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Old 09-25-2013, 11:54 AM   #1
'lizbeth
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Post Entinostat and Lapatinib for HER2-Positive Advanced Disease

Entinostat and Lapatinib for HER2-Positive Advanced Disease

Entinostat and Lapatinib Ditosylate in Patients With Locally Recurrent or Distant Relapsed Metastatic Breast Cancer Previously Treated With Trastuzumab (MDA-2010-0842)


NOTE: INDIVIDUALS WITH INFLAMMATORY BREAST CANCER (IBC) CAN PARTICIPATE IN ONLY THE PHASE I PORTION OF THE STUDY.
Summary

Researchers are looking for new ways to treat HER2+ tumors that do not respond or have stopped responding to the HER2-targeted therapy trastuzumab (Herceptin®). Entinostat is an investigational cancer drug that works by blocking protein enzymes called histone deacetylases (HDAC), which help cells divide. Lapatinib (Tykerb®) is a HER2-targeted therapy approved for the treatment of advanced breast cancer. Researchers are trying to determine the best dose and effectiveness of entinostat when it is given with Tykerb®. To be eligible, participants must have locally recurrent or metastatic HER2-positive disease, and have already been treated with Herceptin.
This is a Phase I-II trial

http://clinicaltrials.gov/show/NCT01434303

Last edited by 'lizbeth; 09-25-2013 at 11:54 AM.. Reason: added link
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Old 10-27-2013, 10:36 PM   #2
donocco
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Re: Entinostat and Lapatinib for HER2-Positive Advanced Disease

Elizabeth

I printed some material about Etinostat at work. As you stated it is a Histone de-Acetylase inhibitor. Histones are proteins that block gene expression. Every cell in your body has the same genetic code, but in each area of the body only some genes are active. In the salivary glands the saliva producing genes are active. You have the same saliva genes in the cells lining your eye but these are blocked by histone proteins. If they were not the eye would produce saliva in addition to tears.

There are genes in the cancer cell (I imagine of any type of cancer) that block the cancer cell growth when active. The cancer cells block these anti-growth genes with histone proteins. The body attempts to reactivate these genes by putting acetate molecules in between the histone protein and the DNA making up the anti-growth gene. The acetate under the histone protein "loostens" its grip on the DNA so the anti growth genes are reactivated. The cancer cells fight back by using an Enzyme, Histone De-Acetylase, to remove the acetate and allow the histone protein to " gum up" the antigrowth gene again. The idea of using an HDAC inhibitor like Etinostat is to inhibit this acetate removing enzyme.

The article I read used Etinostat in a dosage of 4mg/meter square only once a week. Etinostat has a half life in the body of about 5 days, so once a week dosing seems to be sufficient. The Etinostat was combined with Cis Retinoic Acid (the anti acne drug Accutane) at a dosage of 1mg /kg. There are retinoic acid genes in the cancer cells that, when acivated, interfere with cancer cell growth but these genes were being blocked. The idea was to use the Etinostat to prevent the cancer cells from reblocking the gene using their Histone deacetylase Enzyme

The side effects of Etinostat at a dosage of 4mg/m2 weekly
were anemia, neutropenia, and hyponatremia (low sodium)

Paul

PS there is a commonly used anti-siezure drug that has strong action as a Histone Deacetylase Inhibitor. The drug is Depakote, generic name Valproic Acid. I imagine it could be used clinically. Certainly there is a lot of experience with the drug.
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Old 10-28-2013, 10:24 AM   #3
'lizbeth
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Re: Entinostat and Lapatinib for HER2-Positive Advanced Disease

Paul,

Thank you again for giving us all a lesson about how the prospective treatments work. From my Phys/Path classes I have always thought of Histone as an immune defense that cause the allergic in allergic reaction. Perhaps I am once again mixing apples and oranges.

We are looking for the upcoming treatments and we appreciate your insight.
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Old 11-14-2013, 12:43 AM   #4
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Re: Entinostat and Lapatinib for HER2-Positive Advanced Disease

There is a doctor who's been promoting 'histone' treatment for quite a while and finally began a clinical trial a couple of years ago. The name of the drug seems to have the word 'antiplastone' in it.

Found it! It's the 'Burzynski' Clinic using Antineoplastons to treat brain tumor.
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Last edited by Jackie07; 11-14-2013 at 12:55 AM..
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Old 12-21-2013, 01:48 AM   #5
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Velaparib a parp inhibitor

I did some research on Velaparib. This is a Parp inhibitor also known as ABT888. Information is sketchy as most of the trials mentioned were concerned with signing up for them but there were some results, dosages and side effects listed.

Parp is important for DNA repair and Parp inhibitors may potentiate the effect of chemo drugs like Carboplatin and Paclitaxel (Taxol). These drugs damage cancer cell DNA and the cancer cells are dependent on the Parp enzyme to repair the chemo induced damage. Radiation therapy also damages DNA and Parp inhibitors like Velaparib might also potentiate radiation thrapy

There was trial where Velaparib was combined with Whole Brain radiation to treat the brain mets of various kinds of cancers like breast, lung and melanoma. A Velaparib dosage of 200mg twice daily was well tolerated. Since Velaparib was the only drug used in this study, you get a feel for the side effects of the drug when used alone. Fatigue was common, as was headache and decreased appetite and low blood sodium (hyponatremia) and Anemia and Thrombocytopenia and some Hair loss. Also Nausea. As a whole, Velaparib was well tolerated.

It is eliminated mostly by the kidneys (70%) so it shouldnt interact too much with other medications that are metabolized by the liver. This was a human study (the 200mg Velaparib twice a day). In one rat study Velaparib crossed the blood brain barrier well. I think the concentration of Velaparib in the brain was three times the plasma level. This should hold true for humans also.

There was another study that combined Velaparib withCarbolatin AUC 6 plus Paclitaxel (Taxol) 200mg/meter squared. The Velaparib was given in a dosage of 120mg twice daily. Since Velaparib will probably be used to enhance the effects of various chemo drugs 120mg Velaparib twice daily may be a common dose. Parp stands for Poly-Adenosine Ribose Polymerase and this enzyme is used by cells for single strand ad double strand DNA repair. Parp inhibitors prevent cancer cells from repairing the damaged DNA. This post is only fragmentary as far as information goes. Im sure there will be a lot more information in the future.

Paul
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