http://www.sciencedaily.com/releases/2009/07/090701183003.htm

The Latest from the

·         Skin-Cancer Drug Uses Genetics

·         New vaccine shows promise in treating melanoma

·         Plexxikon Announces PLX4032 Phase 1 Data Showing Objective Responses In Metastatic Melanoma Patients

·         Cancer Patients Want Genetic Testing To Predict Metastasis Risk

·         Advanced Melanoma: Vaccine Shows Therapeutic Promise

·         Provectus Reports Encouraging Clinical Data At ASCO On Treatment Of Metastatic Melanoma With PV-10

·         Proteolix Presents Positive Clinical Data For Carfilzomib In Multiple Myeloma At The 2009 ASCO Annual Meeting

·         New Cancer Vaccines Show Promising Results for Melanoma and Lymphoma

Skin-Cancer Drug Uses Genetics

Wall Street Journal (full article available for purchase)

ORLANDO, Fla. -- Results from a small, early-stage clinical trial suggest the burgeoning strategy of attacking tumors based on their genetic characteristics could soon yield effective drugs against advanced melanoma, one of cancer's most lethal and hard-to-treat conditions.

Researchers reported that nine of 16 patients with the malignant skin cancer experienced significant shrinkage of their tumors when given a drug known as PLX4032. Tumors in all of the patients had a mutation in a gene for a protein called BRAF that is believed to play a crucial role in up to 60% of patients with the cancer.

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New vaccine shows promise in treating melanoma

Kare11.com | Twin Cities, MN

It targets cells, shrinks tumors, and cuts the chances that cancer will return: A new vaccine unveiled this week at a national oncology conference is showing success in treating melanoma.

"Melanoma is a subtype that can be quite dangerous," said Dr. Harold Londer, medical director at the Humphrey Cancer Center at North Memorial Hospital in Robbinsdale. "Especially when it's metastasized, once it's spread, melanoma has been resistant to traditional therapy."

Scientists have worked on cancer vaccines for decades. But this time, they gave patients a vaccine with interleukin-2, which stimulates the immune system. And in a large clinical trial, 22 percent of patients saw their tumors shrink.

The Humphrey Cancer Center has held a similar study with similar results. But doctors there caution that while this progress is promising, it's not a sign that we're close to curing cancer, a disease they call unpredictable and complicated since it takes so many forms.

"It's not just one disease. We know that," Londer said. "There are cancers that are extremely sensitive to traditional chemotherapies, like Hodgkins Disease. There are others where it's been unsuccessful,like melanoma."

Dr. Tom Amatruda is a leader in the Humphrey study. He says just as cancer affects people differently, so do vaccines, and their goal now is to narrow down which types of patients and which types of cancers benefit most.

"There are some people who might only have a nine or 10 percent chance of response," Amatruda said. "Some people have a 50 percent chance of response. So we're targeting it more to those people."

And that could be the vaccine's biggest success. While it may not be a cure for cancer, it could be a clue. The vaccine stopped cancer from spreading for about six additional weeks compared to patients who were not treated.

Scientists hope they can use that as a starting point to build other vaccines that will be more effective.

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Plexxikon Announces PLX4032 Phase 1 Data Showing Objective Responses In Metastatic Melanoma Patients

Medical News Today

Plexxikon Inc. today announced preliminary data from a Phase 1 clinical study investigating PLX4032 (R7204). PLX4032 is a novel, oral and highly selective drug that targets the BRAFV600E cancer-causing mutation that occurs in most melanomas and about eight percent of all solid tumors. In patients whose cancer harbors this mutation and who were treated with therapeutic doses of PLX4032, tumor shrinkage and extended progression-free survival have been observed. Currently, two extension studies are being conducted in mutation-positive melanoma and colorectal cancer patients. Following the initial positive findings announced today, larger clinical trials to support a registration program for product approval are targeted to start later in 2009. Plexxikon and Roche are co-developing PLX4032 under their 2006 license and collaboration agreement.

