Patient rights in a clinical trial. An oxymoron???? Redux...

This post is a bit of a re-hash from a recent conversation on one of the melanoma forums.  Forgive me if you've already seen it, but I keep thinking about it all....so I thought it was worth a post for those of you who did not.

It began with 'M' speaking out about her frustrations when dealing with Big Pharma and the way clinical trials operate.  Her husband has been through a lot.  Most recently he joined an ipi/nivo trial which miraculously rendered 8 lung nodules and 5 lymph nodes shrinking or inactive on subsequent scans. However, he developed hemolytic anemia and did continue to have 1 or 2 pesky lesions in his lungs that did not respond.  So, M was very frustrated that though the hemolytic anemia was resolved in February, BMS removed her husband from the trial, and even more disturbing, was the fact that they had no interest in an examination of the tissue that will be available after his upcoming lung surgery to remove the remaining active nodule.

An 'anonymous' Pharma/Clinical Trial defender replied {CAPS = theirs}:   
    "If he is still on a trial, BMS has their hands tied.  There are criteria for staying on a trial DEFINED BY THE FDA and if those criteria aren't met, the patient is dropped.  These criteria are setup PRIOR to the clinical trial starting and only people who fit this criteria can be used in the final drug approval.  The only thing you can do is ask if he could be treated "off protocol" - basically someone who doesn't fit the criteria needed for approval.  The reason you signed so many papers is to protect you and the company, and those papers clearly define the protocol for staying on the trial.  FDA requires this and it is the nature of clinical trials."

I really don't get these folks.  Are they simply completely taken in by the Big Pharma propaganda of 'poor pitiful us, just struggling to make a living and help the world' that their PR departments spew?  Do they just speak out of turn because they have no idea what it is REALLY like to be on a clinical trial?  Or, are they afraid that somehow Big Brother (I mean Big Pharma) is watching....and they don't want to be caught criticizing lest they somehow lose out on treatment when THEY decide they need it???  I really don't know.  But...here's what I said:

Oh, M!  Sorry you are having to deal with all this.  When I was a little girl Marie Curie was my hero.  She still is.  Her work in radioactivity paved the way for the radiographic treatments and diagnostics that exist today.  But perhaps something she contributed apart from her work made an even greater difference.  She refused to patent her processes!!!!  Thus, allowing many other researchers to work on radiation and her ideas simultaneously...moving science forward exponentially....rather than waiting for only those researchers and institutions who could afford it to participate; to build on something that, in her view, belonged to humanity.  Marie Curie's today are few and far between.  Certainly BMS, Merck, et al. operate in a manner that seems to be lacking such a creed.

To the Pharma Defender's point. Yes, that assessment is pretty accurate regarding clinical trial protocols.  However, it is not so clear cut and easy as all that.  Additionally, the protocol is not as much in favor of the patient as is implied.  I have signed many such documents.  They all basically say:  "You will be getting this, for this long.  Here's how you qualify.  Here's how you get kicked out. If you live, die, grow three purple heads...so be it.  The company, researcher and the research institution will bear no responsibility....ethically or financially.  Costs will be paid by you for this, this and this....and for all expenses related to any side effects that may develop."

Now, as a patient...of course...I agreed.  I signed...my life and my rights away.  Patients are desperate.  No one signs up for a clinical trial when there are better options available.  And while various protocols are more fair to the patient than others, they are a legal document designed much more to protect the providers than the rights of those on the receiving end.  The best we can hope for as patients is that we will be giving "informed" consent.  Additionally, researchers, institutions and Pharma change the protocol ALL THE TIME!!!!  I have signed innumerable iterations of my ONE trial!!!  Never once has a patient been able to exact a change in such a document!

