All things BRAFi...latest articles

BRAF mutation status as an independent prognostic factor for resected stage IIIB and IIIC melanoma:  Implications for melanoma staging and adjuvant therapy.
Barbour, Tang, Amour, et al.  Eur J Cancer. 2014 July 25.

5 year survival for melanoma metastasis to regional lymph nodes is less than 50%.  Knowledge of outcomes following therapeutic lymphadenectomy for stage III melanoma related to BRAF status may guide adjuvant use of BRAF/MEK inhibitors along with established and future therapies.  DNA was obtained from patients with TLND who also had 2 or more positive nodes, largest node of greater than 3 cm, or extracapsular invasion.  Mutations were most commonly detected in BRAF (46%) and NRAS (21%).  Patients with BRAF mutations had higher 3-year recurrence rate of 77% vs 54% for BRAF wild-type patients.  The only prognostically significant mutations occurred in BRAF:  median recurrence-free disease and disease specific survival for BRAF mutation patients was 7 mo and 16 mo vs 19 months and not reached for BRAF wild-type patients, respectively.
CONCLUSION:  Patients with BRAF mutations experienced rapid progression of metastatic disease with locoregional recurrence rarely seen in isolation, supporting incorporation of BRAF status into melanoma staging and use of BRAF/MEK inhibitors post-TNLD.

This seems to be important data to consider to me.  Wonder if I would have progressed had I been given BRAFi after my first lymphadenectomy with a positive node.  I would not have met this criteria as it was only one microscopically positive node....but something to think about as I experienced my second primary just before making it 5 years out.


The nature and management of metastatic melanoma after progression on BRAF inhibitors:  Effects of extended BRAF inhibition.
Chan, Haydu, Menzies, et al.  Cancer. 2014 July 1.

"Dabrafenib and vemurafenib have high response rates in BRAF-mutant metastatic melanoma, however, 50% of patients progress by 7 months." 95 of 114 BRAFi treated patients (treated between July 2009 and September 2012, whose data was collected and analyzed) had disease progression.  53 of 95 patients progressed in extracranial sites alone, 18% progressed in intracranial and extracranial sites simultaneously, and 16% progressed in intracranial sites alone. 29 of the 95 patients progressed in a single site or organ, 48% progressed in existing mets only, and 18% had new mets alone.  At the time of progression, 35 of 95 patients received no subsequent systemic treatment, 20% changed systemic treatments and 39% continued BRAFi for a median of 97 days.  BRAFi continued beyond disease progression and known prognostic factors (LDH, RECIST sum of dimension of target lesions) were associated with overall survival from the time of disease progression.

Ok.  So....perhaps continued BRAFi after progression is helpful.

Features and management of pyrexia with combined dabrafenib and trametinib in metastatic melanoma.
Lee, Menzies, Haydu, et al.  Melannoma Res. 2014 July 22.

CombiDT (dabrafenib and trametinib) is an effective treatment for BRAF-mutant metastatic melanoma.  However, over 70% of patients develop drug-related pyrexia [fever].  32 patients reviewed.  14 (44%) developed pyrexia.  Fever was recurrent in 11/14.  Pyrexia was not associated with age, sex, disease burden, RECIST response, progression-free, nor overall survival.  Paracetamol, NSAIDs and/or dose reduction were ineffective secondary prophylaxis for pyrexia, whereas corticosteroids were effective in all patients.  In patients with previous dose reductions who commenced steroids, CombiDT doses were re-escalated without pyrexia. 

So....treating fevers with steroids stops the fever and allows patients to continue effective therapy!


Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.
Curl, Vujic,  van't Veer, et al.  2014 September 8.

Genetically-targeted therapies are both promising and costly advances in the field of oncology.  They extend life but are more expensive than the previous standard of care - dacarbazine.

NOTE:  Don't forget what Weber said about Dacarbazine:  "...when talking about some of these trial options with Dr. Weber, he acknowledged that had ipi or anti-PD1 had been discovered first....Dacarbazine would never have attained FDA approval...yet, we continue to use it.  Incredible."
http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2012/12/new-trials-for-melanoma.html 

Vemurafenib costs $13,000 per month ($207,000 for a patient with median survival).  Patients failing vemurafenib are often given ipi at $150,000 per course.  "Present value of lifetime costs and quality-adjusted life years" were analyzed.   The incremental cost-effectiveness for vemurafenib vs dacarbazine was $353,993 per quality-adjusted life years.  For vemurafenib followed by ipi compared with vemurafenib alone was $158, 139. In sensitivity analysis, treatment cost had the largest influence on results:  the incremental cost-effectiveness for vemurafenib vs dacarbazine dropped to $100,000 per quality-adjusted life years gained with a treatment cost of $3,600 per month.  CONCLUSION:  The cost for time gained by treatments with vemurafenib alone or in combination exceeds...thresholds for cost-effectiveness.  These strategies may become cost-effective with lower drug prices or confirmation of a durable response without continued treatment.

