Thursday, March 20, 2014

Should Melanoma Brain Met patients be allowed in clinical trials???


It still hurts my heart (and my head) that so many people fail to see reason and understand why many of the new treatments for melanoma can't be viewed like old time chemo when it comes to deciding whether to allow melanoma brain met patients to have them!!!  When thinking about the use of novel therapies (ipi and anti-PD1) in regard to brain metastasis, studies and the method of action of these drugs make it clear that the action upon brain mets is NOT due to the DRUG "crossing the blood brain barrier," but for the activated cytotoxic T-cells to do so. In my own study of resected metastatic melanoma patients with Nivo, all 6 of us who had metastatic brain mets out of the 30 in our arm, begun in 2010, were still alive and kicking with NO RELAPSE as of September 2013. Weber and many other researchers have contended for some time that drugs like Ipi and anti-PD1 have as good an effect in the brain as they do in the body. Additionally, in a nivo treatment arm at Moffitt that allowed brain met patients, 1 of the patient's brain mets resolved on nivo ALONE...with NO OTHER TREATMENT. To say they are excited is a definite understatement!

In his presentation and interview @ ASCO, June 2013 - Melanoma: Long overall survival in patients receiving Nivolumab, ...When asked about the likelihood that the drug works on brain metastases, Sznol noted that this trial excluded patients with active brain lesions, but accepted patients with previously-treated central nervous system tumors. Therefore the answer to the question remains unknown. "But we have long-term responders who didn't develop any brain metastases, so that suggests that maybe we are controlling disease in the brain," he said.

Phase II trial of ipi monotherapy in melanoma patients with brain metastases, by Lawrence et al.
CONCLUSION: Ipi has a similar level of activity in brain and non-CNS lesions.

Novel treatments for Melanoma brain Metastases, by Kenchapp et al. 2013. Looked at a study using ipi..."this study revealed that ipi has activity in melanoma brain mets...it is unknown whether the treatment was more effective in larger melanoma brain mets in which the highly permeable blood brain barrier may allow greater ingress of activated cytotoxic T cells."

And finally, Melanoma Brain Metastases: Is it time to reassess the bias? By: Flanigan, Sznol, et al. July 2012. These authors note that melanoma brain met patients are typically excluded from trials. They conducted a chart review of 251 metastatic melanoma patients diagnosed after 2005 to evaluate them in the context of eligibility for treatment with novel agents. And "found median survival of malignant effusion (mets in the pleural cavity) patients was significantly shorter than brain met patients (2 vs 8 months)." Therefore, "exclusion of melanoma brain met patients from clinical research programs is no longer justified and alternate investigational approaches, possibly combining local and systemic therapies, are greatly needed for these individuals."

So....lots of folks ARE on our side!!! Hopefully, archaic, irrational decisions will give way to what the data shows very soon and more patients with metastatic melanoma mets to the brain will have greater treatment options, as the data shows more and more the reality of our situation. - c

12 comments:

  1. There are 2 trials that have begun which are now enrolling patients with brain mets.

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  2. My sister has Stage IVB Non-Small Cell Lung Cancer with a brain met (among others), and we searched long and hard for a trail of a PD-1/PDL-1 drug she could get into. We hoped for MPDL-3280A, but the only study we could find which allowed CNS patients also excluded those who had been treated w/ Carboplatin. She ended up in a Phase one trial of MEDI-4736 with Tremelimumab at Moffit.

    She is 7 weeks into the trial and just had her first scans, and to our surprise, they did not do an MRI on her brain; she was told that it was "not part of the protocol." Given that we had been told that her chemo would not affect her brain met, I became curious as to whether something similar was true about these drugs, and in researching it, I became aware of the blood-brain barrier issue.

    The 6 months since she was diagnosed has been a whirlwind and I haven't learned nearly as much as I need to about standard and experimental therapies. Can anyone point me to forums, or other useful resources, where good information can be found? And is the "ipi" you refer to above ipilimumab?

