Synta announces results from Ganetespib Phase 2b trial on NSCLC

Published on September 29, 2012 at 5:14 AM 

Synta Pharmaceuticals Corp. (NASDAQ: SNTA) today announced results from an interim analysis of the Phase 2b portion of the GALAXY trial, a global, randomized, multi-center Phase 2b/3 study designed to evaluate the efficacy and safety of the Company's lead Hsp90 inhibitor, ganetespib, as second-line treatment for advanced non-small cell lung cancer (NSCLC). The results showed good tolerability for the combination of ganetespib (G) and docetaxel (D), as well as meaningful improvements in overall survival (OS) in adenocarcinoma patients receiving docetaxel plus ganetespib compared to those receiving docetaxel alone. The results were presented by Suresh Ramalingam, MD, Professor, Hematology & Medical Oncology, and Director, Translational Thoracic Malignancies Program, of the Winship Cancer Institute of Emory University, in a poster session at the European Society for Medical Oncology 2012 Congress in Vienna, Austria. A copy of the poster is available at http://www.syntapharma.com/documents/Ganetespib_GALAXY_ESMO_2012_Poster.pdf.
The GALAXY trial is based on a two-stage, operationally adaptive design. The first-stage, randomized, open-label, 240-patient Phase 2b portion of the trial is enrolling Stage IIIB/IV NSCLC patients who have progressed following one prior line of therapy, and is designed to identify the patient population, defined by biomarker or other disease characteristic, for advancement into the Phase 3 portion of the trial.
An interim analysis was planned for when approximately 80% of the target 240 adenocarcinoma patients had been enrolled. A total of 187 patients were enrolled at the time of analysis, of which 172 patients had been entered into the clinical database at the time of data cutoff.
"The preliminary results from GALAXY indicate that the addition of ganetespib to docetaxel is well tolerated and may improve outcomes in patients compared to docetaxel alone," said Dr. Ramalingam, a Principal Investigator of the study. "This includes promising improvements in survival seen across the broad adenocarcinoma population as well as in key predefined patient populations. A well-tolerated combination regimen that extends survival associated with salvage therapy in NSCLC will meet a much awaited need to improve the current standard of care."
Targeting the dependence of cancer cell growth and proliferation pathways on the Hsp90 chaperone represents a new way to interrupt cancer cell signaling and reduce tumor aggressiveness. Hsp90 inhibition by ganetespib simultaneously inhibits multiple critical cancer-promoting pathways, including pathways responsible for tumor metastasis, angiogenesis, and resistance to conventional therapies.

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Posted in: Drug Trial News | Medical Condition News

Tags: Angiogenesis, Biomarker, Breast Cancer, Cancer, Cell, Chemotherapy, Docetaxel, Hematology, Hemoptysis, Immunosuppression, Immunotherapy, Leukemia, Lung Cancer, Medi-Cal, Melanoma, Metastasis, Multiple Myeloma, Myeloid Leukemia, Myeloma, Non-Small Cell Lung Cancer, Oncology, Protein, Radiotherapy, Small Cell Lung Cancer, Smoking, Stem Cell, Translational, VEGF

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A PEEK INTO THE FUTURE!

The article published in the Lancet about Taxotere combined to Selumetinib in 2nd line treatment of lung cancer, opens the door to future therapy to come.  It marks the increasing trend of incorporating Target therapy to standard good old chemotherapy.  Selumetinib is a MEK inhibitor downstream from KRAS.
Already the results are impressive with the doubling of progression free survival and Overall survival.
Already, we have a peek to a new set of toxicity because these are new combinations and the outlook is grim now with almost half of the patients having Nausea, diarrhea, severe Neutropenia and stomatitis.
Not only is MEK down stream from RAS-RAF-MEK-ERK (MAPK) signaling pathway; it is the revolving door between epidermal presentation which should block Metastatic spread and Endodermal transformation that the Cancer chooses to metastasize.
Another question that will rise immediately is if we have a driver mutation, when should we stop inhibiting such target, when do we stop closing this revolving door? The rising need of maintenance therapy follows.  In lung cancer, Alimta, Tarceva and Taxotere have all shown to be beneficial in maintenance setting.  So the choice here would be Taxotere maintenance, or should we continue to push closed MEK with Selumetinib?
This article emphasized the fact that this was the first time that KRAS was used as a biomarker for  Target therapy.  Very true, but mesenchymal transformation and angiogenesis play a role in almost every cancer.
THE FIGHT IS ON.

(LAST POINT: WE HAVE NOT LEARNED ENOUGH ABOUT HOW TO PREVENT THESE SIDE EFFECTS, WE NEED TO STEP UP!)