Additionally, for those who like to tout the lack of control Pharma, the FDA, and researchers have - I beg to differ.  Exceptions can be made any time they choose to make them.  They just don't often choose to do so.  For instance:  Take the case of Ralph M. Steinman.  Don't know Ralph?  Well, he was an amazing researcher in the area of the immune system and cancer....very smart....was awarded the Nobel Prize just three days after his death in 2011...and apparently, a really great guy.  Well.  Ralph got pancreatic cancer.  Perhaps the only cancer along with renal cell carcinoma that gives melanoma a good name.  So what happened?  His research buddies, folks at the FDA and various review boards pulled every string in the book.  "In addition to standard treatment, Steinman ended up enrolled - under a special patent provision - in four ongoing clinical trials of various dendritic cell-based cancer treatments, most of which were not even being tested for pancreatic cancer, along with several other experimental immunotherapy and chemo treatments.  Schlesinger, a member of the Rockefeller Institutional Review Board, steered his treatment through all the necessary IRB and FDA channels..."  [The Patient Scientist, Scientific American,  Harmon, Jan 2012]  Hmmm....  So, did Ralph deserve that special treatment?  Treatment that kept him alive years longer than most folks with his disease...and without said special treatment?  Sure!!!  I think so!  But!  Don't we all????  Must we all be brilliant, well connected scientists in order to be granted such care?

Finally, while it is obvious that patients cannot continue to take meds/treatments that result in life threatening side effects like hemolytic anemia....I think perhaps M's ultimate point was this....  If Big Pharma is really, truly interested in saving lives...not just making money....wouldn't they want to know not just what makes their med work, but what makes it fail?  What in those two last sucky little tumors in M's husband protected them while his other tumors responded to his treatment?  Wouldn't you want to know that?  Now, Pharma defenders will say, "Well, the FDA and pharmaceutical industry is not set up to do things like that when they run a trial."  And, those folks are right.  BUT....WHY NOT???????   Why aren't those in the drug industry REALLY set up to do REAL research?  Not just keep a tally of those who rise and fall? Achieve something more than a count of side effects?  Why ISN'T a research team set up to evaluate tissue samples and patients, de rigueur? 

'M', I wish you and your husband my best...with his upcoming surgery and whatever treatment path you seek next.  While there is much that is good in our system of clinical trials, there is much that is broken.  For what it's worth, this is one rattie who does not plan to stop squeaking anytime soon.
Yours, Celeste

M's response says it all:   
"Patients deserve to have some rights in clinical trials!!!  Unless you are a stage 4 patient that has been on a clinical trial, you have not a clue how powerless you are compared to the companies that make the drug."

Sending my very best to every rattie (plus a mouse or two) and their families - c

Colonoscopy done, feeling a bit better, and...Inhaled IL-2 for lung mets??!!!

Arthralgias and mouth ulcers continue to wax and wane in their random fashion, but decreasing overall.  REALLY wishing my lungs would improve more rapidly!!!  Tired of coughing and lack of sleep, but I think that is slowly getting better as well.  But....as I sit here with my albuterol/pulmicort hooka (as the kids call it)....I found this:

Low-dose inhalation of interleukin-2 bio-chemotherapy for the treatment of pulmonary metastasis in melanoma patients.  Posch, Weihsengruber, Bartsch, et al.  British Journal of Cancer. March 2014.

Interleukin-2 (IL-2) treatment for...metastatic melanoma has shown remarkable durable responses.  Systemic administration of IL-2 may cause severe side-effects, whereas local administration is considered to be a safe alternative.

20 patients with Stage IV melanoma were treated with 3X3 million IU inhalative IL-2 once daily with monthly dacarbazine bolus injections.  5 (prophy group) were treated after surgical resection of lung mets, 15 (treatment group) had active disease.  Radiographic follow-up was done every 3 months.

9 in the treatment group had clinical benefit with partial regression (27%) or stable disease (33%).  4 had progression of lung mets and 2 were not evaluable.  In the prophy group, none of the patients developed new lung mets during the inhalation therapy.  Median f/u was 7.8 months in the treatment group and 25.7 months in the prophy group.  Treatment was well tolerated in most.  Therefore, IL-2 inhalation might offer an effective and safe treatment option for lung mets and may have a prophylactic potential to prevent recurrence in the lungs after pulmonary melanoma metastasectomy.  Can easily be performed in the outpatient setting.

Sounds like a plan to me!  Albeit with small numbers and limited responses.... Perhaps inhaled IL-2 will be investigated further and be at least part of a successful comprehensive treatment plan.  Not sure about pairing it with dacarbazine, but with other systemic treatments like immunotherapies it may hold real promise.