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  3. Hi John,
    This is a personal blog, so you are not likely to be directed anywhere, other than by me. I'm Les, the blogger here. I have taken anti-PD1, at Moffitt, and yes....it has been used with some good effect for non-small cell lung cancer. I have met and spoken with patients for same at the CRU at Moffitt. However, since this blog is about melanoma treatment, I don't know how much I or anybody else can offer you here. Tremelimumab is much like Ipi and yes, that is ipilimumab. I do think any patient with a brain tumor, from whatever origin, should have those monitored. Both ipi and Nivo (anti-PD1) do NOT need to cross the blood brain barrier. It is not an issue. Immunologic therapies trigger T-cells to fight the cancer and THEY, DO cross the blood brain barrier. You might want to talk to your original oncologist about an MRI for the brain at some point. I wish you and your sister my best, Les

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  4. Thank you, Les. My sister had her CAT Scans last Thursday and made arrangements to get an MRI on Thursday when she goes in for her next treatment, so that's squared away. But thank you for your advice nonetheless, and for the great energy you put into blogging and commenting on forums and disseminating quality information.

    Do you happen to know of a forum dedicated to cancer in general on which the information tends to be reliable and where I can continue to educate myself about contemporary treatments? I would greatly appreciate it, and thanks again.

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  5. Hey John,
    Wish I could be of more help...but these are some sites that I would trust, though you may have already perused them.

    http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/Patient/page1

    http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer

    http://www.nlm.nih.gov/medlineplus/ency/article/007194.htm

    http://www.webmd.com/lung-cancer/guide/no-small-cell-lung-cancer

    http://emedicine.medscape.com/article/279960-overview

    These two links give pretty good descriptions of the meds your sis is taking and how they work. When judging "reports" on trials and drugs...you do have to be watchful of the source...as they may be skewed to influence stock holders etc into believing the company has just "hit it rich" with the next wonder drug. These do come out of Moffitt and Astra Zeneca....but they are pretty informative...

    http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=6&ved=0CFgQFjAF&url=http%3A%2F%2Fmoffitt.org%2FFile%2520Library%2FMain%2520Nav%2FResearch%2520and%2520Clinical%2520Trials%2FCancer%2520Control%2520Journal%2Fv21n1%2F80.pdf&ei=4tdXU7n_HubEsAT0yoCYBQ&usg=AFQjCNEFcRzuaykn17thf0h7I9NfwA8PNA&sig2=IVO3yvxwBdYAkVVma2s-eg&bvm=bv.65177938,d.cWc

    http://www.astrazeneca.com/Research/news/Article/20130930--az-oncology-update-from-european-cancer-congress

    This one is something you may or may not be interested in. It houses info as well as a place for patients to tell their stories, which vary in their scientific accuracy depending on the source.

    http://www.cancercommons.org/tag/medi4736/

    Hope this helps. Hang in there. I will of course continue to post updates re: anti-PD1 and PDL1, etc, here, as things develop. There is a good deal of overlap in their potential uses. You seem like an awesome brother. Your sister is lucky to have you in her court!

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  6. PS
    Super glad you got the scans and MRI set up. As much as I hate having them...they are essential. Best, c

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  7. Thank you. I was not familiar with several of these sites, so I have a lot of reading to do...

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  8. Hi - thanks so much for all the great information. I have a friend with brain mets/melanoma - he is being denied access to clinical trials because of the mets. Are there any trials allowing brain mets that are currently running (that you are aware of)? Any and all help is greatly appreciated. Thank you so much!

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    1. So sorry, Sarah. It is very difficult to find a triall for a patient with melanoma brain mets. There was an arm for such patients at Moffit, with nivo, but I am not sure there are still openings. I would contact Dr. weber anyway! It never hurts to ask! There is a trial using MK-3475 (Merck's anti-PD1 product) ongoing that does allow brain mets. The down side is that it requires a biopsy of the lesion. Not always so easy. If you check out my March 2 post....you will find a variety of search engines that will allow you to search for trials in a variety of ways. Additionally, search for 'brain mets' in the top left circle of my blog and you will get a lot of info about their treatment. The good news is that brainmets are more treatable than people sometimes realize...SRS, ipi, the anti-PD1 products, and BRAF inhibitors have all proven to be effective to some degree. Wishing you and your friend my best....c

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    2. Thank you so much for your response. We will look into it some more (and quickly). All the best to you.

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  9. By the way, Les, my sister's MRI showed that her brain met has shrunk by approximately a third, and the CAT scans showed dramatic shrinkage in most of her other tumors. Unfortunately, her lung tumor - her primary tumor - hasn't shrunk (although it hasn't grown, either). The doctors tell us it still might. She just had her 4th treatment and gets her next scans in 2 1/2 weeks. Prayers and crossed fingers...

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    1. John,
      Well, at least there is a good deal of great news! Hopefully the lung tumors will respond soon! C

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