Wow Curl and Vujic et al.  I hope you don't get melanoma.  You can't afford it!!!!


BRAF V600 mutations and pathological features in Japanese melanoma patients.
Yamazaki, Tanaka, Tsutsumida, et al.  Melanoma Res. 2014 July 19.

Primary sites of melanoma and the frequency of BRAF mutations might differ between races.  Melanoma is rare in Japan (1500-2000 cases per year compared with 132000 per year worldwide) and frequency and distribution of BRAF V600 mutations are unknown. Testing methods were defined.  BRAF V600 mutations were found in 41.8% of tested tumours.  Mutation rate = more than 60% in patients aged less than 60 years and more than 36% of patients with stage III/IV disease.  BRAF V600 mutations were detected in 18.8% of acral lentiginous melanomas. 64.7% of superficial spreading melanoma, 50% of lentigo maligna melanomas and 20% of nodular melanomas.

I'd have to do a little research to be positive, but those percentages for BRAF positive peeps seem about equivalent to folks in the states and Europe.  As far as BRAF status, perhaps the Japanese do better in avoiding the sun and other risk factors (known or unknown) that contribute to melanoma...or there are genetic factors we don't even know anything about...that are keeping their rates of melanoma lower than those for the rest of us.

Not sure what all this is worth....but there you go!  Best - c

Ipi induced hypophysitis

Ipilimumab-induced Hypophysitis:  A detailed longitudinal analysis in a large cohort of patients with metastatic melanoma.
Faje, Sullivan, Lawrence, et al.  J Clin Endocrinal Metab.  2014 Jul 31

"Little is known about ipi-induced hypophysitis, an important treatment complication."  Retrospective review.  154 patients with metastatic melanoma, treated with ipi between March 2008 and December 2013.  Evaluated:  Pituitary MRI, pituitary hormone assessment, and patient survival. Condition was found in 17 patients (11%).  Being male and older were risk factors, cumulative dose of ipi was not.  All patients had anterior hypopituitarism, none had diabetes insipidus.  Was persistent in most (76%).  "Diffuse pituitary enlargement was observed exclusively in all cases and, upon retrospective review of MRI's, this finding preceded the clinical diagnosis of hypophysitis in 8 patients.  Median survival in patients with ipi induced hypophysitis was 19.4 vs 8.8 months in the remainder cohort."
Conclusions:  "Male gender and older age are risk factors.  Pituitary enlargement is sensitive and specific....can precede clinical diagnosis, and resolves rapidly.  Anterior pituitary function recovery is uncommon.  Incidence of hypophysitis may positively predict survival in melanoma patients treated with ipi."

 For what it's worth....hang in there ratties!!! - c

So.....is it really ok to hit your kid..even if it's with a switch?

A "paddle"?  A hair brush?  A coat hanger?  A hand?  A belt?  Flyswatter?  Broom?  When was that ever ok?  How do folks rationalize it...EVER???  "Well, my pappy beat the shit out of me, so if it was good enough for me....it is good enough for my kids!"  That's called a cycle of abuse, people.  Does it really take a little four year old kid, with linear cuts and bruises to his legs, buttocks and scrotum to garner national attention to basic child abuse?  And that horrible, unwarranted, disgusting, atrocious "punishment" meted out by an incredibly powerful, adult, male, athlete to a pre-schooler...provided appropriate punishment for what?  What could a four year old, 6 year old, 8, 10, 12 year old possibly do to deserve such treatment?  AND....not at the hands of a "child abusing "STRANGER!!!  NO!!!  By his own father!!!  Worse yet, is it because of the unacceptable horror of this act, that this story has made headlines in every grocery store tabloid, cable and network news, reputable magazines and NPR????

Sadly, no.

It is because his father can run really fast, catch a ball, and make more money in one year than hundreds of folks will see in their cumulative lifetimes.  Wow.  What excuses adult abusers will give themselves.  Picture these children in your mind.  Not just this one.  Their sweet dimpled elbows.  Their extreme desire to please.  Their gooey little hands.  Their sweet breath and soft arms akimbo as they sleep.  What would we, as a nation, be saying if this child had been abducted by a poorly shaved, unkempt fellow...who fed the kid a good meal, did nothing pervy with "private" body parts...just simply, beat the crap out of him with a switch, leaving stripes of bloody, bruised flesh on the parts already noted, and returned him, "safe and sound" - though now duly punished for his horrid 4 year old crimes - to his loving father?   I don't think we would say that was ok.  No, not at all.  There would be a huge manhunt - for the guy who "disciplined" the fast running man's kid!