In news from the other end...colonoscopy was completed.  The day of starvation and "other" sundry activities was not too bad.  All was well within.  No sign of colitis at the moment...perhaps never was.  One 3mm polyp was removed and sent to pathology for review, but it was not ominous looking and is gone now.   In the midst of all that, B did let it be known that 50-60% of all melanoma patients are found to have melanoma in their gut on autopsy. [Clinical Study - Emergency Surgery for Metastatic Melanoma.  Mantas, Tsaparas, Charalampoudis, et al.  International Journal of Surgical Oncology  June 2014  "At autopsy, metastatic deposits are reportedly present in 50 to 60 percent of patients with melanoma; however less than 4 percent of patients are found to have gastrointestinal metastasis during the course of their disease..."]  Hmmmm...  The factoids that man keeps close to his chest.  I'm thinking the next time I do any gut checking, beyond the occasional emotional one, should perhaps wait til MY autopsy!!!  What 'cha think?

From Dinotopia (and folks doing inhaled drugs everywhere) - Breathe deep. Seek peace!  -  c

Arthritis associated with anti-PD1

Here's a bit from a post I made in September regarding my check-up at Moffitt, then 15 months after my last dose of Nivo and 45 months after starting my trial:

    'Sadly, as it has been for some time, the questions I have, have no absolute answers. I, and my fellow ratties, ARE the answer.  But, I asked a few none-the-less.  The one of most importance:
"Having completed anti-PD1, is my immune system permanently changed, or was the change temporary?"
After some discussion and recognition that no one really knows the answer to this...the answer was:
"Yes, it is most likely that your immune system has been altered permanently via your central memory T cells."
     The good news, if this is indeed the case, is that, theoretically, my memory T cells will be around for a good while and continue to kill off any horrid little melanoma cells fluttering about. On the down side, a forever changed immune system could continue to put me at greater risk for immune stimulated disease processes...but what's a girl to do?  And mostly...time will tell all.'

My answer is, "Soooo very changed indeed!"  Given the way immunotherapy works, that is the hope.  But, it is not without issues.  Personally, my difficulties have been minimal compared to what folks have dealt with on and post ipi, and even mild compared to what some ratties have experienced on anti-PD1.   However, events that I am certain are side effects of the treatment I received continue to this day.  The weird thing about them...or more likely, about me!!!...is that I never see them for what they are at the start.  It's kind of like living with an unstable person.  You're just kind-of rolling along, thinking, "Whew, we're doing pretty well here.  Everything seems cool."  When apropos of nothing, the request, "Pass the potatoes, please." has a certain tenor, a tenseness, a harsh screech, hanging, just under the surface.  And you know...  Shit!  Here we go again.

For instance, my last/current tadah~  Got a bit of a cold, nothing terrible, from one of my critters at work.  As per my usual, such a thing flared up my asthma a bit, that's a norm for me for my whole life.  So, no worries.  The nurses ask why I am limping at work.  I reply, "I don't know.  I think I must have twisted my hip funny putting down some mulch for a friend."  An activity that I had participated in just a few days before. Then, I realize,"Man, this cold weather sure has my skin dry and itchy!"  Ok, then, wow, "Did I bite my tongue?  I don't remember doing that.  Wait a minute!!!"  And, sure enough...a peek in the mirror shows lesions all along the side of my tongue, red and angry.  By the next day they are along the other side as well.  The itchy skin is full blown welts in places and all the residual granulomas from my vaccine injections are red, warm and swollen.  The fact that my wheezing has continued, and even worsened, over the past four weeks despite aggressive nebulizations for my asthma...makes me pretty confident that I am dealing with a mild pneumonitis, much like what would happen with some regularity after my anti-PD1 infusions.  Add to that the fact that my joint aches have roamed like the Greek humors from right hip to left ankle, right knee, left wrist and any mixture of the above.  There has been no putting down of mulch.  No strain.  Just me.  Post anti-PD1 with my weird T cells.  My personal theory is that whenever I get a mild viral process, and perhaps sometimes even when I don't, my T cells go a bit nuts and cause various autoimmune problems.  Here is what  more important folks have to say:

Arthritis and Tenosynovitis Associated with the Anti-PD1 Antibody Pembrolizumab in Metastatic Melanoma.  Chan, Kefford, Carlino, et al.  J Immunother.  2014 November 20.

