(Good) News on anti PD-L1 MPDL3280A / Immunotherapy

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Maia
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(Good) News on anti PD-L1 MPDL3280A / Immunotherapy

Postby Maia » Sat Feb 01, 2014 8:06 am

Some good, hopeful news to share, in the middle of too many sad news.

A NEW clinical trial with Roche-Genentech's anti-PD-L1 agent (MPDL3280A or RG7446) has just started. It will test MPDL3280A in combination with other new agent -Cobimetinib, which is a MEK inhibitor. Anti-PD-L1 agent is administered IV, cobimetinib is oral, given by mouth.

A Study of the Safety and Pharmacology of MPDL3280A Given With Cobimetinib in Patients With Locally Advanced or Metastatic Cancer
http://clinicaltrials.gov/ct2/show/study/NCT01988896

The study is interventional, not randomized -all participants receive the drugs. There are 2 phases planned: dose finding and dose expansion.
There are many locations(this time, outside the States too: Canada (yes! : ), Germany, Australia, UK, Spain, etc. Right now (Feb 1st) they seem to be recruiting only in New York (I guess, Sloan), Tennessee and North Caroline.

Drugs that target the PD-1 and PD-L1 'pathway', in cancer biology, are not chemotherapy but immunotherapies; these agents have been the stars at ASCO and ESCO 2013. MPDL3280A is the agent that looks more promising for CRC.
If this this board, we have been talking about this topic very often ( viewtopic.php?f=1&t=42504 viewtopic.php?f=1&t=42504#p314278 viewtopic.php?f=1&t=39022 )
Our good friend Dianne has been in a trial with MPDL3280A plus Avastin since August 2012 and generously has been sharing her experience, here and there (viewtopic.php?f=1&t=38822&p=310705#p310705 viewtopic.php?f=1&t=38822&start=360#p320385 viewtopic.php?f=1&t=45437&p=329217#p329206 )

I'm keeping on eye on it and will be updating when new locations change from "Not yet recruiting" to "Recruiting" :)

ETA: The older, up-going trials with MPDL3280A, relevant for CRC, are the one in combination with Avastin and/or chemo (http://clinicaltrials.gov/ct2/show/NCT01633970 ) and the one as single agent (http://www.clinicaltrials.gov/ct2/show/NCT01375842 )

NWgirl
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Re: (Good) News on anti PD-L1 MPDL3280A / Immunotherapy

Postby NWgirl » Sat Feb 01, 2014 1:43 pm

Thank you for posting this Maia. I have to confess, the whole trial thing is completely overwhelming to me. You seem to stay on top of things amazingly well - so I hope you don't mind if I ask you a question that is probably answered elsewhere in one or more threads. I guess that means I'm admitting up front I'm too lazy to do lots of searching and reading.

I'm stage 4 with mets in my lungs/lymph nodes between my lungs. I'm relatively healthy other than being sick and tired from too much chemo. Currently on Erbitux/Irinotecan. Next scan in a month or so. Last couple of scans have shown growth in my lungs (had radiation to the biggest spot in October).

My question is this. I'm about 3 hours south of Seattle - I thought in one thread you posted something about a promising trial in Seattle. At what point should I consider doing a trial? I don't want to wait too long - on the other hand, I'm afraid to step away from my current regimen for fear it would allow the cancer to grow. From all you've posted here, in your opinion, is there stuff in Seattle I should check into? I know you're not a doctor - any information you share I would discuss with my oncologist of course.

I hope I'm not overstepping asking you these specific and direct questions - it's just that you really do seem to keep close track of what's going on with trials and I respect your opinion.

