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Vemurafenib is a very focused PLX4032-medication with BRAF mutation and turns out molecules targeting tumors with good results to ensure melanoompatienten in stage IIIc with and IV. FDA gives official approval as per direct vemurafenib-zelboraf melanoompatienten with appropriate medication for BRAF expression. Article update 18 april 2012

19 August 2011: source: FDA-US Food and Drug Adminstration

The FDA has per direct vemurafenib-officially classified as a medicine for Zelboraf melanoompatienten in advanced stage (stage III/IV), with the correct BRAF expression. Click here for permission report.  Also read the following article with a link to the full study report that served as a basis for the FDA permission.

6 jun i 2011: Source cape Meds and Asco

The Center also known under the codename vemurafenib, PLX4032 became known at ASCO 2011 presented as a breakthrough in the treatment of melanomas with a BRAF expression. ca. 50% to 60% of people with a melanoma would these have, according to the researchers at ASCO BRAF expression 2011. On the results from a phase III study were ASCO presented. Incidentally, that study is not placebo-controlled but the control group received the usual chemo dacarzabine. All patientsin thestudyhad a inoperabele,not previously treatedstageIIICorstageIVmelanoma andtested positivefortheBRAFV600Emutation. That means that patients were not double-blind randomised preselected so. Noteworthy is also that only 5% of the group that dacarzabine only got this succeeded. This study therefore would simply show that dacarzabine just not a good chemo for melanoma patients with a BRAF expression. That would explain a lot about the study results.

Turned out after 6 months desurvival 84% (95%confidence interval [BI], 78to 89)indeGroup that had gotten added vemurafenib and 64% (95%CI, 56to 73)intheGroup. dacarbazineThere are still Nomedian overall overlevingcijfers of thestudy, becausethedata still not the end of the follow-up study, the authors have thus achieved, The resultsforprogression-free survivalare final;patientswhovemurafenib5.3 had had gottenmonths disease-free time to progression occurred, comparedwith 1.6months intheGroup, says Dr.dacarbazineChapman, research leader at ASCO 2011. All in all, a result which is not bad, but not described as a breakthrough can be like their audience wanted to do what the researchers believe.

Here is the abstract of the study and if you want to read the entire study report click here, it's free.

Source: NEJM

Improved Survival with BRAF V600E Mutation in Melanoma with Vemurafenib

Paul B. Chapman, M.D., Axel Gina, M.D., Caroline Robert, M.D., Ph.d., John B. Haanen, M.D., Paolo Ascierto, M.D., James Larkin, M.D., Reinhard Dummer, M.D., Claus Garbe, M.D., Alessandro Testori, M.D., Michele Maio, M.D., David Hogg, M.D., Paul Lorigan, M.D., Celeste Lebbe, M.D., Thomas Jouary, M.D., Dirk Schadendorf, M.D., Antoni Ribas, M.D., Steven j. O'Day, M.D., Jeffrey a. Sosman, M.D., John m. Kirkwood, M.D., Alexander m.m. Eggermont, M.D., Ph.d., Brigitte Dreno, M.D., Ph.d., Keith Nolop, M.D., Jiang Li, Ph.d., Betty Nelson, M.A., Jeannie Hou, M.D., Richard j. Lee, M.D., Keith t. Flaherty, M.D., and Grant a. McArthur, M.B., B.S., Ph.d. for the BRIM-3 Study Group

June 5, 2011 (10.1056/NEJMoa1103782)

Abstract

Article

References

Background

Phase 1 and 2 clinical trials of the BRAF kinase inhibitor response rates or vemurafenib (PLX4032) have shown more than 50% in patients with metastatic melanoma BRAF V600E mutation with the.

Methods

We conducted a phase 3 randomized clinical trial comparing dacarbazine in patients with previously untreated vemurafenib with 675, with the BRAF mutation V600E. metastatic melanoma Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were progression-free survival rates of overall and. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths.

Results

At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and progression-free survival, final analysis for vemurafenib was associated with a relative reduction in the risk of death and or 63% or 74% in the risk of either death or disease progression, as compared with dacarbazine (P < 0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from vemurafenib to dacarbazine was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with arthralgia, rash, fatigue, alopecia vemurafenib were, squamous-cell carcinoma, keratoacanthoma or photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects.

Conclusions

Vemurafenib produced improved overall and progression-free survival rates of patients with previously untreated in BRAF mutation V600E melanoma with the. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.