"We report the acute onset of polyarticular inflammatory arthritis in 2 patients receiving the immune check-point inhibitor, pembrolizumab....after 14 and 11 months of therapy, respectively....Good symptomatic control was obtained with bisphosphonates (drugs to prevent bone loss like Boniva and Fosamax) and salazopyrin (Sulphasalazine - an anti-inflammatory), avoiding use of T cell immunosuppressants.  These cases raise important questions on whether anti-PD1 therapy allows preexisting autoimmune  T cell clones to escape tolerance by suppressing regulatory T cells or whether they allow autoimmunity to develop de novo.  These conditions heighten our awareness of complications associate with the use of these agents..."  

So...basically...these folks are noting other patients who have developed joint problems much as I have. Their question is.... Did I (and these peeps) have the propensity, though unrevealed prior to anti-PD1 therapy, for an arthritic process?  OR...did anti-PD1 cause the arthritic process on its own?  As more folks take these drugs, I think more examples of autoimmune problems not only while on anti-PD1, but in the months and years(!!!) afterwards - arthralgias as well as issues related to derm (itching), gastro (mouth ulcers, colitis), pulmonary (wheezing, pneumonitis, strange spots on CXR) - will be noted.  Of course, to be able to sit here kvetching about my little aches and itches 55 months out from Stage IV melanoma and 17 months post a 2 1/2 year trial of Nivo makes me incredibly lucky indeed.

Oh, on a lighter note!!  I'm a good 12 hours into my post-Thanksgiving/pre-New Year's CLEANSE!!!!  Yep!  Decided good ol' Gwennie and other celebs who like to publish the contents of their intestinal tracks (or absence of contents in that area) had the scoop on health and beauty!  Why should I pass up such a good thing?!  NOT!!!!  In an episode of what I am certain was an event similar to those noted above, several months ago, I got a gastro bug that was going around the critters in the office.  A little headache (ok...it did last two weeks), some vomiting and a little diarrhea....turned into 12 hours of profusely bloody diarrhea.  So, B, Tammy B, Weber, and now my gastroenterologist (Yes, Virginia....I am rapidly acquiring EVERY sort of doctor now!!!) have gone into complete panic and melt-down mode (all at different times, thank goodness....SHEW, you people wear a girl out!!!!) and tomorrow at the ever lovin' BUTT CRACK of dawn (6:40am!  W.T.H. people??!!)...and BOY!!!!...it will be BUTT CRACK fo sho!!!...I will be having a colonoscopy.

I'll be lettin' y'all know how that all comes out!!!  I know you can't wait to hear!!!

Salud! - c

#Throwback Thurday/Thanksgiving!!!!

When I say I've been cooking forever, I'm not kidding!!!  I was three in this pic and I still love me some pie!!!

If you want to make your own pie dough, be my guest...but unless I'm making a tart that is savory or one that needs to stand up to special flavors, I just roll with the store bought version...though I am partial to this style.

Roll it out a little more after a sprinkle of flour.... 

And place it in your dish...

For any berry pie...the basic recipe is:  3 cups berries, 4 tablespoons flour, 2/3-1 cup sugar depending on taste and sweetness of your berries, butter to dot over the top of the fruit...and your pastry.  I do like to add some lemon zest to blueberries or blackberries as you see here.  Nutmeg and cinnamon are nice additions with peaches and apples.

Mix.  Then place fruit mixture in your pastry lined dish.  Use a brush or your finger to dampen your pastry edge with water...that will be your 'glue' when you put on either a solid pastry "lid" or the lattice top shown below....

For a lattice top, roll out the other half of your dough as you did for the bottom, but afterwards, cut into strips.

Choose strips of appropriate lengths and smish their top edge into your water dampened edge of the bottom pastry. 

You could just lay pieces across one way and then across in the other, but I think it is fun to actually layer mine in an alternating fashion!!! 

After you have finished creating the lattice with your strips, make sure all ends are pressed into the sides of the bottom layer of pastry.  Trim off excess by running a knife around the edge of your dish and crimp it all together using your fingers or mash with the tines of a fork. AND....if you're like me and tend to forget to dot your top with butter...you can always squich it in the spaces between your lattice!  Handy, right?