Thanks for all that you do for all of us here!
Belle - "Don't Retreat - Reload"DX 10/07 Stage III Rectal
Surgery 11/07; 27 of 38 nodes
Perm Colostomy 8/11
12/10 recurrence lungs & LN's
VATS Jan 2011
Radiation Oct 2013
Chemo for Life
2012 Colondar Model

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Maia
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Re: (Good) News on anti PD-L1 MPDL3280A / Immunotherapy

Postby Maia » Sat Feb 01, 2014 4:13 pm

Belle, I've read your blog so I never would think you're lazy! :) But you have so much going on --I'm happy to help you in any way I can, and save you some time searching.
As you said, I'm not a doctor so I'll give it just my laywoman opinion, based in what I've read and based on emotion, probably. Also, know that I only have been focused in trials that involve immunotherapy (harnessing the own immune system against the cancer), cancer stem cells inhibitors (agents that go against the 'seeds' of the disease) *or* a bit of chemotherapy with the idea of long-term remission (or cure). I'm not really aware of those that involve new chemotherapies; if there are still any, they go under my radar, I'm afraid.
At what point should I consider doing a trial? I don't want to wait too long - on the other hand, I'm afraid to step away from my current regimen for fear it would allow the cancer to grow.

*If* you're considering to do a trial, I'd say don't wait until you had 2nd or 3rd line of treatment. I feel that's a frequent mistake in treatment strategy.
First, there is the problem of the inclusion criteria: yes, some trials will take only people for whom all lines of therapies have failed but others won't take people who exhausted all options. Also, people may be in not good shape to travel and do all the errands that trials usually involve, if they wait until the disease is too advanced.

Second, if you're going for trials with immunological agents (like vaccines, these PDL / PDL1 agents, etc.), you need to have some immune system left, because the idea is that your own immune system will take care of the cancer -with chemotherapy at the maximum tolerated doses that the standard-of-care uses, the treatment is destroying cancer, yes, but also your immune system *and* it's promoting stemness (the persistence of cancer stem cells, the 'seeds'). So, just my opinion, but I think it's best if you don't consider a clinical trial as 'last chance'. I'd go for a clinical trial even before having second line chemotherapy, for example.

Said that, clinical trials are that... trials. Experimental. That an agent is 'new' doesn't mean is best, or free from side effects. So one need to do some research about what side effects people are getting from them, what results; sometimes you go for a Phase I clinical trial (say, certain agent as monotherapy), which may sound scary (Phase I!), but if you know that there is also an ongoing Phase III trial for that same agent in combination with something else, and it's safe... that gives you some reassurance.
Also, you always can quit the trial -because you don't like the side effects, because you're tired of traveling, etc. I'd be a bit cynic and say that maybe the researchers themselves will leave you out of the trial if you're in any danger, not only because they are doctors but because they want their numbers to look good : ) Reality is that you're watched with hawk's eyes if you're in a clinical trial. If a cancer is not responding, the patient will be probably out of the trial and back to standard treatment. And, as a stage IV unresectable patient, you may get some decent months thanks to the 'failed' trial, which is not little.

I said *if* you're considering to do a trial because I realize that they are not for everybody; I don't think everybody should go or can go for a trial. Some people can be very smart using the regimens that the standard of care offers, or alternative/ complementary stuff, or both, and find it's way during long time with that.

Since you asked direct questions, I'm giving you direct answers: being in Seattle, I'd go to the Seattle Cancer Care Alliance to see Dr Edward Lin. He would know if you are eligible for the trial he's doing (ADAPT trial capecitabine + celecoxib http://clinicaltrials.gov/show/NCT01729923, in your case it'd be without radiation), or he would give you chemotherapy but doing a lot of tweaks so your life is not miserable with the idea of put you in long, long term remission, because the treatment would be targeting the *stem* cancer cells (say, ten years; for me, it would be very different to endure chemo for some months if there is that goal, than doing chemo just until my body can take it. Sorry to be blunt, but I see your signature and I've read your blog, so I know you're a realistic person and you know that chemo won't cure you or allow you to live lots of years with good quality of life. Isn't great to think that you may have a new chance? Watch this, if you have the chance: http://www.youtube.com/watch?v=aIyUSAHtPBI). He would also add immunological agents (GMCSF shots, for example) and other out of the box ideas, if you're game. And even if you go there and don't like him at all, you'd be in the place where this trial I posted here, MPDL3280A, will be held (I'm pretty sure the location listed there in Seattle, Washington, is the SCCA).
I've posted ad nauseam about Dr Lin protocol and I know many may think I'm his agent but you're in Seattle so I have not other option that tell you about him : )
PM if you want me to be even more direct : )
And, hey, thank you for the trust... makes me blush. I'm just a stubborn book editor who wanted and failed to help her friend, not other credentials : )