Just a few facts:  Spanking children with an open hand, paddle or switch is NOT illegal in the United States.  It IS illegal in more than 30 other countries including Sweden, Bulgaria, and Kenya.  More than 100 nations have banned corporal punishment in schools, yet 19 U.S. states allow teachers to paddle a child.  We in the U.S. remain self righteous in our bad parental behaviors even though years of psychological data prove that hitting children as punishment is ineffective and dangerous.  Corporal punishment has been proven to lower I.Q. while increasing the incidence of depression, low self esteem, aggression, spousal and child abuse (down the line) as well as crime.  So...good times!  Way to teach that kid a lesson!

At least at this point, Adrian Peterson has been indicted by a grand jury and stands accused of reckless/negligent injury to a child and public outcry has been enough to make his team at least ponder what the viewing public will think if they continue to pay a child abuser a zillion dollars per game.  It's time to break the cycle of abuse.  Time to stop condoning and excusing, irresponsible, heinous, adult behavior. Time to think about the kids.  And...if you did this shit?  You should at least tell your kid you're sorry.  And mean it. No excuses.

Think about it.  Cause if there is a God.  He ain't smilin no rainbows at you. - c

Weber presentation on ipi combo's and combo's coming soon!

Here is a link to Weber's presentation in Paris July 2014:
Combination therapy presentation by Weber

My synopsis:

Nivolumab (anti-PD1) and ipilmumab (anti-CTLA-4) given concurrently-
Nivo at 1mg/kg and ipi at 3mg/kg for 4 doses then followed by nivo alone for 96 weeks.
Best results so far, but with significant toxicities.
Trial requires that when dose limiting toxicity develops, patient must stop trial.
Weber feels you can treat the patient with steroids and then safely resume with nivo alone.
Positive or negative BRAF status did NOT matter in regard to response.
PDL1 tends to "fall out" as a factor...folks positive or negative for it could still respond to concurrent therapy.
In concurrent cohorts = 43% overall response, 17% complete response, 79% 2 year survival
Though that still leaves 50% of patients who did not respond.

Nivo and ipi given sequentially-
Group with nivo first, followed by ipi - another with ipi first, followed by nivo
He is working on the study currently with Hodi.
The hope is that a higher dose of ipi can be administered in this manner without invoking dose limiting toxicity and yet increase response rates.

Ipi and Tvec-
The idea here is that one could prime an immune response by injecting a tumor with an oncolytic virus, eliciting a T-cell influx, and follow with systemic ipi.
Overall response rate of 56%, with 6 of 18 patients acquiring complete responses.
Weber likes the idea of priming tumors locally and following with systemic therapy, either ipi or anti-PD1.

Ipi and INCBO24360 (an IDO inhibitor)-
The problem with immunotherapy is that there are suppressive influences in the immune system - the absence of effector cells, the presence of t-reg suppressor cells (activated by LAG-3), myeloid suppressor cells, IDO (which is generated by antigen presenting cells as well as T-cells)....all working to prevent an immune response against melanoma! In this study, an IDO inhibitor was given (at either 25 or 50mg) orally, twice daily, everyday.  Ipi was given at 3mg/kg every 3 weeks.
Was well tolerated.  33% response rate.
Immunotherapy naive patients did better.
This study speaks to the ability to overcome micro-environmental immune suppression as well as increase the influx of effector cells by decreasing IDO.