You can then bake in a 400 degree oven for about 40-50 minutes, until the filling is bubbling and the pastry nicely browned, as is.  But it does protect the crust on the outer edge from getting too browned if you place a little foil collar around the edge.  You can remove it, oh around the last 10 minutes of cooking.  And using a brush to apply a little milk or egg wash to the pastry edges makes them shiny and a bit more tasty, especially if you add a sprinkle of sugar or cinnamon sugar like a special glitter topping! If you want a solid top to your pie - just lay that pastry piece on top and attach and finish the edges per previous instructions.  Do remember to add some slits (as simple or as fancy as you like) to provide vents for the steam...else-wise your pie might suffer a blow out!

No matter the style pie you choose, there will always be a little remnant of dough.  Ball it all back together, roll it out and make a tart!!! 

Fill with raisins and cinnamon sugar, blueberries and lemon curd, or any preserves you have on hand, dot with butter, fold over! 

Press edges together after they are dampened with water, crimp, and make your poke holes. 

After baking with the big pie for oh, about 15-20 minutes, depending on how big, thick or the sort of filling you put in...you now have a snack to enjoy ahead of time or a little tart for breakfast! 

Ta dah!!!!  

Enjoy!!!  Happy Thanksgiving.  May there always be pie!!!  Love - c

For Kim...

Yup!!!  Surprised you didn't I?  Just wanted to let you know that I appreciate your reading of my meanderings, laughing at my jokes, passing over things that don't mean that much to you...yet coming back for more on another day, and sharing YOUR thoughts about MY thoughts!!!  THAT is a gift my friend!  A real gift.   I appreciate it and you...everyday.

I know there are many other faithful readers out there.  Some of you come here to find the information you need about melanoma for yourself or your loved one.  Some of you read because of an interest in me.  Some people land here for rather strange reasons....like google-ing "Black Silky Chicken" (Been there, done that myself...hope my recipe helped cause there ain't that much out there on that one!!!!) and recently "another form of Botox"!  I'm sure my suggestion that the 'numbing' process for the halo application was the new wave in beauty treatments didn't help!  Or, at least I hope it didn't!!!

There are those whose role in my life would imply that they SHOULD read and comment, but purposefully choose not to.  I could focus on that.  It is rather bizarre, overwhelming, and sad.  But, to focus on that would do no good.  It would also negate all the beauty that has come my way because of those who choose to share...their lives...with me...the good and the hard.  Jonathan and Francoise, Lucy and Sue, Elaine, PJ, Eric, Steven, Jeanne....and so many more.  Friends from afar, now friends in my heart.  There are friends of my youth..now dear again....Terrie, Terri, David and the rest of you...reconnected...making me whole.

And, there are those of you I will never know...almost 150,000 peeks all together....from all over the U.S., the U.K., France, Turkey, China, Russia, Ukraine, Canada, Australia, Belgium, Germany, Spain, Netherlands, Finland, Poland, India...I wish you well.  I hope I helped.  I hope you smiled.

There are my faithful soldiers.  My rocks.  My battalion.  Ready at a moment's notice.  Your love, the armor you provide....immeasurable.  There are no words.  

So, Kim.  You make my work load lighter.  You make my day brighter.

Happy Thanksgiving.  For Kim...and all of you...I am thankful.  Love - c

Data on BRAFi combo's and effects of ipi before and after

Combined Vermurafenib and Cobimetinib in BRAF-Mutated Melanoma. 
Dreno, Atkinson, et al.  N Engl J Med 2014 September

Phase 3 study.  495 patients, previously untreated with unresectable BRAF V600 mutated melanoma got either vemurafenib and cobimetinib or vermurafenib and placebo.

	Vermurafenib and Cobimetinib	Vermurafenib and placebo
Progression free survival	9.9 months	6.2 months
Complete or partial response	68%	45%
Complete response	10%	4%
Overall survival at 9 months	81%	73%

Combined BRAF and MEK inhibition versus BRAF inhibition alone in Melanoma.
Long, Stryakoviskiy, et al.  N Engl J Med.  2014 September.

Phase 3 trial.  423 BRAF V600 of V600K mutation melanoma patients with unresectable Stage IIIC or  Stage IV disease.