"PLX4032 has shown both tumor shrinkage and delay in tumor progression in patients whose tumors harbor a BRAF mutation as well as reports of clinical symptom improvement in some patients," stated Keith T. Flaherty, M.D., assistant professor at the Abramson Cancer Center of the University of Pennsylvania and principal investigator for the PLX4032 Phase 1 clinical trial. "Seven years after BRAF mutations were first identified, we have validation that this mutation is a cancer driver and therapeutic target. This is a new and important chapter in the story of targeted therapy development in cancer, and we are especially excited for our melanoma patients, for whom there are currently few treatment options." Link to video clip of Dr. Flaherty

In the dose escalation phase of the study, 55 cancer patients have been treated, including 24 mutation-positive melanoma patients and 3 mutation-positive thyroid patients, as well as 28 melanoma, rectal and ovarian cancer patients who did not have the mutation or whose mutation status was not known.

In 16 BRAF mutation-positive melanoma patients treated with PLX4032 doses at or above 240 mg twice daily (BID), representing targeted drug exposure levels, data show:

- PLX4032 is well tolerated at very high doses, with 960 mg BID under evaluation as the maximum tolerated dose

- Partial responses in 9 patients showing greater than 30% tumor regression by RECIST (Response Evaluation Criteria in Solid Tumors) criteria, with 7 confirmed

- Regression of metastatic lesions in every site to which melanoma commonly spreads, including liver, lung and bone

- Minor responses in 4 patients showing tumor regression greater than 10% but less than 30%

- Disease control lasting up to 14 months with continuous therapy, with many patients still receiving treatment

- Interim median progression-free survival of at least six months, with many responding patients still receiving treatment

By contrast, no treatment response was observed in a small group of patients without the mutation, and progression-free survival was less than 2 months, consistent with historical data.

Dose-limiting toxicities, primarily rash, fatigue and joint pains, were seen at 1120 mg BID. Drug-related adverse events have been predominantly mild in severity and transient, including rash and photosensitivity. Serious adverse events were observed in some patients after chronic treatment, including possibly drug-related cutaneous squamous cell carcinoma. A risk management plan has been implemented for baseline evaluation of the skin and monitoring of all patients while on study. Cutaneous squamous cell carcinoma is typically excised by a patient's dermatologist.

"This is a significant day for us at Plexxikon. The clinical data for PLX4032 so far support our hypothesis that a truly selective drug can target tumors harboring this cancer-causing mutation, while at the same time, deliver a treatment that is well tolerated by patients," stated K. Peter Hirth, Ph.D., chief executive officer of Plexxikon. "In conjunction with bio-response markers and a companion diagnostic test, PLX4032 has all the hallmarks of an ideal personalized medicine. Plexxikon's pipeline includes several highly selective kinase inhibitors, including novel therapies for other cancers as well as other chronic diseases such as rheumatoid arthritis where such precision is anticipated to provide a safety advantage."

Companion Diagnostic in Parallel Development

Along with the development of PLX4032 therapy, a diagnostic test to identify patients with the BRAF mutation is being co-developed by Plexxikon and Roche, under a separate 2005 agreement. This test is already being used to identify mutation-positive patients for ongoing clinical trials. Most importantly, this companion diagnostic enables the identification of mutation-positive cancer patients considered most likely to respond to PLX4032 treatment.

Exploring PLX4032 in Colorectal and Other Cancers

The prevalence of the BRAF mutation is about eight percent of all solid tumors. Preclinical studies in colorectal cancer models also suggest that PLX4032 causes tumor regression, either as a single agent or in combination. Hence, future clinical trials may evaluate PLX4032 in tumor types beyond melanoma.

Currently, one of two extension cohorts is recruiting mutation-positive colorectal cancer patients in order to evaluate PLX4032 in this target population. In a retrospective study of 600 patients with colorectal cancer, including all stages and both genders, tumor tissue was tested for the presence of the BRAF mutation and correlated with outcomes. The data confirmed that approximately 10 percent of colorectal cancer patients carry this mutation, which is independent of the KRAS mutation, and those BRAF mutation-positive patients have a much poorer prognosis than patients with wild-type BRAF (ASCO 2009 Abstract #1103).

Additionally, in the Phase 1 dose escalation study which enrolled patients with several different tumor types, one mutation-positive thyroid patient showed a confirmed partial response, while two others showed stable disease with prolonged therapy.

