabolic equilibrium so the immune system doesn’t start an autoimmune response and cause it to attack itself. One of these receptors is Cytotoxic T lymphocyte-associated antigen (CTLA4).
It was hypothesized back in the 1980’s that if you replaced the CTLA4 with Anti-CTLA4 that it might block the B7 receptor causing an enhancement of the T-cell activation, leading to a more robust antitumor immune response.
It was shown in mice with a disrupted CTLA-4 genes that their immune response ran unabated causing autoimmunity which was fatal.
It was also shown that the anti-CTLA-4 antibodies had a greater affinity to CTLA-4 than the B7 receptor. So by doing the CTLA-4 Therapy, it allowed signal 1 to become active.
So in the presents of the CTLA-4 antibody Therapy, I my case, we may have extended the antitumor response of the T-cells. This left Signal 1 active.
We then, hit the immune system with High dose of IL-2. This must have stimulated the cell to cell communication (Signal 2) causing the immune response to kick in against the foreign molecule (The Tumor)
AS YOU GUESSED IT, I MUST HAVE JUMP STARTED MY IMMUNE SYSTEM!!!!!!
Just don't know how long it will last.
AS you can see , I am passionate about finding a cure. My Life depends on it. So if I can pass along information that may help others, I do. And that is why I am asking for your Permission on post this information.
I hope to here from you soon
Thanks for your time and Keep the good research coming!!!!
Sincerely,
James M. Breitfeller
The information contained is intended for the confidential use of the intended recipient(s) only and may be legally privileged. If it has been received other than by an intended recipient, it may not be reviewed, disseminated, distributed, copied or retained. Therefore, please notify the sender immediately and delete the original message and all copies.
Thank you
James M. Breitfeller
Rajini Katipamula; Svetomir N Markovic
Expert Rev Anticancer Ther. 2008;8(4):553-560.
Posted 07/09/2008
Dear Mr. Breitfeller,
Thank you for your note.
I just got back from a trip and am catching up with e-mail. I must say, I really enjoyed reading your message.
Our thoughts on the matter (as summarized in my brief article you noted) are basically that there are 3 elements to the puzzle that need to be addressed:
(1) the tumor; (2) its vascular supply; and (3) the body's immune system.
Addressing each one of these alone, will only gain little benefits for most, transient benefits for some and awesome results in a lucky few patients. So, why not look at the problem in the context of the patient.
And, that is basically where we are right now. We are crafting therapies that will engage all 3 elements; we measure the impact on all 3 and gain insights into what's working, what's not, and what we need to do next.
The first study we did using this approach was just published in Cancer this month. And, we did reasonably well for the majority of patients (best progression free survival result in a single arm phase II study done by the US cooperative groups in patients with metastatic melanoma).
What was most interesting is that we learned that the drugs we used may have worked in a completely different mechanism... The combination of chemotherapy and an inhibitor of angiogenesis may have yielded the good clinical outcomes via an immunological mechanism (paper in preparation).
I think that there may be something to this, and we'll keep plugging on this path. Hopefully we will be able to lend some insights that may be helpful to our patients and colleagues.
Take care,
Svetomir
--------------------------------------------------------------------------------
From: dbreitfe [mailto:dbreitfe@rochester.rr.com]
Sent: Monday, January 05, 2009 8:28 AM
To: Markovic, Svetomir N., M.D., Ph.D.
Subject: permission to post on Carepages "Emerging Therapies for Melanoma"
Svetomir, I am a cancer patient under the care of John M Kirkwood at the Hillman Cancer Center. I think you paper is very fascinating. Let me give you a little back ground of my dealings with Melanoma:
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. I asked my wife to take a look at it. It was just a mole. So I decide to go to the dermatologist. To make the log story short, it was cancer. It took about a month and a half to get it biopsied . (Sept. 26 2005) I contacted a surgical oncologist and on October 27 2005 I had a wide incision to remove the tumor off my back. I also had a PET scan and a sentinel lymph node biopsy done and it showed no cancer except the localized one on my back. 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. They all recommended to start with Interferon treatment. In the meantime, my back got infected and it took until Feb. 14 2006 to heal. On March 6 2006, I started the High Dose Interferon treatment that was to last 4 weeks with daily infusions. The treatment lasted only 2 ½ weeks because my blood sugar went completely out of control. I also have type 2 diabetes.