	Dabrafenib and Trametinib	Dabrafenib and placebo
Progression free survival	9.3 months	8.8 months
Overall response at 6 months	93%	85%
Overall response rate	67%	51%
Fever	51%	28%

 

Combined Dabrafenib and Trametinib in patients with BRAFV600 mutant melanoma experiencing progression with single-agent BRAF inhibitor.
Johnson, Flaherty, Weber, Infante, Kim, Hamid, Sznol, Sosman, Daud, et al. J Clin Onc, 2014 Oct

Phase I/II study.   Group B = 26 patients treated with dabrafenib and trametinib after disease progression with BRAFi before study enrollment.  Group C = 45 patients treated with dabrafenib and trametinib after progression on dabrafenib monotherapy as cross over treatment.

	Group B	Group C
Overall response rate	15%	13%
Progression free survival	Treated with Dabrafenib less than 6 months – 3.9 months Treated with Dabrafenib more than 6 months – 1.8 months	3.6 months
Overall survival	Tx more than 6 months – 26% Tx less than 6 months – 0%	11.8 months

Conclusion:  Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF i resistant melanoma.  This may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy for more than 6 months but demonstrated minimal efficacy after rapid progression with BRAFi therapy.

Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in phase 1/2 clinical trial.  Menzies, Ashworth, Flaherty, Weber, Infante, Hamid, Sosman, Daud, et al.  Ann Oncol. 2014 November

Pyrexia = fever, in this case defined as a temperature at or greater than 100.4 or related symptoms.
59% of patients developed pyrexia.  24% had symptoms with recorded increased temp.  Median onset of first pyrexia was in 19 days, median duration of 9 days.  Pyrexia patients had a median of two pyrexia events, but 21% had three or more events.  No baseline features predicted pyrexia and it was not associated with clinical outcome.

Objective responses can be obtained by CTLA-4 inhibition in metastatic melanoma after BRAF inhibitor failure.  Schreuer, Chevolet, et al.  Melanoma Research.  2014 November

64 patients with unresectable Stage III/IV BRAF V600 mutant melanoma.  33 had been treated with BRAFi before ipi.  31 patients were treated with ipi first.  In BRAFi first patients:  three complete responses and 6 partial responses, with median overall survival of 10 months from start of ipi therapy.  Ipi first patients:  no complete responses and 4 partial responses, with median overall survival from start of ipi therapy was 12.3 months.  Response rate did not differ significantly between the groups.

So....not really new news.  Combo's offer better results.  Fever occurs often and can be worse in the combos, but no patient specific features can predict who develops fevers and fever has not been associated with outcome, for better or worse.  In the final study, for all their numbers, there was apparently no statistical difference in response whether you took BRAFi followed by ipi or vice versa.  Best wishes - c

I'll stand by you....

For all of you who have been there for me...  For those who have no one with whom to stand....I'll stand by you.

The Pretenders, I'll stand by you...

Oh, why you look so sad?  Tears are in your eyes. Come on and come to me, now.  Don't, be ashamed to cry.  Let me see you through, 'cause I've seen the dark side, too.

When the night falls on you, and you don't know what to do.  Nothin' you confess, could make me love you less. I'll stand by you.  I'll stand by you.  Won't let nobody hurt you, I'll stand by you.

So, if you're mad...get mad.  Don't hold it all inside, come on and talk to me now.  Hey, what you got to hide?  I get angry, too.  Well, I'm a lot, like you.

When you're standing at the crossroads, and don't know which path to choose, let me come along.  Cause, even if you're wrong....

I'll stand by you.  I'll stand by you.  Won't let nobody hurt you.  I'll stand by you. Take me in, into your darkest hour.  And I'll never desert you.  I'll stand by you.

And when, when the night falls on you, baby - You're feeling all alone.  You won't be on your own.
I'll stand by you.  I'll stand by you.  Won't let nobody hurt you.  I'll stand by you.  Take me in, into your darkest hour.  And I'll never desert you.  I'll stand by you.

For all my loves...those I've just met...those who know me well and are my circle of support...those I've known from their first breath....I'll stand by you.  Always.  No matter what.  No matter how far you may think I am.  I am here...always...for you.

Love -c