References

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23 January 2011: Meds cape

New results would demonstrate that the new experimental drug, PLX4032, code name RG7204 or for a longer disease free time can provide patients with melanomas with a BRAF expression. This producer Roche/Genentech informs Meds cape but yet no study results can and want to publish. Bit strange but perhaps also understandable if you look at the other study results and doctors say that it means known for many patients respond but only short time is employed. Yet other oncologists optimistic and positive about latest study results. Read below in succession a number of publications on this new medium. Starting with quote from article by Meds cape d.d. 19 January 2011.

"A Major Breakthrough"

The results of a phase 1 trial presented last year drew praise and enthusiasm from the oncology community. In a phase 1 dose-escalation study, 81% of patients whose melanomas had an activating mutation in BRAF responded to the treatment (N Engl J Med2010; 363:809-819.). This represents "a major breakthrough," according to the authors of an editorial that accompanied the published study (N Engl J Med2010;363:876.-879).

The results of an open-label phase 2 trial seemingly confirmed these early dates. As reported by Meds cape Medical News, or the 132 patients with advanced melanoma positive for the BRAF mutation, 82% experienced a response (52%) or stable disease (30%), and 52% experienced a decrease in their tumor size or 30% or more.

In the median progression-free survival phase 2 trial, was 6.2 months, which was much higher than the 2 months historically seen in this patient population. Overall survival is usually in the range of 6 to 9 months, but median overall survival had not yet been reached when the results were presented at the 7th International Melanoma Research Congress of the Society for Melanoma Research in Sydney, Australia in November 2010.

At that time, Antoni Ribas, Jonsson Comprehensive Cancer Center at MD, from the the University of California in Los Angeles, who was involved in both the phase 1 and phase 2 clinical trials, told Meds cape Medical News that the responses were not durable. However, he speculated that response to RG7204 might lead to an improvement in survival by shifting the first part of the survival curve about by a few months.

26 november 2010: cape Meds Source

A new phase II study has confirmed that the response, hitting the new drug, PLX4032 (RG7204) against melanomas, remains high (see below abstract of promising study). There, however, it now appears that this response is not so very long persisted. Turns out it worked out already after 2 to 7 months. This will be apparent from a phase II study with 132 patients with BRAF mutation melanomas that the good had. A quote from article by meds cape about this new study, which you can read the full article if you click here.

In Early results from a phase 1 study of melanoma — 32 melanoma patients with a mutation in a BRAF — showed "remarkable 81% of patients responses," which "represent a major breakthrough," enthused the authors of an editorial that accompanied the publication of the study in the NewEngland Journal of Medicine (2010; 363; 809-819, 876-879).

The latest clinical results, presented recently at the International Melanoma Research Congress of the Society for Melanoma Research in Sydney, Australia, confirm the high response rates.

They come from an open-label phase 2 trial of 132 patients with previously treated advanced melanoma positive for the BRAF mutation. Researchers report that 82% of patients had a response (52%) or stable disease (30%), and 52% had a decrease in their tumor size or 30% or more.

The median progression-free survival in these patients was 6.2 months; typically progression-free survival for such patients is only about 2 months, according to the researchers. Overall survival is typically around 6 to 9 months, they add, but the median overall survival has not yet been reached in the trial.

The safety profile is similar to that already reported for the experimental agent, and includes the development cutaneous squamous cell carcinoma or the grade 3 again, this time in 26% (34 or 132) patients. In these cases, the cutaneous squamous cell carcinoma lesions were excised and the patients continued with the experimental therapy. In addition, abnormal liver function was reported in 14% of patients, joint pain/arthritis in 11%, and gastrointestinal symptoms (including gastritis and pancreatitis) in 10%. Rash, photosensitivity, and hair loss were also reported.

......

The responses are not durable; they last for an average of about 7 months before the disease progresses, Dr. Ribas noted. Even so, he speculates that the response to the drug might lead to an improvement in survival by shifting the first part of the survival curve about by a few months.

24 February 2010: source: Pubmed and Plexxikon Inc.

Seems to be a drug PLX4032 that part of the incurable melanoompatienten can give hope back on a recovery. Several studies in recent years have already proved that a drug PLX4032 (RG7204), with a very focused on tumors, particularly with those melanoompatienten BRAF mutation BRAF mutation (ca. 50% of all melanoomtumorn have these BRAS mutation, the researchers said) achieved good results. Last week came the producer of the first results of PLX4032 outward ett a randomized phase III study that confirmed the earlier results from phase II studies.

Plexxikon Inc. successively a press release from here and a few quotes from article from Elsevier Global Medical News. Here you can read a comprehensive article on targeted approach with molecules.