Biomarkers Enhance Development of Personalized Medicine

The development of PLX4032 has employed a variety of translational tools, including bio-response markers and an in vitro diagnostic test. These tools can potentially enable early detection of targeted pathway modulation and treatment response, as well as identification of the targeted patient population for this treatment.

Biomarker data from patient tumor biopsies before and after PLX4032 treatment showed early target modulation and when dosed at higher levels, have shown nearly complete inhibition of the desired target (ASCO 2009 Abstract #9021).

About PLX4032 (R7204)-A Personalized Medicine for Cancer Treatment

PLX4032 is a novel, oral small molecule for the treatment of melanoma and other cancers harboring the V600E mutation of the BRAF kinase gene. This defect is present in approximately 60 percent of melanoma skin cancers, and occurs in about eight percent of all solid tumors, including melanoma, colorectal, thyroid and other cancers. Preclinical data suggest that Plexxikon's novel anti-cancer compound selectively targets and inhibits tumor cells which contain this cancer-causing mutation. In contrast to many other kinase inhibitors available, PLX4032 is highly selective for its primary target, and does not have significant activity on other kinase targets.

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Cancer Patients Want Genetic Testing To Predict Metastasis Risk

Medical News Today

If you had cancer and a genetic test could predict the risk of the tumor spreading aggressively, would you want to know - even if no treatments existed to help you?

An overwhelming majority of eye cancer patients would answer yes, according to a new UCLA study published in the June edition of the Journal of Genetic Counseling.

"Our goal was to explore what people with cancer want," explained Dr. Tara McCannel, director of the Ophthalmic Oncology Center at UCLA's Jules Stein Eye Institute and a Jonsson Comprehensive Cancer Center researcher. "We learned that patients want to know their prognosis, good or bad, even when there are no treatments at present for their condition."

The UCLA study surveyed 99 patients who had been diagnosed with ocular melanoma, which develops in the pigmented layers under the retina. Half of the patients had undergone localized radiation to shrink the tumor. The rest of the group also underwent radiation, but first had cells biopsied from their tumors. These cells were grown in culture and studied for a missing copy of chromosome 3 - the genetic marker most strongly linked to rapid metastatic disease.

Patients whose tumors contain the genetic marker have at least a 50 percent chance of death within five years, due to swift spreading of the tumor to the liver and other organs. Aggressive cases can result in blindness and death in as quickly as a year.

In the UCLA study, all patients were asked to evaluate their interest in receiving genetic testing results related to prognosis. A whopping 98 patients responded that they would have wanted predictive testing at the time of their treatment. Only one patient declined.

Additionally, 98 percent of the respondents stated that supportive counseling should be offered when patients receive their test results.

"We were surprised to see such a unanimous response," admitted McCannel. "We expected some patients would prefer not to know, but the numbers consistently said otherwise."

"People understand that no good treatment currently exists after their cancer spreads. Everyone wants to know what their risk is for metastasis," said coauthor Annette Stanton, UCLA professor of psychology, psychiatry and biobehavioral sciences. "If the risk is low, it's a huge relief and emotional burden off patients' shoulders. If the risk is high, it enables patients to plan arrangements for their family and finances and make the most of their time alive."

The UCLA survey also measured quality of life and depression symptoms in patients who received genetic test results and compared their rankings to those of untested patients.

"Regardless of their test result, all of the patients rated themselves about the same in terms of quality of life and emotional well-being," said Stanton, who is also a Jonsson Cancer Center member. "We hope that these findings reduce clinical resistance and pave the way for prognostic testing to become the standard of care in the management of ocular melanoma."

"The issue of genetic testing has been a huge source of clinical controversy," said McCannel. "People want information; they have a lot of things they still want to do in life. Knowing their prognosis offers a tool that helps them plan their lives. Our research demonstrates that it's valuable to give people these details, even when their disease is not presently treatable."

"Our results emphasize how important it is for patients to be treated in a full-service hospital research center that offers genetic testing and counseling and treats the whole patient, not just their disease," said Stanton.