PLATELET DERIVED GROWTH FACTOR, A DEADLY MISNOMER
====================================================

By naming this compound PDGF, the scientist who described this cytokine not only picked the wrong name,
but also sent researchers on the wrong path to understanding just how important this growth factor is.  As a result, some people are probably dying because the emphasis brought by the name was not clearly defined.
First of all, PDGF does not come solely from Platelets alone. It is made by a number of cells including Muscle cells, Endothelial cells and even Macrophages.
And when you think of Platelets, Coagulation comes to mind, weakening of platelets and the like.  If this PDGF does this, it is at a strictly minimal or insignificant level.  The effect on Platelets is only mentioned by those who clearly have been fooled and kept looking for rare effects which eventually can be found.  This PDGF works on Mesenchymal cells since creation.  It participates in Embryogenesis, cell survival, proliferation, angiogenesis and differentiation. In adults, its main effect is on Fibroblast and Glial cells.
When you think Platelet, platelet Aggregation, adhesion and so forth.  PDGF kills by Fibrosis in cirrhosis of the liver and Pulmonary hypertension, one of the worse silent killers of our time.  Pulmonary Hypertension is a deadly killer because physicians don't know how to best monitor it.  AND BECAUSE WE CLEARLY DO NOT TREAT IT AGGRESSIVELY.  HOW MANY PHYSICIAN GIVE CIALIS TO THEIR PATIENT FOR PULMONARY HYPERTENSION?   If you raise your hand, you are my hero!
The point is that by misnaming the PDGF, people will assume Aspirin would be the more likely inhibitor.  Think again.  There are almost 20 inhibitors of PDGF listed on the SELLECHEM list.  Believe me it starts with Nexavar and Sutent. Aspirin is not on the list!
HOW MANY PEOPLE THINK OF NEXAVAR IN THEIR TREATMENT OF SCLERODERMA, A DISEASE KNOW TO HAVE PROMINENCE OF PDGF ACTIVITY?    HOW MANY ONCOLOGISTS GIVE GLEEVEC TO TREAT THEIR GLIOBLASTOMA.  (CLUE, AVASTIN IS INDICATED IN REFRACTORY BRAIN DISEASE-YOU THINK AVASTIN-ANGIOGENESIS, THINK NEXAVAR, TELLS SELLECHEM).

In a short study, 11 out of 12 GLIOBLASTOMAS had amplification of PDGF.  This is one of the drivers of GBM.  Forget Platelet, think Mesenchymal derived growth factor, and let us put the right emphasis on this Cytokine!

STRATEGIES FOR THE CURE

Since the work of Weinberg and Hanahan, we know that despite the varieties of cancer, 6 driving forces lead to cancer cell survival.  The "Hallmarks of cancer" result from:

1.Self sufficiency in growth signals: Cancer cells escape Anoikis,  They secrete their own growth factors to achieve an autocrine stimulation.

2.Insensitivity to anti-growth signals. This is achieved by changing membranes' receptors composition and number, boosting its own global growth, and secreting Tumor Necrosis factors to tamper with surrounding cell machinery.

3.Sustained Angiogenesis, to maintain "feeding" of the new tumor mass.  This is mostly critical for solid tumors.  It is critical in tumors that bleed easily such as renal cell cancers.

4.Limitless replicative potential.  By removing stops to mass formation, natural boundary sensors which contribute to shaping organs, Telomerase activation again.

5. Suppressing or escaping Apoptosis: By using cyclins and Bcl-2 and related molecules. Shielding Mitochondria and avoiding FAS/BAX, activating loopholes routes and impairing ubiquitination of growth molecules!

6.Tissue invasion and metastasis. Here the tumor cells alter composition, nature and amount of the cell receptors and adhsions molecules, cluster of differentiation (CD), and produce Tumor growth factors (TGF) which give it growth advantage vis-a-vis the surrounding tissue.

This list is by no mean exhaustive given the variety of possible oncogene mutations.  However, when one gene is causing one of the 6 pathways, it is dubbed a DRIVER mutation for that cancer, and may have significant therapeutic importance.

This 6 venues are made of important molecular structures that can be a Target for therapy. Researcher are combing them one by one and targeting them.  The successful experience with Multikinase therapy suggest that interrupting several points of the cascade appears beneficial.  Computer models are being developed to see if sequential attacks or coordinated combinations would be better models for future therapies.  The CRBCM is working to develop such a model. Our model will be complete after we enumerate all laws of nature (see our related series).

Model of cures should embrace these 6 venues in a mathematical equation...the challenge is launched!