Nivo and peptide vaccine-
Idea was that if you gave multi-peptide vaccine you could amplify the immune response against the peptide, and get a better response from nivo.  No evidence that this worked at all, though nivo itself did well.
100 patients, initial ones got peptide vaccines with escalating nivo dose, depending on cohort, every 2 weeks for 6 months, then nivo alone every 3 months for 2 years.
Cohort was added (later) that allowed patients who had dose limiting effects on ipi-
20 evaluable patients as one dropped out.
Got nivo alone (no vaccine).
8 confirmed partial responses and 3 stable patients at 24 weeks.  All patients who responded still remain in remission, with one being out 1 1/2 years.
Only 2 patients had dose limiting toxicity on nivo...rash and pneumonitis.
However, these were not the same DLT that they had experienced on ipi.
40% response rate.
Most anti-PD1 trials haven't allowed patients with prior bad responses to ipi.  Weber feels as these patients go to doctors seeking anti-PD1 as it comes on the market, they should be treated with it!
Back to general results-
The presence of peptides or not, ipi refractory or naive - made no difference in results.
26% response rate in these very ill patients, s/p multiple treatments.
NOTE by Weber:  The pembro studies demonstrate a significant difference in response rate between ipi naive and ipi refractory patients [with refractory doing less well].  "It makes you wonder- Are these drugs really the same?"
Looking at pretreatment parameters in the periphery and the tumor-
Only baseline MDSC, myeloid derived suppressor cells, proved to be significant.
These are CD14, HLA-DR low, CD11 B+ cells, classic myeloid derived suppressor cells which express high levels of PDL1 and other check point proteins.
Neutrophil derived MDSC cells were not related.
The more myeloid suppressor cells you have, the worse the patient did both in response rate and survival. 
Weber hopes to soon have results of the levels of MDSC from within the tumors of these patients and see how that level related to outcomes.
You can block MDSC by incubating it with PD1 antibody as well as other check point proteins, so he is writing a grant proposal currently to test a combo of nivo with MDSC depletion.
Measurements of the T-regs in the periphery - Levels decreased in responders, in non-responders it went up. For this reason, also thinks that nivo with T-reg depletion is worth investigation.
There was worse overall survival in female patients.
Given responses in this group with 2 1/2 year end-point of anti-PD1 infusion...Weber questions whether patients really need to continue anti-PD1 infusions until progression as the Pembro trials/indications have been written.

Ipi and Peg interferon-
Ipi at 3mg/kg every week for four doses with 3mg/kg peg interferon sub-q weekly for up to 3 years.
30 patients. 1 compete response. 13 partial responses. 3 with stable disease.  46% response rate.

Planned combo's-
Pembro and T-vec
Pembro and IDO inhibitor
Pembro plus BRAF plus MEK
MEDI 4736 and anti-PDL1
Nivo and anti CD137 (to start in the next month or so!!!)
Nivo and anti-LAG-3
Adjuvant ipi and Nivo (now being expanded with 1,500 patients!!!!)
     So far, in patients in the first cohort - there has been a 45% response rate, with only 20 patients and only at 8 month f/u...no relapses, and includes patients with Stage IV/IIIC melanoma.

So there you have it folks.  Hope this helps! - c

My melanoma stats and update on my Nivolumab trial cohort

CT's of neck, chest, abdomen and pelvis along with an MRI of the brain were all negative a couple of weeks ago.

At this point, I am:
133 months post original melanoma diagnosis in 2003
53 months Stage IV
47 months NED
45 months since starting the Nivolumab (BMS' anti-PD1)/peptide vaccine trial
15 months after my last Nivo dose