Tumor biopsy also helps researchers search for key genes that play a role in aggressive metastasis, improving clinicians' ability to provide the best care.

"After analyzing the tumor specimens, we grow the biopsied cells in a culture dish and can add drugs to test which ones block cancer growth," said McCannel. "That is how we're going to beat this cancer. Developing drugs to target these genes will one day result in therapies and a cure."

The technique of fine-needle aspiration biopsy for collecting cancer cells from the living eye has been utilized at the Jules Stein Eye Institute since 2004, but adopted by only a handful of other ophthalmic centers in the nation.

Although rare, ocular melanoma is the most common eye cancer to strike adults. The National Eye Institute reports some 2,000 newly diagnosed cases of the cancer - roughly seven in 1 million people - per year. The disease spans the age and ethnic spectrum, and is not hereditary.

The study's UCLA coauthors included first author Tammy Beran, Dr. Bradley Straatsma and Barry Burgess.

The research was supported by funding from the UCLA Jonsson Comprehensive Cancer Center.

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Advanced Melanoma: Vaccine Shows Therapeutic Promise

Medical News Today

A vaccine for one of the most lethal cancers, advanced melanoma, has shown improved response rates and progression-free survival for patients when combined with the immunotherapy drug, Interleukin-2, according to researchers from The University of Texas M. D. Anderson Cancer Center.

The findings, presented at the American Society of Clinical Oncology (ASCO), mark the first vaccine study in the disease - and one of the first in cancer overall - to show clinical benefit in a randomized Phase III clinical trial. Patrick Hwu, M.D., professor and chair of M. D. Anderson's Department of Melanoma Medical Oncology, presented the findings on ASCO's press program.

According to the American Cancer Society, melanoma has one of the fastest growing incidence rates of all cancers. In 2009, more than 68,720 people in the U.S. are projected to be diagnosed with melanoma and 8,650 will likely die from the disease. The five-year survival rates for those with regional and metastatic disease are 65 percent and 16 percent, respectively.

"Obviously, this is a disease, in its advanced setting, in need of better therapies for our patients," said Hwu, a co-investigator on the study. "While more follow up is needed, this study serves as a proof-of-principle for vaccines' role in melanoma and in cancer therapy overall. If we can use the body's own defense system to attack tumor cells, we provide a mechanism for ridding the body of cancer without destroying healthy tissue."

During their tenure at the National Cancer Institute (NCI), Hwu and Douglas Schwartzentruber, M.D., who is currently medical director of the Goshen Center for Cancer Care, were involved in the vaccine's development and early basic and clinical studies. The peptide vaccine, known as gp100:209-217 (200M), works by stimulating patients' T cells, known for controlling immune responses.

"This vaccine activates the body's cytotoxic T cells to recognize antigens on the surface of the tumor. The T cells then secrete enzymes that poke holes in the tumor cell's membrane, causing it to disintegrate," explained Hwu.

After an NCI-led Phase II study combining the vaccine with Interleukin-2 (IL-2) showed response rates of 42 percent in metastatic melanoma patients, a Phase III randomized trial with the two agents opened more than a decade ago.

Conducting a large, multi-institutional trial with IL-2, however, had its own set of unique challenges, explained Hwu, as not all cancer centers and community hospitals are capable of administering the immunotherapy. A highly specialized therapy associated with such significant side effects as low blood pressure and capillary leak syndrome, which poses risks to the heart and lung, IL-2 is often delivered in intensive care units. Just last month, M. D. Anderson opened a special in-patient unit exclusively designed for the drug's delivery; before, the institution was offering the therapy in its ICU.

In the Phase III trial, 185 patients at 21 centers across the country were enrolled in the study. All had advanced metastatic melanoma and were stratified for cutaneous metastasis, a known indicator of response to IL-2. Patients were randomized to receive either high dose IL-2, or IL-2 and vaccine. In the IL-2 arm, 94 patients were enrolled and 93 were treated and evaluated for response; 91 were enrolled and 86 treated and evaluated in the IL-2 and vaccine arm.