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CRguy
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O/T reply for Maia

Postby CRguy » Sat Feb 01, 2014 4:45 pm

Maia wrote:....... not other credentials : )

.....except maybe being a loyal friend and supporter to many here on the CClub, tireless infohound/"researcher" who gets the good news out online and has made many friends here by being the good person you are .....

Only those other credentials.
:mrgreen:
Harmony
CRguy
Caregiver x 4
Stage IV A rectal cancer/lung met
12 Year survivor
my life is an ongoing totally randomized UNcontrolled experiment with N=1 !
Review of my Journey so far

NWgirl
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Re: (Good) News on anti PD-L1 MPDL3280A / Immunotherapy

Postby NWgirl » Sat Feb 01, 2014 5:22 pm

Thank you Maia. That was extremely helpful and informative. I read the study. I'm concerned I may not be eligible as I did have disease progression while on Xeloda. I've been off Xeloda for a few months now to let my hand/foot syndrome heal up. Should I even bother to contact him or do you read this the same way? I was in Seattle about the same time they were recruiting for this trial ( at the Hutch) and no one mentioned this trial to me at the time.
Belle - "Don't Retreat - Reload"DX 10/07 Stage III Rectal
Surgery 11/07; 27 of 38 nodes
Perm Colostomy 8/11
12/10 recurrence lungs & LN's
VATS Jan 2011
Radiation Oct 2013
Chemo for Life
2012 Colondar Model

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Maia
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Re: (Good) News on anti PD-L1 MPDL3280A / Immunotherapy

Postby Maia » Sat Feb 01, 2014 5:27 pm

contact him anyway. I'll PM you.

rp1954
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Re: (Good) News on anti PD-L1 MPDL3280A / Immunotherapy

Postby rp1954 » Sat Feb 01, 2014 9:57 pm

Mild immunotherapies are readily available and could be considered from the beginning, like cimetidine, PSK, vitamin D3 and others, such as in naturopathic or CAM sites. In medical papers, PSK and cimetidine appear additive in effect to 5FU's overall survivals. One can even see increased WBC or other changes in bloodwork, depending on the agent. There are reasons to think earliness, addition of effects, length of use, and continuity are levers of survival.
watchful, active researcher and caregiver for stage IVb/c CC. surgeries 4/10 sigmoid etc & 5/11 para-aortic LN cluster; 8 yrs immuno-Chemo for mCRC; now no chemo
most of 2010 Life Extension recommendations and possibilities + more, some (much) higher, peaking ~2011-12, taper to almost nothing mid 2018, mostly IV C

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Bev G
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Re: (Good) News on anti PD-L1 MPDL3280A / Immunotherapy

Postby Bev G » Sat Feb 01, 2014 10:19 pm

Just to add to what RP said, a very long time ago Gaelen told me that she would tell EVERYONE on the board to take Cimetidine if she were allowed to. Gaelen was a cancer drug researcher and she was doing stuff she was banned from discussing publicly. She had a great deal of confidence in the value of Cimetidine. When she and I discussed this, I got an rx for the drug. It has now been sitting around in my house for >3 years. Why do I not take it? I have NO idea. I surprise even myself with the crazy decisions/forgetfulness I possess. I have a great deal of confidence in all I learned from our dear Gaelen.

