News on the 'other' anti PD-1: Nivolumab. Immunotherapy

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Maia
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News on the 'other' anti PD-1: Nivolumab. Immunotherapy

Postby Maia » Fri Mar 07, 2014 12:39 pm

We have a thread about the promising Genentech's anti-PD L1 but the 'other' deserves a separte thread. I was talking about this privately with someone these days, so I'm copying the PM : )
---------------------------------------
I was going to post about this but got side-tracked for events regarding personal life.
The famous anti-PD-1 drug we have been talking more on the board is from Genentech, but Bristol-Myers has its own devlopment. It's called BMS-936558 nivolumab. They have patients with complete response (thank you to lohidoc for sending this one to me).


Durable Cancer Regression Off-Treatment and Effective Reinduction Therapy with an Anti-PD-1 Antibody
Clin Cancer Res January 15, 2013 19; 462

Abstract

Purpose: Results from the first-in-human phase I trial of the anti–programmed death-1 (PD-1) antibody BMS-936558 [nivolumab] in patients with treatment-refractory solid tumors, including safety, tolerability, pharmacodynamics, and immunologic correlates, have been previously reported. Here, we provide long-term follow-up on three patients from that trial who sustained objective tumor regressions off therapy, and test the hypothesis that reinduction therapy for late tumor recurrence can be effective.

Experimental Design: Three patients with colorectal cancer, renal cell cancer, and melanoma achieved objective responses on an intermittent dosing regimen of BMS-936558. Following cessation of therapy, patients were followed for more than 3 years. A patient with melanoma who experienced a prolonged partial regression followed by tumor recurrence received reinduction therapy.

Results: A patient with colorectal cancer experienced a complete response, which is ongoing after 3 years. A patient with renal cell cancer experienced a partial response lasting 3 years off therapy, which converted to a complete response, which is ongoing at 12 months. A patient with melanoma achieved a partial response that was stable for 16 months off therapy; recurrent disease was successfully treated with reinduction anti-PD-1 therapy.

Conclusion: These data represent the most prolonged observation to date of patients with solid tumors responding to anti-PD-1 immunotherapy and the first report of successful reinduction therapy following delayed tumor progression. They underscore the potential for immune checkpoint blockade with anti-PD-1 to reset the equilibrium between tumor and the host immune system.
full article: http://clincancerres.aacrjournals.org/c ... l.pdf+html


A good trial of this drug along with other (immunological too): Safety Study of IL-21/Anti-PD-1 Combination in the Treatment of Solid Tumors http://clinicaltrials.gov/ct2/show/NCT01629758

And this one (recruiting at some locations) that combines nivolumab and Ipilimumab (Yervoy, immunological agent approved for melanoma) for CRC:
A Study of Nivolumab and Nivolumab Plus Ipilimumab in Recurrent and Metastatic Colon Cancer (CheckMate 142) http://clinicaltrials.gov/ct2/show/NCT02060188
(*the* one trial, lohidoc : targeting CTLA-4 and PD1/PD-L1)

This one, Nivolumab and Ipilimumab, is not for CRC but for other solid turmours, and it's recruiting; maybe one could check anyway:
A Phase 1/2, Open-label Study of Nivolumab Monotherapy or Nivolumab Combined With Ipilimumab in Subjects With Advanced or Metastatic Solid Tumors http://clinicaltrials.gov/ct2/show/NCT01928394
Last edited by Maia on Tue May 13, 2014 3:08 pm, edited 2 times in total.

some
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Re: News on the 'other' anti PD-L1: Nivolumab. Immunotherapy

Postby some » Fri Mar 07, 2014 1:02 pm

Maia! I love that you post these as they seem so promising but when can we expect them to be in large scale trials? Everything seems to take so long. I love this direction and am very hopeful for what immunotherapy can offer without all the hard effects that chemo has.

Praying for a cure daily.

Xoxox

Serena
DH (age 41) diag Stage IV mets to peritoneum - July 2012 (undetectable on CT PET or MRI)
Folfox 7 & Avastin started July 2012 CEA, CA 19-9 not indicators
HIPEC surgery 1/18/13
Folfiri/Erbitux - March 2013
Lots of prayers.