     As per routine we drove down to Atlanta and flew on to Tampa last Thursday.  It was not our strangest trip by any means, but traveling on September 11 made it a little nervy.  And whether that had anything to do with anything, the TSA peeps in Atlanta seemed a bit on edge as well. For grins and giggles, the chaos that is the Atlanta airport, that I know all the in's and out's of at this point, is under construction...inside and out.  So much so, that they are actually paying people to stand and direct "people" traffic within the terminal.  But, if I've walked it once, I can do it again, so that was OK, though parking and driving about was not so easy. I was yelled at, loudly, by one TSA lovely, to stand directly in front of his podium, rather than the three inches to his left I was inadvertently pushed into given the crowd.  After gaining his blessing, we were herded, as ever, into lines for the scanners.  As we (hundreds of us!!!) were wearily getting ready to lay our carefully zip-locked 3 ounces of shampoo and deodorant into plastic bins and shed our shoes...a commanding voice boomed overhead:  "DO NOT REMOVE ANY ITEM FROM YOUR BAG!!!!!"  "DO NOT REMOVE YOUR SHOES!!"  "I REPEAT...DO NOT REMOVE ANY ITEM FROM YOUR BAG!!!"  Now, I grant you, in a normal world, reasonable people would say, "Duh!!!?  Why on earth would I take off my shoes and unpack my bag as I am about to board a flight!!?  Are you kidding me?"  However, in our current altered reality, this admonition brought forth a great deal of confusion. But, we wonderingly complied.  All of us certain we would be slapped up side the head when we entered "the area" with our little baggies still ensconced within our luggage and our shoes on our feet.  But....it was not so.  Indeed, we simply put our bags on the conveyor with all precious liquids still hidden within and our wee little shoes still in place, and just walked through the metal detectors!!  Some folks had their hands swabbed...Lord only know why!...but B and I were even waved past that.
     The flight was rather unremarkable as was the night in Tampa, other than the fact that I did select a grey standard car-like Hyundai with some trepidation, given the memory of difficulties Ruthie and I have experienced in finding such a typical grey car-car in any parking area.  But, it was the most reasonable option.  And, sure enough, on returning to the car park after dinner I saw a line of more than 5 grey cars lined up with ours.  "It had to be grey, didn't it?" I muttered to Brent.  So, I click the remote, which I had already struggled with a bit, as it was separate from the key and there were actually two...with strangely different purposes.  (Why, Hyundai?  Why!!?)  At any rate...nothing happened.  I worked with the other remote.  Still nothing.  I decide to resort to the old fashioned key-in-lock approach.  As I was deciding upon the key to use for that (there were three!) B remarks, "It's amazing how much these Hyundai's look like Honda Accords."  In my head, I ran through this list:
1.  B knows nothing about cars.
2.  Hyundai's look nothing like Accords.
3.  Holy Shit!!
I walk to the back of the....yep, a Honda Accord!  And NOT our Hyundai, which is three grey car-cars down!!!  I can hardly get it open because I am laughing like a hyena.  Guess B knows more about cars than I thought, though he stood ready and willing to get into a car that was not his own!!!!
     Up at our usual Butt-Crack-of Dawn, in order to have labs, see Weber, and make our return flight.  To Moffitt we go, straight to the lab.  And...just for the record...honesty is NOT the best policy...something I can never seem to learn.  When finally positioned in the chair for stabbing, cute little girl asks if I have a port.  "No," I reply.  Which is met with a very disappointed face.
     "Oh, I see."  Bit of a pause.  "Have you ever have lymph nodes removed from your arms?"  
     "Yes," I say.  "Complete lymphadenectomies, bilaterally." 
     "Then, do you have a standing order?"
     "For, what?  Drawing lab?  I have no idea.  But, I've been having it drawn here for the past four years!"
     That is met with a look of extreme consternation.  "Well, I have to have an order.  You should not have blood drawn in your arm if you have had lymph nodes removed!"
     I reply, "You're absolutely correct.  Nor blood pressures, or finger sticks, or pretty much anything.  However, like many of the patients here, I would imagine, I seem to have run out of options."
    Well, I'll have to see about this!"
     "OK."  And, off she goes.  A bit later, she returns with a rather jolly lady.  B has been standing rather dejectedly this whole time.  The lady explains that Moffitt lab services has a new policy that requires the oncology doc to give permission for their patients to be stuck post lymph node removal, but happily says she'll just call Weber for the order and we are shooed back into the waiting room.  It is clear to me that the surgeons have pitched a fit, and some lab supervisor, or VP of laboratory services, as they like to be called, caught shit because someone was stuck against their surgeon's orders, without an oncology order, and developed lymphedema.  Whether that unfortunate development was really due to that stick is certainly debatable, but they do not intend to be the peeps with their ass on the line any further!  All speculation on my part, of course...but given my years on both sides of the aisle in this weird world...I'm pretty certain that's how that all went down. 
     "Great!" says B.  "That's one way to let Weber know you're in Tampa!"
     How this is all my fault, I do not know...oh, yeah - I told the truth.  Anyhow, after a bit of a wait, we are waved back into the stabbing area by the jolly lady.  She is quite funny and entertaining, and very good at her job.  Weber, it appeared, had given her the order, along with a good deal to say on the subject as well.  She offered the donkey (aka B) a "stool specimen" so he could take a load off.  The woman can certainly recognize a donkey on the edge when she sees one.  B was taken aback,  as he is the one generally cracking those sorts of jokes.  After a few more laughs we were back out and on our way upstairs to Weber's office.  Sign-in remains bizarre.  How many places within one building and a gigantic computer system must one show id and have them repeatedly scanned in?  Oh!  And the lady checking me in?  Actually asked for my "ids"...not 'I' period 'D' period....as in the letters...but my "ids"...as though that is a word...like - id and ego!!!  I almost allowed my id to take over....but having dealt with her before when she complained endlessly about how hard she had been working, because "all morning there had been patients, standing wall-to-wall in the waiting room" and I had replied, "Wow!  That must have been nice for the cancer patients!"...a remark that had completely no meaning for her and slowed her complaints not at all....I merely handed her my license.  My ego in control.  Freud would be so pleased.
     After a bit of a wait, while a tiny little wheel chair bound old lady spoke in a  non-stop mono-tone, "Yep.  She used to take care of me and then she passed.  But, Martha would come up to the house and we would....mumble, mumble....and then she passed.  And, you remember so-and-so, we always went to church...mumble, mumble...but then he passed."  All this to her 300 pound female companion, who was making full use of the "love seat" sized straight chairs you see in waiting rooms these days, and managed to put on a full face of make-up, from foundation to blush to eye liner to mascara while waiting and making the occasional, "Umm huh" to her talkative friend.  It was all quite impressive.
    Completely new set of MA's to do BP and such.  But, Jennifer, Weber's right-hand nurse, the most amazing woman in that office, who has been a God-send to us on many occasions....especially when we were just starting the trial and trying to coordinate all the visits and the every two week regimen...poked her head in to say hi.  A bright light for us and many others I am sure.