Bev
58 yo Type1 DM 48 years
12/09 Stage IV 2/22 nodes + liver met, colon resec
3 tx FOLFIRI, liver resec 4/10
9/10 6 mos off chemo, Neg PET&CTC CEA nl
2/11 finished total 10 rounds chemo

9/13 ^17th clean PET/CT NED for now

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Maia
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Re: (Good) News on anti PD-L1 MPDL3280A / Immunotherapy

Postby Maia » Sun Feb 02, 2014 5:24 pm

CRguy... thanks : )

rp1954 wrote:Mild immunotherapies are readily available and could be considered from the beginning, like cimetidine, PSK, vitamin D3 and others, such as in naturopathic or CAM sites.(...)There are reasons to think earliness, addition of effects, length of use, and continuity are levers of survival.


Absolutely agreed, rp1954. That's why I said
Some people can be very smart using the regimens that the standard of care offers, or alternative/ complementary stuff, or both, and find it's way during long time with that.

What you've mentioned, plus low-dose/ metronomic chemotherapy (opposed to the MTD regimen, standard of care a the moment), is something that can be done, by doing your own research and reading and hunting for an oncologist who understand the metronomic chemotherapy paradigm, and wants to help. I know that's what you're doing at your household and I take this opportunity to say you how much I appreciate your approach -and your persistence on mentioning it on the boards. You're helping to get the word out about it.

Bev, cimetidine is totally underutilized in CRC and specially in mCRC, in prevention of new metastasis/ spread during surgery (and procedures like biopsies). Why, I don't know. I have a folder in Google Drive that I'll share, about cimetidine but just as some examples:

Ann Surg. 2009 May;249(5):727-34. The perioperative period is an underutilized window of therapeutic opportunity in patients with colorectal cancer. van der Bij GJ, Oosterling SJ, Beelen RH, Meijer S, Coffey JC, van Egmond M.

Gan To Kagaku Ryoho
. 2003 Oct;30(11):1794-7. [Effect of cimetidine with chemotherapy on stage IV colorectal cancer].Yoshimatsu K, Ishibashi K, Hashimoto M, Umehara A, Yokomizo H, Yoshida K, Fujimoto T, Iwasaki K, Ogawa K.

Int J Mol Med.
2011 Apr;27(4):537-44. Epub 2011 Feb 14. Cimetidine inhibits the adhesion of gastric cancer cells expressing high levels of sialyl Lewis x in human vascular endothelial cells by blocking E-selectin expression.Liu FR, Jiang CG, Li YS, Li JB, Li F.
Gan To Kagaku Ryoho. 2006 Nov;33(12):1730-2.
[Can the survival of patients with recurrent disease after curative resection of colorectal cancer be prolonged by the administration of cimetidine?].
Yoshimatsu K, Ishibashi K, Yokomizo H, Umehara A, Yoshida K, Fujimoto T, Watanabe K, Otani T, Matsumoto A, Osawa G, Ogawa K.

*********
Update on the anti PD-L1 clinical trial for those in NEW YORK: yes, the location in New York is the Sloan Kettering and Dr Wolchok is co-investigator. See here: http://www.mskcc.org/cancer-care/trial/13-223

If this is at the MSK, the time for the champers is near! : )

Asterix
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Re: (Good) News on anti PD-L1 MPDL3280A / Immunotherapy

Postby Asterix » Mon Feb 03, 2014 1:49 am

Maia,
How would I find out the details of who to contact in Australia? They list only some vague addresses in Victoria.

I read with interest your reply to NW Girl. I also am wondering when I should consider trials. I'm basically living a normal life on Regorafenib, but we don't know if it's working. CEA went down and then up, next test in a few weeks. Only LN mets at present. I've had a few side effects from Regorafenib but it actually seems to be getting better this cycle.