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Maia
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Re: News on the 'other' anti PD-L1: Nivolumab. Immunotherapy

Postby Maia » Fri Mar 07, 2014 1:09 pm

I don't know when, Serena. Believe that I do know this arrives to late for many...
But the two trials recruiting are quite large, many locations... take a look at the trial pages.

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Re: News on the 'other' anti PD-L1: Nivolumab. Immunotherapy

Postby some » Fri Mar 07, 2014 1:43 pm

Maia,

I of course know the struggle and how hard it is. I think you are VERY generous with your time and all you share here. Thank you!

I checked these out. (had been viewing on my cell which was hard to scroll). I see that they are still recruiting for one that is supposed to have the results pending in April 2015. What happens then? If promising, then phase III? When do drugs make it to mainstream? I was disappointed to see that neither study was recruiting in CA. I don't mean that for our case (we do live here), but wonder how certain facilities get interested or scoped out to host trials. We have many NCI and research hospitals here. I was happy to see MSK on there too because they seem to run things well there.


I am always hopeful. Just wish we could find answers faster.
DH (age 41) diag Stage IV mets to peritoneum - July 2012 (undetectable on CT PET or MRI)
Folfox 7 & Avastin started July 2012 CEA, CA 19-9 not indicators
HIPEC surgery 1/18/13
Folfiri/Erbitux - March 2013
Lots of prayers.

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lohidoc
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Re: News on the 'other' anti PD-L1: Nivolumab. Immunotherapy

Postby lohidoc » Fri Mar 07, 2014 2:00 pm

One of the problems with the PD-L1 drugs is that they will affect any tissue that manifests this particular antigen. The side effects therefore can be severe and even life threatening. Nothing is easy here. We are learning more, but I suspect there is a long way to go.
"Half of what I know is wrong. I don't know which half."

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vilca11
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Re: News on the 'other' anti PD-L1: Nivolumab. Immunotherapy

Postby vilca11 » Fri Mar 07, 2014 3:23 pm

Dear Maia, you are such a blessing, such an angel sent to all of us here.... Thank you so very much for your beautiful, generous heart, for all the time you put into research for the sake of others! May God Bless you and your family for everything you are doing to help struggling people - your desire to help, your compassion, your dedication are so much in need and are so very much appreciated!
Hugs, Vilca :)
11/2005 CC stage 1, F,50yo@dx
Mod dif adenocar, MSS, APC, TP53, CEAs1.6-4.8
1/12 1met liver@Vena Cava, RFA, 3oxi,11 5FU
8/13 2 mets same place,SBRT
4/14 2 Xeliri+Avastin
5/14 Nano Knife liver same 2 mets
6/14 2 Xeliri, ADAPT
4/15 PET, 2 same mets,Cryo Liver
5/15 MJ Oil, Herbs, Suppl, ADAPT
10/15 PET, same area, doubled in size, high SUV
10/15 RH, HAI, visceral involv., no LN
2/16 red FF, 50% red dose FUDR, CEA trends up
3/16 CT, PET, MRI L.Lobe all in small tumors
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Re: News on the 'other' anti PD-L1: Nivolumab. Immunotherapy

Postby Guinevere » Fri Mar 07, 2014 4:02 pm

lohidoc wrote:One of the problems with the PD-L1 drugs is that they will affect any tissue that manifests this particular antigen. The side effects therefore can be severe and even life threatening. Nothing is easy here. We are learning more, but I suspect there is a long way to go.

I was just wondering what kind of side effects have manifested themselves, doc. For some reason, I started feeling dread. I had to give myself a talking to. I'm not on it, I'm not in the trial and I like that some have had a complete response. I wish it was more widespread but it's a start.