So....Here's the important stuff ~ WHAT WE LEARNED ~ (as best as I can tell you!!!)

Of the 33 patients in my NED cohort (the first batch of which were given Nivo 1mg/kg [me], the next had 3 mg/kg, with the last getting 10mg/kg...all of us with peptide vaccines...every 2 weeks for 6 months...and then our set dose of Nivo alone every 3 months for the next 2 years) most are doing well.  10 have relapsed.  Most within the first 6 months.  5 of those have passed.  The last two of those who relapsed had their new tumor surgically removed and remain NED currently.  I am not clear about what treatment the other three were given and what their current condition is.  None of the brain met folks have relapsed so far.  And at this point, if you do the expected math, 16 of us should be dead, rather than the poor 5 we have already lost.

20 additional NED melanoma patients were added in cohort 4, to my trial.  They were given Nivo at 1mg/kg along with ipi at 3mg/kg.  Their clinical response was very good, but 1/2 of them had to stop the trial due to side effects.

A new cohort #5 has been created.  It will accept 1,500 resected melanoma patients, from Stage III B/C to Stage IV.  Due to the high incidence of side effects with the prior combo....the dosages were flipped.  These patients will now be given Nivo at 3mg/kg and Ipi at 1 mg/kg.  Side effects remain a concern, especially for those at Stage IIIB as their risk for their melanoma is less than that of NED patients Staged IIIC/IV, and such side effects always have to be weighed against risk of disease, but should be decreased for everyone with this particular dosing plan.  There is no HLA typing requirement as no vaccines will be given.

Here is a link to the trial on the NIH website:  Ipi/nivo combo for NED melanoma patients!!!!

Questions asked:
     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. (Their life span and function will have to wait for a different post as this one is over-long already!!!)  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.
     One other bit of good news....as proven by those lovely graphs where melanoma patients seem to fall precipitously downward, into the pit of despair....there is a leveling off.  And...theoretically, that occurs....just about....NOW!!

Around 5 years out.  Which is where I and my other ratties are rapidly headed.  It's just that a little Jiminy Cricket inside me knows....I once, almost, made it out 5 years....only to go round the mulberry bush again.  Granted, that was when I was only status post melanoma lesion and node removal.  I have the cherry trees to prove it.  So.....we shall see.  We shall see.

More about me, my labs, and those good old memory cells later.  Love to the ratties! - c

It's a new dawn, it's a new day, it's a new life, and I'm feeling good....

It takes a special person to make a change, to push forward, to persevere when things are less than fun.  For all my besties...feeling better, working hard, moving forward, living it all...the good and the bad....a day at a time...without a magic wand....Jonathan, David, Fred-o, Roo, Jeanne, Frank, Ruthie, Char and Shane.  It's not easy.  But...Nina knows....

Nina Simone - Feeling Good - Bassnectar Remix

Birds flying high, you know how I feel.
Sun in the sky, you know how I feel.
Breeze driftin' on by, you know how I feel.

It's a new dawn, It's a new day, It's a new life, For me
And I'm feeling good, yeah.

Fish in the sea, you know how I feel.
River running free, you know how I feel.
Blossom on the tree, you know how I feel.

Dragonfly out in the sun, you know what I mean,
don't you know?
Butterflies all havin' fun, you know what I mean:

Sleep in peace when day is done,

Stars, when you shine.. you know how I feel.
Scent of the pine, you know how I feel.
Oh freedom is mine
And I know how I feel.

It's a new dawn, It's a new day, It's a new life, For me
And I'm feeling good.

Y'all got this.  It's a new dawn, It's a new day, It's a new life.....for all of you....and that makes me....feel good.  Love - c

Our lives are not our own...

....From womb to tomb, we are bound to others.  Past and present.  And by each crime and every kindness, we birth our future.

My life extends far beyond the limitations of me.

Thanks, Cloud Atlas....again.  C

Anti-KIR (lirilumab) with Nivo - New Trial!!!