About 2 weeks after the interferon treatments, I noticed my right lymph node growing to golf ball size and they were aching. I had them biopsied (April 4 2006) and 9 out of 11 nodes were cancerous. On April 24th , I had my lump nodes removed under my right arm. This had move me from a stage 3 to a stage 4. The cancer was spreading quite rapidly. Strong did not have any specialists in the field of malignant melanoma. So, I was in contact with Dr. John Kirkwood in Pittsburgh. So with my oncologist approval, my wife and I went down to Pittsburgh and had a consultation with Dr. Kirkwood (June 12, 2006) Kirkwood wanted another PET scan (June 16 2006) to see if the cancer was contained to my lymph nodes. The results showed 4 tumors on my back, one under my right arm, and two spots, one in each lobe of my lungs. It wasn’t good.
So, On July 10, 2006, I started my clinical trial of Dicarbazine and Patrin cycle 1. Each cycle is 21 days. On day 3, I am injected with dicarbazine at the Hillman Cancer Center in Pittsburgh. On the 11th day I go back to have a check up. Twice a month I traveled to Pittsburgh at least with this trial. I started my 2nd cycle on July 31 2006. On August 17 I had a CT scan and the report showed new tumors in my lungs so they stopped the Dicarbazine trial.
On September 6th, I had another CT scan and MRI for the next trial which was Anti-CTLA-4. On September 13 I had my first infusion. On October 8, 2006 My wife noticed two new growths on my back. It was confirmed on October 11th it was new tumors.
Dr. John Kirkwood has decided that IL 2 Interlukin 2 would be next course of action. I have completed another round of tests (CT scan, Pulmonary Function, and a Nuclear Stress Test). The CT scans shows 40+ nodules in my lungs ranging from 15mm to less than 5mm.
I am slated to be High dosage IL-2 on November 1st 2006.
I am presently washed out an IL-2 clinical trial that started in November 1, 2006. On the fourth cycle I had a heart attack and the doctors determined to abort the IL-2 on February 2, 2007. On August 23 2007 there was no change to the tumors in my back or lungs but also no growth. In October 24 2007 I got the word that the tumors and the lung nodules were shrinking. In April 14, 2008, the 40 + nodules in my lungs decrease to 2. In July 2008, the nodules in my lungs were undetectable and the ones on my back were all but one gone. Presently, CT and MRI
In November 2008 show no signs cancerous activity. I am stabilized for the time being.
As you can see I did the CTLA-4, one dose and then went on to IL-2 until I had a heart attack. Base on your 5 year View, in my case, my overall survival rate has doubled so far.
“Five-year View”
“Several advances are being made in the field of immunological and targeted therapies. In our opinion, the agents of most interest in the next 5 years would be the anti-CTLA-4 antibodies and angiogenesis inhibitors combined with cytotoxic therapy. While most of these novel agents may not have significant single-agent activity, combining them with systemic chemotherapy might be the key to clinical success in melanoma. Ultimately, rational combination therapeutics of multimodal targeting agents (immunotherapeutics, cytotoxic therapy, angiogenesis inhibitors) will likely lead to substantive clinical benefit in this patient population. Our hope is that this massive clinical research endeavor will soon yield the long sought after improvement in the overall survival of patients with advanced melanoma.”
Being a researcher myself, I came up with a theory.
11/06/08 This is my Theory
Posted Nov 6, 2008 9:59am
11/06/08 This is my Theory
The Interlukin-2
IL-2, which works by stimulating killer T-cells to attack melanoma. In some cases with the right body chemistry, helps communicate that message to the killer T-cells and the body begins to fight off the Beast.
In other cases, your body chemistry is different than mine and may lack some sort protein/? or what ever. So in this case, the communication is lost like a drop signal from your cell phone. What you need is another Cell Tower to transmit that signal. That is where CTLA-4 coming in to play. It builds the tower to help with the communication. I may be over simplifying the biochemistry but I am not in the lab to do the right experiments. So, I have to take an educated guess.
So, I did a little online research
As you can see, Dr. Kirkwood and I wanted to induce tumor regression by using my own immune system. If we could get my immune system to recognize the tumors as foreign, then we might have a fighting chance.
So we decide to try the CTLA-4 Therapy, Antitumor response with prolonged time to progression has been seen in patients with melanoma who have received either of the CTLA-4 antibodies and durable antitumor responses have been observed with ipilimumab in patients with melanoma ovarian cancer, prostate cancer, and renal cell carcinoma It has been seen, antitumor responses may be characterized by short-term progression followed by delayed regression.
An important, possibly unique, clinical characteristic of anti-CTLA-4 antibodies is that the duration of clinical response -- and even stable disease -- is often quite prolonged.
This is what I believe is going on in my case but I have no proof.
So lets combine the two clinical trials and that was done by Dr. Rosenberg at the National Cancer Institute. This did not yield the Better outcome.
I think it is because doing the therapy at the same time my be jamming the signals or changing the micro-chemical in the cell and surrounding environment so that it is not inductive to passing on the communication cell to cell.. protein to protein .