Plexxikon Announces First Patient Dosed In Phase 3 Trial Of PLX4032 (RG7204) For Metastatic Melanoma

Berkeley, CA — January 8, 2010

Plexxikon Inc. announces that enrollment has been initiated and the first patient dosed in a pivotal Phase 3 trial has been or in patients with metastatic melanoma PLX4032 (RG7204). PLX4032 is a novel, oral and highly targeted drug that is designed to inhibit the causingmutation that occurs in BRAF cancer-about 50 percent of melanomas and about eight percent of all solid tumors. The randomized, controlled, Phase 3 "BRAFInhibitor in Melanoma" (BRIM3) in previously untreated patients trial is part of the planned registration program for PLX4032. The initiation of the Phase 3 trial has triggered a significant milestone payment to from Roche, its co-development partner Plexxikon, under their 2006 collaboration agreement. Plexxikon is also entitled to receive additional payments for further milestone achievements as well as royalties on sales of PLX4032. A Phase 2 trial in previously treated melanoma patients (BRIM2) was initiated in September 2009, with ongoing enrollment.

"With some tumor mutation-positive melanoma patients krimp in nearly all, and 70 percent of patients achieving at least 30 percent tumor in our most recent clinical study, krimp PLX4032 has shown meaningful anti-tumor activity. The Phase 3 trial, with a primary endpoint of overall survival, will provide an assessment of clinical benefit in a randomized, controlled study design or PLX4032, which should further build our registration program for this drug, "stated k. Peter Hirth, Ph.d., chief executive officer or Plexxikon.

BRIM3 is a Phase 3 trial expected to enroll approximately 700 previously untreated melanoma patients who will be randomized one-to-one with PLX4032 at a dose or 960 mg BID or dacarbazine (DTIC), a drug approved for the treatment of metastatic melanoma comparator. Patients will be monitored throughout the study for safety and efficacy endpoints. The primary endpoint of this trial is overall survival. Secondary endpoints include duration of response, progression-free survival and best overall response rate (BORR). The trial is a multicentre study being conducted BRIM3 at approximately 100 sites, including sites in the United States, Australia, Europe and Canada, with sites continuing to open through Q2 2010.

BRIM2 is a Phase 2 trial expected to enroll approximately 100 patients and is a single-arm study in previously treated melanoma patients. This trial is enrolling patients at 13 sites in the U.S. and Australia.

Patients enrolling in both BRIM3 and BRIM2 are being selected using an investigational companion diagnostic test that detects the BRAF mutation. This diagnostic is being developed in parallel with co-PLX4032 by Roche Molecular Systems, Inc. and Plexxikon. Patients interested in enrolling in the BRIM2 or BRIM3 trials may find additional information at the Roche Clinical Trials Registry (http://www.roche-trials.com/), at genentechclinicaltrials@druginfo.com, by visiting www.clinicaltrials.gov, or by contacting the Roche/Genentech Call Center at 888-662-6728.

Phase 1 Data Support Advanced Clinical Development Program for PLX4032

Promising data from the Phase 1 extension in mutation-positive melanoma patients cohort were recently presented at the ECCO/ESMO conference September 2009, and provided support for the initiation of the pivotal Phase 2 and Phase 3 trials in melanoma. These data showed some tumor in nearly all patients treated with PLX4032 krimp, and 70 percent of patients achieving at least 30% tumor by krimp RECIST criteria. Patients in the Phase 1 melanoma extension cohort were treated with PLX4032 960 mg twice daily at a dose of (BID), which was well tolerated. Drug-related adverse events were predominantly mild in severity, including rash, joint pain, fatigue and photosensitivity. Skin squamous cell carcinoma (subtype keratoacanthoma) was observed in 20 percent of patients and removed by excision while treatment with PLX4032 was continued.

Plexxikon conducted the Phase 1 dose escalation cohort and mutation-positive melanoma patients cohort in an extension. The company has also completed enrollment in a second mutation-positive colorectal cancer patients cohort extension or. Roche, Genentech, and its wholly-owned subsidiary, are conducting all future clinical trials or PLX4032, including BRIM2 and BRIM3.

BRAFMutation in Melanoma and Other Cancers

The BRAF mutation has been shown, both in preclinical studies and clinical studies, to be a key driver PLX4032 or cancer, particularly in melanoma. This mutation is present in approximately 50 percent of melanoma skin cancers. Overall, about eight percent of all solid tumours carry this mutation, including melanoma, colorectal, thyroid, biliary tract, prostate, ovarian, lung and glioma cancers. The BRAF mutation represents a unique target for cancer therapy since the mutation occurs only in tumor cells and not in normal cells. The high degree of selectivity or PLX4032 for this target has enabled sufficient dose levels to achieve about 90 percent inhibition required for tumour krimp.  