Same disclaimers, but I guess you would recommend that I seriously look into this?
Stage IVb age 37 Nov11
FOLFOX+Avastin, Xeloda+Avastin
1 year NED
regorafenib Oct13-Feb14
lymph node, lung, spine, rib and liver mets
GNAQ Q209P mutation > Mekinist Jul14
Radiation bone mets Aug14
Pain>hospital Oct14
FOLFIRI Nov14 >
Home Xmas 14

dianne052506
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Re: (Good) News on anti PD-L1 MPDL3280A / Immunotherapy

Postby dianne052506 » Mon Feb 03, 2014 2:51 am

The best news about this trial is that it doesn't require a positive test for the required protein. The current single agent MPDL3280A trial requires that CRC patients be positive for the protein, either with a recent biopsy, or from stored material. I've heard numbers that only have of the CRC patients have the protein, but that might not be accurate.

Asterix, to find out the location in Australian, I would write to the sponsor at the email given: global.rochegenentechtrials@roche.com

Just my (very) humble opinion, but for anyone who asks when they should look at a clinical trial, my answer is going to be "sooner, rather than later." If you can, make an appointment at the research center and start the paperwork process, even if you are in the middle of 2nd line treatment.
My reasoning on contacting them sooner:
There may very well be a waiting list of patients
If this trial works the same as the one I am on, it will add only a few patients at a time (a cohort) then monitor those patients through X number of treatments before adding another cohort. If there is not a space for you when you first contact the clinic, there could be on a following cohort.
The paperwork takes a fair amount of time. The research clinic wanted all my surgical notes, pathology reports, contact info on all the
doctors I had seen, etc.
All that paperwork then has to be submitted to the sponsor for review even before you are considered a potential candidate.
HOpe this helps.
Dianne
May 06 Stage IV CC: liver,ovarian mets
Oct 07 inoperable lung mets
Feb 08 - Apr'12 chemo
allergic to oxaliplatin, irinotecan
Aug '12-Feb'14 Genentech PD-L1/Avastin trial
Mar '14 -radiation to largest lung nodule
still recovering; looking at trials again

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Maia
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Re: (Good) News on anti PD-L1 MPDL3280A / Immunotherapy

Postby Maia » Mon Feb 03, 2014 9:00 am

Asterix wrote:Maia,
How would I find out the details of who to contact in Australia? They list only some vague addresses in Victoria.

You can assume they'll run the trials at important cancer centers, and there is the postal code there, so doing a Google search with that address (postal code included), plus the word 'cancer', you get results that make me assume this will be the locations:

East Melbourne, Victoria, Australia, 3002 Peter MacCallum Cancer Centre http://petermac.org/

Heidelberg, Victoria, Australia, 3084 Olivia Newton-John Cancer & Wellness Centre at the Austin Hospital http://www.austin.org.au/austin-hospital

Parkville, Victoria, Australia, 3050 Cancer Trials Australia http://www.cancertrialsaustralia.com/Contact-Us.aspx
:wink:

They are not recruiting yet but Dianne is right about why not try and put the records together (if only because all that takes time). Asterix, if I remember correctly you have what seems to be a clever oncologist that proposed you to try regorafenib at a lower dose than what's being used (I think that's why it's working for you!), and before trying irinotecan... right? So yes, I'd put this information together for him/her (about the results, so far, of Genentech's anti PD-L1 agent trials, and also about Cobimetinib). He/she may think of a good plan for you.
The other agent, cobimetinib, BTW, has shown good results in trials for melanoma -so it's not a drug totally unknown. One of the centers where they tried for melanoma is the Peter MacCallum Cancer, the first in your list.