Guinevere
Hrt atk - Feb 11
CRC4 DX - Apr 11
APR liver rsct, procto - Jul 11
Folfox/Avastin - Sep 11
Xeliri - Nov 11
Iritux - Jun 12
Break - Jan - Mar 13
Iritux - Mar 13
Stivarga - Aug 13
Folfiri - Oct 13
Exhausted treatment options - May 14

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Re: News on the 'other' anti PD-L1: Nivolumab. Immunotherapy

Postby NWgirl » Fri Mar 07, 2014 4:50 pm

Both trials are available near me. One I already don't qualify for due to some mutations in my tumor, the other one I'm trying to get someone to return my call. I wouldn't have known about either without Maia's persistence and kindness. I'll keep you all posted if this goes anywhere.
Belle - "Don't Retreat - Reload"DX 10/07 Stage III Rectal
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Re: News on the 'other' anti PD-L1: Nivolumab. Immunotherapy

Postby GrouseMan » Fri Mar 07, 2014 5:33 pm

I'll point you to the post I made in Maia's other PD-L1 thread, which she said prompted her to start this one. This drug had generated some interest on another blog that I read recently (I am a little behind because I was out of town recently). This particular Blog is written by a medicinal chemist named Derek Lowe and is called "In the Pipeline". It discusses many drug discovery issues including the cost and many fold difficulties in bring a drug to the marketplace. It so happened that PD-1/PD-L1 recently caught his attention. Here is the Link:

http://pipeline.corante.com/archives/20 ... cancer.php

Guinevere, if you read down to comment 11 someone posted about the effects in his father, whom had from the sounds of it Melanoma which was very bad. Grapefruit sized tumors he says. But after treatment in this combination trial they disappeared. Now like as not I am betting the severity of the side effects was related to the tumor burden that they had. The larger and more wide spread the tumors I am betting resulted in a pretty severe immune response.

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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Maia
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Re: News on the 'other' anti PD-L1: Nivolumab. Immunotherapy

Postby Maia » Fri Mar 07, 2014 9:16 pm

I know you lohidoc are referring to other matter but wanted to agree with GrouseMan on this
the severity of the side effects was related to the tumor burden that they had. The larger and more wide spread the tumors I am betting resulted in a pretty severe immune response.

That was observed for Coley and all who followed him, in that field.
And the severity of the immune response can be huge, and life threatening, yes; that's why you need doctors looking with haw's eye. This is for other cancer (not solid tumour; leukemia) but certainly illustrates such severity: "we knew she couldn't get any sicker when she actually died". But oh the reward... 'Oh, when the tide brings us back/ How sweet it is'. :) Watch if you need a smile and some hope http://www.youtube.com/watch?v=h6SzI2ZfPd4
I think Dr Carl June could be buddies with several of our bike fan members on this forum... : ) He received the 2012 William B. Coley Award for Distinguished Research in Tumour Immunology, by the Cancer Research Institute: http://www.youtube.com/watch?v=7b7SDEeEkD8

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Maia
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Re: News on the 'other' anti PD-L1: Nivolumab. Immunotherapy

Postby Maia » Sat Mar 22, 2014 1:23 pm

Update March 22 2014:

This trial (Nivolumab and Ipilimumab, for solid turmours), is now recruiting at all the USA and UK locations; one in Spain and the one in Finland (Italy still not recruiting).
///Edited to add: as raym pointed out below, CRC is not listed now as one of the solid tumours treated; anyone interested should check if that's the case).///
A Phase 1/2, Open-label Study of Nivolumab Monotherapy or Nivolumab Combined With Ipilimumab in Subjects With Advanced or Metastatic Solid Tumors http://clinicaltrials.gov/ct2/show/NCT01928394

*****
Serena, sorry I missed your questions until now.
some wrote:I see that they are still recruiting for one that is supposed to have the results pending in April 2015. What happens then? If promising, then phase III?

Phase I, II, III; some drugs, while still in Phase III, could be approved for compassionate use
When do drugs make it to mainstream?