"If I have a young, talented medical oncologist at a cancer center, now I would have no reservations to recommend him to become a melanoma specialist because it's going to become a very exciting field instead of a graveyard," Prof. Eggermont Erasmus University in Rotterdam said at a press or briefing. "One of the fellows here said, ' Wow, this is fantastic; now I will get time to get to know my metastatic melanoma patients. ' That's how bad the field was. So this is simply fantastic. "

The phase I extension metastatic melanoma patients who had a trial included 31 BRAF mutation V600E and who were treated twice daily known as with 960 mg or PLX4032. Among 27 evaluable patients, the response rate was 70% by RECIST (Response Evaluation Criteria in Solid Tumors), including 18 partial responses and 1 complete response. One partial responder subsequently became a complete responder after the data analysis cutoff date.

Progression-free survival is about 8.5 months, although the median has not yet been reached, lead author Dr. Paul Chapman said during a presidential session. Overall survival was not measured. Tumor on MRI showed that after just 15 days krimp or treatment, FDG (fluorine-18 2-fluoro-2-deoxy-D-glucose) uptake was essentially shut down.

"We are seeing responses in sites we don't see, like the bowel," he said. "Liver metastases are also susceptible to this treatment. Bone metastases, which I've rarely seen, respond. "

Enthusiasm for the study, which was supported by Plexxicon Inc., was not diminished by the preliminary nature of the data or a string or disappointing late-phase results from other promising melanoma agents.

"My take – and I think it's pretty representative of many in the academic world – is that this is cataclysmic melanoma; this is hugely important, "Dr. David e. Fisher, chief of the dermatology service and director of the cutaneous biology research center at Massachusetts General Hospital, Boston, said in an interview. "The distinction or this from the vast majority of prior early trial data that looked promising is that this has a predictive component to it."

Clinicians can predict which patients will respond and which won't, based on the presence of the BRAF^V600E mutation. In addition, there is a very compelling precisely how this drug works and mechanistic connection between the nature of the clinical response, he said.

In a previous phase I dose-escalation trial in 55 patients with a variety of cancers, partial responses were reported in metastatic melanoma patients with 9 or 16 the BRAF^V600E mutation who received sufficiently high doses or PLX4032. Patients lacking the BRAF mutation did not respond, according to data presented at this year's annual meeting of the American Society of Clinical Oncology.

Because of the selectivity of the molecule, adverse events have tended to be mild, said Dr. Chapman, an attending physician on the melanoma/sarcoma service at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York. Common grade 3 events in the current trial were arthralgia (3%), rash (3%), photosensitivity (3%), and fatigue (7%). About one-quarter of patients had to take a 1-to 3-week drug holiday or had to decrease their dosage because of side effects, typically rash. Squamous cell carcinoma of the skin was seen in 23% of patients, but was easily treated with excision, he said.

A Disease or Subtypes

Dr. Chapman told reporters that genetic screening will have to become universal in melanoma, just as is essential in treating colorectal cancer. KRAS testing Screening can be completed in 1-2 weeks at active, participating centers.

The BRAF mutation is not the first example of a genetic subtype targeted in metastatic melanoma; Dr. Fisher and his colleagues reported dramatic results last year after targeting the c-KIT mutation with imatinib. Although the armamentarium is not deep for drugs that block BRAF, there are several available agents that target c-KIT, including nilotinib and sunitinib. This mutation, however, occurs in fewer than 5% of melanoma patients, and typically in the palms and soles and those melanomas or along the GI tract.

Although the signal from the PLX4032 trials is strong, the early data suggest that the single agent is not going to be enough, Dr. Fisher said. Future strategies will likely include combination therapy and the use of agents prior to the development of metastatic disease.

"We need complete remission. We need these tumors to melt away, "he said.

Dr. Chapman responded, "If you shrink the tumor too much with, it may not be as sensitive to PLX4032 VEGF [vascular endothelial growth factor] inhibition, but from a toxicity point of view, I don't think there's any reason why we couldn't combine them."

Dr. Richard Carvajal, a medical oncologist also with MSKCC, said in an interview that the clinical efficacy observed with PLX4032 nicely mirrors the preclinical data developed with various inhibitors of RAF and MEK, PLX4032 – either alone or in combination and that will play an important role – for the treatment of this particular molecular subgroup or melanoma in the future.

Steun ons! Banknr. 37.29.31.138 t.n.v, Stichting Gezondheid-actueel, Amersfoort