A phase I dose escalation and cohort expansion study of lirilumab (anti-KIR, BMS-986015) in combination with Nivolumab (anti-PD-1, BMS-936558, ONO-4538) in advanced solid tumors.

Abstract from ASCO 2014 - Segal, Hodi, Sanborn, Wolchok, Topalian, et al.

Killer cell immunoglubulin-like receptor (KIR) and programmed death-1 (PD-1) are immune receptors that down regulate natural killer (NK) cells and T-cell activity.  Immune checkpoint blockade is emerging as a novel form of cancer immunotherapy.  Lirilumab, an anti-KIR antibody, potentiates NK actitivity and innate immunity, with only modest side effects per a phase I monotherapy trial.  Nivo, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, potentiates T-cell activity and adaptive immunity, and has shown durable activity in various solid tumors, including melanoma, kidney cancer and non-small cell lung cancer.  We hypothesize that [together...they will result] in greater clinical activity than with either agent alone.

This is the first collaborative trial to be conducted by the International Immuno-Oncology Network.  150 patients with any solid tumor (excluding primary central nervous system tumors) will be given Nivo at 3mg/kg IV q2wks plus lirilumab 0.1, 0.3, 1, or 3mg/kg q4wks, in 8 week cycles (max 12).  Primary objectives are to determine safety, tolerability, dose limiting toxicities, and max tolerated dose of the combo.  Secondary objectives = anti-tumor activity, drug action, and immunogenicity, as well as effects on tumor infiltrating lymphocyte subsets in melanoma and squamous cell carcinoma patients.  Exploratory objectives include assessment of innate and adaptive immune responses in peripheral blood and/or tumor specimens and correlation with clinical outcomes.

Trial info -NCT01714739

Still recruiting as of August update!! Locations in the US = University of Chicago - IL, John Hopkins - Maryland, Dana-Farber - Mass, Sloan Kettering - NY, Providence Portland - Oregon.

Wishing my best to all the ratties!!! - c

Studies listed as adjuvants for melanoma (including uveal, mucosal and ocular)....not advocating all of them, but adjuvant options are out there...forgive formatting, best I could do! Call the sites if interested!!!