There is a trial of cobimetinib plus other agent for KRAS mutant patients, upcoming too: A Study of MEHD7945A and Cobimetinib (GDC-0973) in Patients With Locally Advanced or Metastatic Cancers With Mutant KRAS

ETA: for those interested, MEHD7945A is an antibody -anti-HER3/EGFR http://cancerres.aacrjournals.org/cgi/c ... acts/CT-08

Asterix
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Re: (Good) News on anti PD-L1 MPDL3280A / Immunotherapy

Postby Asterix » Thu Feb 06, 2014 10:36 pm

Maia and Dianne,

Thanks for the extra info. I have sent an email to the sponsor but haven't heard back yet. I'm currently in the US and the end of a 6 week holiday so I will chase up the Victoria sites when I get home in a few days.

Maia, you were correct about my onc, so I think he would support me entering a trial. Thinking about this more since I posted, and I see traditional treatments has only slowing things down at best, and requiring constant treatment, whereas an immunotherapy treatment as some hope (even if small) of a longer remission without treatment or even maybe a cure.
Stage IVb age 37 Nov11
FOLFOX+Avastin, Xeloda+Avastin
1 year NED
regorafenib Oct13-Feb14
lymph node, lung, spine, rib and liver mets
GNAQ Q209P mutation > Mekinist Jul14
Radiation bone mets Aug14
Pain>hospital Oct14
FOLFIRI Nov14 >
Home Xmas 14

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Maia
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Re: (Good) News on anti PD-L1 MPDL3280A / Immunotherapy

Postby Maia » Fri Feb 07, 2014 3:58 pm

Asterix wrote: I see traditional treatments has only slowing things down at best, and requiring constant treatment, whereas an immunotherapy treatment as some hope (even if small) of a longer remission without treatment or even maybe a cure.

I have to agree with that. The good thing is you probably have your onc on board, already : ) I'm happy to hear that, even being in the big R, you went for a 6 week vacation from Australia to US!! That's fantastic : )

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GrouseMan
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Re: (Good) News on anti PD-L1 MPDL3280A / Immunotherapy

Postby GrouseMan » Fri Feb 07, 2014 4:31 pm

You may find this new item interesting as well:

http://finance.yahoo.com/news/pfizer-me ... 00948.html

MK-3475 (Lambrolizumab) is Mercks anti PD-1 monoclonal antibody.
http://en.wikipedia.org/wiki/MK-3475

Pfizers PF-05082566 is a fully human IgG2 that binds to the extracellular domain of human 4-1BB. Which enhances T-cell function and promotes anti-tumor activity.
http://www.ncbi.nlm.nih.gov/pubmed/22406983

Pfizers axitinib (INLYTA®) primary mechanism of action is thought to be Vascular epidermal growth factor receptor 1-3, c-KIT and PDGFR inhibition, this, in turn, enables it to inhibit angiogenesis (the formation of new blood vessels by tumours). Similar to Avastin, but its a small molecule inhibitors that is active against more VEGEFr pathways.
http://en.wikipedia.org/wiki/Axitinib

and lastly: Pfizers palbociclib (PD-0332991) which is a CDK4/6 cyclin D inhibitor. Its being fast tracked by the FDA I believe. Another drug candidate area I once worked in. These are showing great promise.
http://en.wikipedia.org/wiki/Palbociclib

So it appears Pfizer is interested in the PD-1 in combination with several of its new anti-cancer drugs and monoclonal antibodies.

Regards,
GrouseMan
DW 53 dx Jun 2013
CT mets Liver Spleen lung. IVb CEA~110
Jul 2013 Sig Resct
8/13 FolFox,Avastin 12Tx mild sfx, Ongoing 5-FU Avastin every 3 wks.
CEA: good marker
7/7/14 CT Can't see the spleen Mets.
8/16/15 CEA Up, CT new abdominal mets. Iri, 5-FU, Avastin every 2 wks.
1/16 Iri, Erbitux and likely Avastin (Trial) CEA going >.
1/17 CEA up again dropped from Trial, Mets growth 4-6 mm in abdomen
5/2/17 Failed second trial, Hospitalized 15 days 5/11. Home Hospice 5/26, at peace 6/4/2017


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