But since there was a lag between my two therapies, My cells began to communicate and jump started my immune system. Do I think is a one off, NO!!!!! I have been in touch with another patient that did IL-2 then, CTLA-4 and got the same response. The trick is to get the timing and the dose right!!!!!
So I took it apon myself to to a little research and this is what I came up with. I believe it all makes sense. I still may be over simplifying the actual process but I am not a biochemist. So Here goes:
Dendritic cells (DCs) are immune cells and form part of the our immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system, thus functioning as Antigen-Presenting Cells (APC).
The dendritic cells are constantly in communication with other cells in the body. This communication can take the form of direct cell-to-cell contact based on the interaction of cell-surface proteins. An example of this includes the interaction of the receptor B7 of the dendritic cell with CD28 present on the lymphocyte. However, the cell-cell interaction can also take place at a distance via cytokines. These components of the immune system communicate with one another by exchanging chemical messengers. These proteins are secreted by cells and act on other cells to coordinate an appropriate immune response.
Cytokines include a diverse assortment of interleukins, interferons, and growth factors.One cytokine, interleukin 2 (IL-2), triggers the immune system to produce T cells. IL-2’s immunity-boosting properties have traditionally made it a promising treatment for several illnesses which include Hepatitis C and Melanoma.
There are several steps to activation of the immune system against a foreign molecule. The T cell receptor must first interact with the MHC molecule. The T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells) that is, in general, responsible for recognizing antigens bound to Major Histocompatibility Complex (MHC) molecules. MHC the most gene-dense region of the Human genome and plays an important role in the immune system, autoimmunity.
This first interaction involves the CD4 or CD8 proteins which form a complex with the CD3 protein to bind to the MHC molecule of the (APC). Antigen-presenting cell This is also called "Signal 1" and its main purpose is T cell activation.
However, this is insufficient for producing a T cell response by itself. In fact, lack of further stimulatory signals sends the T cell into anergy. Anergy is a term in immunobiology that describes a lack of reaction by the body's defense mechanisms to foreign substances.
The Second costimulatory signal necessary to continue the immune response can come from B7-CD28 and CD40-CD40L interactions. The primary role of the B7 proteins is to give a second signal to the T cell. The B7 protein/receptor is present on the Antigen-presenting cell and is able to interact with the CD28 receptor on the T cell surface; this is also known as "Signal 2". There are other activation signals which play a role in immune responses.
On these T cells there is are family receptors whose job is downregulate the T cell activation so the immune system maintains metabolic equilibrium so the immune system doesn’t start an autoimmune response and cause it to attack itself. One of these receptors is Cytotoxic T lymphocyte-associated antigen (CTLA4).
It was hypothesized back in the 1980’s that if you replaced the CTLA4 with Anti-CTLA4 that it might block the B7 receptor causing an enhancement of the T-cell activation, leading to a more robust antitumor immune response.
It was shown in mice with a disrupted CTLA-4 genes that their immune response ran unabated causing autoimmunity which was fatal.
It was also shown that the anti-CTLA-4 antibodies had a greater affinity to CTLA-4 than the B7 receptor. So by doing the CTLA-4 Therapy, it allowed signal 1 to become active.
So in the presents of the CTLA-4 antibody Therapy, I my case, we may have extended the antitumor response of the T-cells. This left Signal 1 active.
We then, hit the immune system with High dose of IL-2. This must have stimulated the cell to cell communication (Signal 2) causing the immune response to kick in against the foreign molecule (The Tumor)
AS YOU GUESSED IT, I MUST HAVE JUMP STARTED MY IMMUNE SYSTEM!!!!!!
Just don't know how long it will last.
AS you can see , I am passionate about finding a cure. My Life depends on it. So if I can pass along information that may help others, I do. And that is why I am asking for your Permission on post this information.
I hope to here from you soon
Thanks for your time and Keep the good research coming!!!!
Sincerely,
James M. Breitfeller
The information contained is intended for the confidential use of the intended recipient(s) only and may be legally privileged. If it has been received other than by an intended recipient, it may not be reviewed, disseminated, distributed, copied or retained. Therefore, please notify the sender immediately and delete the original message and all copies.
Thank you
James M. Breitfeller
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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.
Jimmy and Dee
Carepage: Jimmybreitfeller
Jimmy Breitfeller
It was he, who showed me How to live and give back. He was wise beyond his years.
Jimmy and Dee
Carepage: Jimmybreitfeller
Jimmy Breitfeller
My Profile as of 2009
- jimmy_B
- 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
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
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.
http://www.melanomaresearchalliance.org/news/PSA/
Source Fastcures blog
"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
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.
http://www.melanomaresearchalliance.org/news/PSA/
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!!!
Sincerely,
Jimmy Breitfeller