Recruiting	A Phase II Study of Imatinib Versus Interferon as Adjuvant Therapy in KIT-mutated Melanoma   NCT01782508 For-Melanoma, Drug = Imatinib, interferon
Recruiting	A Study of the BRAF Inhibitor Dabrafenib in Combination With the MEK Inhibitor Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma After Surgical Resection.  NCT01682083 For-Melanoma, Drug = Dabrafenib, trametinib, placebo
Recruiting	Adjuvant, Combined Interleukin 2 (Proleukin) and DTIC (Dacarbazine) in High-risk Melanoma Patients   NCT00553618 For-Metastatic Melanoma, Drug = Proleukin, Dacarbazine
Recruiting	Adjuvant Crizotinib in High-Risk Uveal Melanoma Following Definitive Therapy NCT02223819 For-uveal melanoma, Drug = crizotinib
Recruiting	Adjuvant Dabrafenib (GSK2118436) in Patients With Surgically Resected AJCC Stage IIIC Melanoma Characterized by a BRAFV600E/K Mutation NCT01682213 For-Melanoma, Drug = Dabrafenib
Recruiting	Tumor Cell Vaccines and ISCOMATRIX With Chemotherapy After Tumor Removal NCT01341496 For-sarcoma, melanoma epithelial and pleural malignancies.  Drug = Modifies autologous tumor, cyclophosphamide, celecoxib
Recruiting	Phase II/III Clinical Study CSF470 Plus BCG Plus GM-CSF vs IFN Alpha 2b in Stage IIB, IIC and III Melanoma Patients NCT01729663 For-cutaneous mel, Biological-CSF470 vaccine, BCG, molgramostim, Drug-interferon alpha 2b
Not yet recruiting	Study of Neoadjuvant Vemurafenib for BRAF Mutant Melanoma and Palpable Lymph Node Metastasis NCT02036086 For-melanoma, Drug = vemurafenib
Not yet recruiting	Adjuvant Sunitinib or Valproic Acid in High-Risk Patients With Uveal Melanoma NCT02068586, For-ciliary body and choroid melanoma and intraocular mel,Drug-Sunitinib, valproic acid
Recruiting	BRIM8: A Study of Vemurafenib Adjuvant Therapy in Patients With Resected Cutaneous BRAF Mutant Melanoma  NCT01667419, For-mel, Drug = vemurafenib
Recruiting	Ipilimumab for Uveal Melanoma NCT01585194, For-uveal mel, Drug, ipi
Recruiting	Messenger Ribonucleic Acid (mRNA) Transfected Dendritic Cell Vaccination in High Risk Uveal Melanoma Patients NCT00929019, For-uveal mel, Drug = autologous dendritic cells.
Recruiting	Peptide Vaccine and Temozolomide for Metastatic Melanoma Patients NCT01543464, For-malignant mel, Drug = chemo-temozolomide
Recruiting	Ipilimumab or High-Dose Interferon Alfa-2b in Treating Patients With High-Risk Stage III-IV Melanoma That Has Been Removed by Surgery NCT 01274338 For-recurrent mel, Stages 111B, IIIC, and IV.  Drug = ipi, recombinant interferon
Recruiting	Phase I/II Trial of a Long Peptide Vaccine (LPV7) Plus TLR Agonists NCT02126579, For-mel – metastatic and mucosal.  Drug = peptide vaccine LPV7+tetanus peptide, polyICLC, Resiquimod
Recruiting	Dendritic Cells Plus Autologous Tumor RNA in Uveal Melanoma NCT01983748 For-uveal mel, monosomy 3 positive, no mets.  Drug = autologous dendritic cells
Recruiting	NY-ESO-1 Vaccine in Combination With Ipilimumab in Patients With Unresectable or Metastatic Melanoma NCT01810016 For-unresectable mel.  Drug = ipi, NY-ESO-1protein vaccine, NY-ESO-1OLP4 vaccine
Recruiting	A Phase I Study With a Personalized NeoAntigen Cancer Vaccine in Melanoma NCT01970358 For-mel, Drug = poly-ICLC peptides
Recruiting	Trial of Ipilimumab After Isolated Limb Perfusion, in Patients With Metastases Melanoma NCT02094391 For-in-transit mel Stage IIIB and IIIC. Drug = ipi
Recruiting	Safety and Immunogenicity Study of Multi-phosphopeptide Vaccine Plus PolyICLC in Participants With Melanoma NCT01846143  For-mel, Drug = biological phosphopeptides
Recruiting	A Phase I Trial of a Vaccine Combining Multiple Class I Peptides and Montanide ISA 51VG With Escalating Doses of Anti-PD-1 Antibody Nivolumab or Ipilimumab With Nivolumab For Patients With Resected Stages IIIC/ IV Melanoma NCT01176474 For – mel. Drug = Nivo, ipi {NOTE – my trial….peptide vaccines no longer given}
Recruiting	Vaccine Therapy and Resiquimod in Treating Patients With Stage II-IV Melanoma That Has Been Removed By Surgery NCT01748747 For-mel, Drug = montanide, MART 1 antigen
Recruiting	Immunotherapy of HLA-A2 Positive Stage II-IV Melanoma Patients NCT01308294. For-mel, Drug = vaccine
Recruiting	Neurotropic Melanoma of the Head and Neck NCT00975520, radiation
Recruiting	Vaccination With Autologous Dendritic Cells Loaded With Autologous Tumor Lysate or Homogenate Combined With Immunomodulating Radiotherapy and/or Preleukapheresis IFN-alfa in Patients With Metastatic Melanoma: a Randomized "Proof-of-principle" Phase II Study NCT01973322 For-nonresectable Stage III or IV mel, Drug = Autologous dendritic cell vaccines, radiation, IFN
Recruiting	CDX-1401 and Poly-ICLC Vaccine Therapy With or Without CDX-301in Treating Patients With Stage IIB-IV Melanoma NCT02129075 For-ciliary body, choroid, extraocular, iris, intraocular, mucosal mel or melanoma Stage IIB – IV Drug = recombinant flt3 ligand, vaccine
Recruiting	A Phase I Study of Intralesional Bacillus Calmette-Guerin (BCG) and Followed by Ipilimumab Therapy in Patients With Advanced Metastatic Melanoma  NCT01838200 For-metastatic mel, Drug = BCG vaccine, ipi
Recruiting	Vaccine Therapy With or Without Interleukin-12 Followed by Daclizumab in Treating Patients With Metastatic Melanoma NCT01307618 For-recurrent mel, stageIV.  Drug = peptide vaccine, MAGE-3.1 antigen, interleukin-12, Mart-1 antigen
Recruiting	Trial of pIL-12 Electroporation Malignant Melanoma NCT01502293 For-mel, Drug=Plasmid interleukin-12
Recruiting	Imiquimod to Detect Residual Lesions and Prevent Recurrence of Lentigo Maligna NCT01088737 For-lentigo maligna, Drug = imiquimod