The study found that those who received the vaccine had a significant response rate, 22.1 percent, and progression-free survival, 2.9 months, compared to 9.7 percent and 1.6 months respectively in those that did not. While not statistically significant, the median overall survival for those receiving vaccine trended positive, 17.6 months vs. 12.8 months.

"This is one of the first positive, randomized vaccine trials in cancer and the findings represent a significant step forward for treatment of advanced melanoma," said Schwartzentruber, the study's lead author. "However, we've learned a lot over the last decade, and we need to incorporate these new discoveries as we proceed with our validation of this vaccine."

Schwartzentruber, who with Hwu was involved in the earlier trials and the vaccine's development, presented the findings on ASCO's plenary session on May 30.

Hwu agreed that more research with the vaccine is needed, including long-term follow up of the Phase III patients, as well as researching ways to make the study inclusive of more metastatic melanoma patients.

"Right now, the vaccine only can be given to half of those with melanoma because it has to match a patient's tissue type, or HLA. A major priority for us is to figure out ways to broaden our approach and use mixtures of peptides so that more patients are eligible," Hwu said. "We also would like to improve upon it by including other immune-stimulatory agents, such as anti-CTLA4, an antibody that can take the breaks off the immune cells."

The study was funded, in part, by the National Cancer Institute and Novartis, the makers of IL-2.

In addition to Hwu and Schwartzentruber, other collaborators on the study include: David Lawson, M.D., Winship Cancer Institute; Jon Richards, M.D., Ph. D., Lutheran General Hospital Cancer Care Center; and Robert M. Conry, M.D., UAHSF Comprehensive Cancer Center.

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Provectus Reports Encouraging Clinical Data At ASCO On Treatment Of Metastatic Melanoma With PV-10

Medical News Today

Provectus Pharmaceuticals, Inc. (OTC Bulletin Board: PVCT), a development-stage oncology and dermatology biopharmaceutical company, has announced interim data from the first 40 subjects in its Phase 2 clinical trial for the treatment of metastatic melanoma. PV-10 treatment was well tolerated and caused selective tumor destruction in the majority of subjects. Additional data on untreated tumors corroborated observations of a possible bystander effect seen during earlier Phase 1 testing. These data were presented today at the American Society of Clinical Oncology 2009 Annual Meeting, Abstract #9060, entitled "Chemoablation of melanoma with intralesional rose bengal (PV-10)," in the General Poster Session.

Key interim data from the first 40 subjects in the Phase 2 study included:

-- Objective response of PV-10 treated lesions was observed in 60% of subjects.

-- Locoregional disease control of treated lesions was observed in 75% of subjects.

-- Response of untreated bystander lesions was consistent with observations from Phase 1 testing.

-- Interim safety data were comparable to Phase 1, with transient mild to moderate locoregional pain, vesicles, edema or swelling most common.

"These data provide us much encouragement as they continue to demonstrate how potentially safe and effective PV-10 is for the treatment of metastatic melanoma," said Dr. Sanjiv Agarwala, Principal Investigator for Provectus' Phase 2 PV-10 trial site at St. Luke's Hospital & Health Network in Bethlehem, PA, who presented the abstract at ASCO. "Particularly positive is further evidence of the 'bystander effect,' which appears to induce the patient's immune system to attack and shrink untreated tumors. Because melanoma often metastasizes in areas of the body that are difficult to treat, such as the head and neck, the 'bystander effect' could dramatically improve the prognosis for many patients. We are excited about these results and look forward to continued development of this therapy."

Dr. Craig Dees, PhD, Chairman and Chief Executive Officer of Provectus said, "The progress we are making in the clinical trials of PV-10 helps pave the way for its possible future as a safe and effective therapy for metastatic melanoma patients. The results presented from the first 40 subjects in the Phase 2 trial bring us another step closer to helping the many thousands of individuals afflicted each year with this insidious disease, whose incidence is rising faster than any other cancer in the U.S. today."

The American Cancer Society estimates that there are 120,000 patients in the United States with Stage III or Stage IV melanoma, and that 68,000 new cases will be reported in 2009. The World Health Organization reported that it expected 48,000 global deaths in 2008 alone from Stage III or Stage IV melanoma.