It really varies a lot. For example, some crazies (LOL) went for a Phase I trial with CPT-11 (that was the name of irinotecan, back then) in 1993. It received accelerated approval by the FDA only in 1996, and full approval in 1998. That was a 'fast' development (there was nothing new for CRC since 5-FU).
For this one, nivolumab (BMS-936558) Bristol-Myers Squibb submitted a manufacturing and marketing approval as a drug targeting the PD-1 pathway (for the treatment of melanoma) this past December 2013 (most immunotherapies are getting approved first for melanoma). Can't really say how much time until it gets approved for CRC (if that happens).

I really don't know how certain facilities get interested or scoped out to host trials, but wanted to mention that the other anti-PDL1 antibody, the one from Roche, MPDL3280A, has two locations in CA, recruiting (Los Angeles and Standord). http://www.clinicaltrials.gov/ct2/show/NCT01375842
Last edited by Maia on Sat Mar 22, 2014 3:50 pm, edited 1 time in total.

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Re: News on the 'other' anti PD-L1: Nivolumab. Immunotherapy

Postby raym » Sat Mar 22, 2014 2:22 pm

I don't see Colorectal cancer as a type they are treating, but see Gastric which is different. Am I reading it wrong? thanks
3/11 IIIC +/FOLFOX
4/12 HIPEC
6/12 Chmo/Rad
9/12 XELIRI+Avast/Zltra
9/13 Plvic Absc,stpd chemo
11/13 Tumr rmvd frm Lap Port incis
12/13 Xeloda
1/14 Cardiac Issue no Xeloda/5FU
3/14 Irinotecan
6/14 Stopped chemo
8/14 Clin Trial
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Maia
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Re: News on the 'other' anti PD-L1: Nivolumab. Immunotherapy

Postby Maia » Sat Mar 22, 2014 2:43 pm

You're right! That changed: the inclusion criteria was before just "Advanced or Metastatic Solid Tumors", now they have a list of cancers and CRC is not included, apparently. Anyone interested in this should check personally.
Thank you, R., good catch. Hope you're still living large these days, uh? :)

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Re: News on the 'other' anti PD-L1: Nivolumab. Immunotherapy

Postby raym » Sun Mar 23, 2014 9:43 am

Maia wrote:You're right! That changed: the inclusion criteria was before just "Advanced or Metastatic Solid Tumors", now they have a list of cancers and CRC is not included, apparently. Anyone interested in this should check personally.
Thank you, R., good catch. Hope you're still living large these days, uh? :)



Eh, still doing what can but a low point, different chemo drug, Irinotecan, which I''ve had before but dose went from 180 to 250, bad dehyrdation, shortness of breath. It's been a bad week..but still managed to fit 2 band gigs, bday dinner for daughter and visiting wineries today. Unfortunately on Bactrim and alcohol is contradicted :(. I'm a point where if the Irinitecan has no effect (or it wipes me out beyond quality of life) I'm into clinical trials. Looking at one at Hopkins:

http://www.hopkinsmedicine.org/kimmel_cancer_center/research_clinical_trials/clinical_trials/search_results/J1282
3/11 IIIC +/FOLFOX
4/12 HIPEC
6/12 Chmo/Rad
9/12 XELIRI+Avast/Zltra
9/13 Plvic Absc,stpd chemo
11/13 Tumr rmvd frm Lap Port incis
12/13 Xeloda
1/14 Cardiac Issue no Xeloda/5FU
3/14 Irinotecan
6/14 Stopped chemo
8/14 Clin Trial
9/14 Infectn - Stpd Trial

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Maia
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Re: News on the 'other' anti PD-L1: Nivolumab. Immunotherapy

Postby Maia » Thu Mar 27, 2014 8:22 pm

Fingers crossed that irinotecan doesn't wipe you out beyond QOL, Ray. Happy you had a good birthday dinner for daughter : )

That one looks like a really good trial with the agent we are discussing here. Just curious, why do you/ your onc consider this trial instead of this one, also at MSK: http://www.mskcc.org/cancer-care/trial/13-223 (the one with other anti PD-L1 agent, in this case, the one from Roche/Genentech, as discussed here: viewtopic.php?f=1&t=45485 )? Maybe you have some particular tumour profiling done?


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