Dr. Agarwala added, "Advanced melanoma is an extremely difficult disease to treat, even with the approved chemotherapy or immunotherapy drugs that exist. In the last decade there have not been any new drugs approved for melanoma, which demonstrates how resistant this devastating disease is to the traditional methods of treatment. That is one of the many reasons that I find these newly published data very important and am encouraged by their implications."

Background and Summary of the Data Presented at ASCO (Abstract # 9060):

Expanded Phase 2 testing of PV-10 commenced in late 2007 in 80 subjects with Stage III or IV melanoma, and enrollment was completed in May 2009. Enrollment for this multi-center study was conducted at seven sites in Australia and the United States. Thirty five subjects with Stage III disease and five with Stage IV disease comprised the cohort analyzed, with a median of 8 lesions treated per subject over 2 treatment cycles. The reported safety and efficacy data demonstrate that therapy with PV-10 compares favorably with available therapeutic options for this patient population.

PV-10 treatment was generally well tolerated, with most adverse effects transient, locoregional and mild to moderate in severity. Locoregional pain (reported by 60% of subjects), vesicles (30%), edema (28%) or swelling (18%) were most common. Severe (Grade 3) adverse effects were relatively rare (1 case each of vesicles, cellulitis and skin flap necrosis and 2 cases of severe pain), with no Grade 4 or 5 adverse effects attributed to PV-10. These results were comparable to observations from Phase 1 testing of PV-10.

Interim efficacy data for the first 40 subjects were also comparable to that of Phase 1, with 30% of subjects achieving a Complete Response (CR), and an additional 30% of subjects achieving a Partial Response (PR) in their treated lesions during the first 24 weeks following initial PV-10 treatment, for an Objective Response (OR) of 60%; Stable Disease (SD) was achieved by 15% of subjects, while 25% experienced Progressive Disease (PD), equating to a 75% rate of locoregional disease control of treated lesions. Just over half (52%) of subjects had one or more evaluable untreated bystander lesion, and 48% of these subjects exhibited an improvement in their bystander lesions qualifying as a CR (24%) or PR (24%); an additional 14% achieved SD in these lesions, for a 62% rate of locoregional disease control of bystander lesions. As previously reported for Phase 1 testing, this apparent bystander effect was strongly correlated with successful ablation of the subject's PV-10 injected lesions, with a majority of bystander responses qualifying as a CR or PR (OR = 69%) among those subjects that achieved an OR of their injected lesions. In contrast, subjects that did not achieve an OR in their injected lesions experienced minimal benefit (12% OR) in their non-injected bystander lesions.

In addition to these Phase 2 results, extended survival data were reported from the Phase 1 study, showing a survival advantage in terms of both overall survival (median 42.1 months vs. 12.3 months) and disease specific survival (44.1 months vs. 14.6 months) for subjects that achieved an OR in the Phase 1 study versus those that did not respond so robustly to PV-10. Such data support a possible systemic benefit for PV-10.

About PV-10

PV-10 is a proprietary, injectable formulation of Rose Bengal, a compound that has been in use for nearly thirty years by ophthalmologists and optometrists to assess damage to the eye. It has also been used to detect ailments of the liver. Rose Bengal has an established safety history, a short half-life in the bloodstream, and is excreted via the liver and kidneys. Provectus has discovered a novel use for Rose Bengal based on the observation that it is selectively toxic to cancer calls via a process called chemoablation whereby cells undergo a form of cell death that mimics both features of necrosis and apoptosis.

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Proteolix Presents Positive Clinical Data For Carfilzomib In Multiple Myeloma At The 2009 ASCO Annual Meeting

Proteolix, Inc. presented results from the company's most advanced clinical trial of single-agent carfilzomib demonstrating anti-cancer activity and progression-free survival in patients with relapsed and refractory multiple myeloma. Carfilzomib is the first in a new class of selective, irreversible proteasome inhibitors being developed by Proteolix for the treatment of hematologic malignancies and solid tumors.

Data from the Phase 2 clinical trial of relapsed and refractory multiple myeloma patients were presented today in an oral session by Sundar Jagannath, M.D., Chief of the Multiple Myeloma Program, Bone Marrow and Blood

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