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New Dynamic Case Report – Patient with GIST

Posted on by Tony Blau in Uncategorized | No Comments

PPO was asked to provide assistance in the case of a 52-year-old male patient with a gastrointestinal stromal tumor (GIST), and a past medical history that is outlined as follows.

In July 2002 the patient presented with a cough, indigestion and a lump in his sternal area. Diagnostic imaging revealed a 30 cm x 16 cm x 10.5 cm multicentric abdominal mass. He underwent debulking surgery including a transverse colectomy demonstrating extensive involvement of the omentum and invasion of the muscularis propria involving both the small and large intestine. Pathological diagnosis was GIST. Immunohistochemistry revealed uniformly positive staining for c-kit. In mid-September 2002, about 3 weeks after surgery, the patient began treatment with imatinib, 400 mg per day. By that time the patient had cumulatively lost 37 lbs. After starting the imatinib the patient returned to his baseline weight and had a complete response as determined by repeated imaging studies.

In August 2006 an abdominal PET-CT scan showed multiple peritoneal implants consistent with recurrent GIST. A biopsy in September 2006 was consistent with recurrent GIST and the imatinib dose was increased to 600 mg per day. In December 2006 a repeat PET-CT showed a decrease in the size of the abdominal masses and no metabolic activity. As the 600 mg daily dose of imatinib was well tolerated the dose was increased to 800 mg daily. However in April 2007 the patient was found to have progressive intra-abdomenal disease and was switched to sunitinib. In August 2007, following 2 cycles of sunitinib, repeat PET-CT imaging showed a reduction in the size of the abdominal masses, however subsequent imaging in November 2007 showed progressive disease, especially in the right pelvis.

The patient was referred to Dr. Blanke at Oregon Health Sciences University (OHSU) and subsequently, UCLA, where he participated in a randomized clinical trial of nilotinib versus imatinib beginning in January 2008. The patient was randomized to the imatinib arm and received imatinib for 6 months. During this interval the patient had progressive disease. He subsequently received an approximately 4 month course of nilotinib, which was associated with a small reduction in disease, lasting approximately 3 months, followed by evidence of subtle disease progression. Study criteria required that the patient be taken off of nilotinib and imatinib was resumed.

By January 2009 the patient had extensive intra-abdomenal disease consisting of multiple large mesenteric and peritoneal implants and new sub-capsular hepatic disease. Due to progressive severe abdominal pain, the patient was referred to the University of Washington for an attempt at repeat surgical debulking. In March 2009 he underwent an exploratory laparotomy with partial resection of a mass thought to be causing his pain, but significant debulking was not possible due to the extent of his disease. Post-operatively it was possible to resume nilotinib treatment (off-study), which appeared to significantly slow the rate of disease progression compared to imatinib. By June 2009 the patient had progressive symptoms and underwent a palliative course of radiation therapy to the abdomen, however this was interrupted early because of nausea, vomiting, diarrhea and a 15 lb weight loss. An effort was made to obtain sorafenib but a requested authorization for payment by his insurance company was denied.

By July 2009 the patient developed intractable nausea and vomiting with increasing abdominal girth. A rising creatinine was attributed to urinary obstruction requiring the placement of a foley catheter. At the time of a scheduled visit on August 4, 2009 the patient was placed on hospice care due to intractable vomiting in the setting of progressive disease. However, at around the same time the insurance company reversed its decision and agreed to pay for sorafenib. The patient was admitted to the hospital from August 7th through August 17th for placement of a jejunostomy tube, rehydration, and the initiation of sorafenib, which was started at a dose of 400 mg twice daily. On September 4, 2009 the patient presented with an extensive erythematous rash. Sorafenib was held for 48 hours, then the dose was reduced to 200 mg twice daily. By the time of his clinic visit on September 10th the patient was noted to have a decrease in abdominal girth and the sorafenib dose was increased to 400 mg in the morning and 200 mg in the evening. A CT-angiogram performed on September 24 for evaluation of acute chest pain (which subsequently resolved) showed a reduction in size of a crescent-shaped mass between the peritoneum and posterior right lobe of the liver, consistent with a response to sorafenib, and the dose was increased back to the original 400 mg twice daily. By November 2009 the patient was able to discontinue his foley catheter and TPN, and by December 4, 2009 he was able to hang Christmas lights. Repeat CT scans documented shrinkage of his disease, and he tolerated full doses of sorafenib (400 mg twice daily) without recurrence of the skin rash. By January 2010 the patient no longer required the jejunostomy tube and this was removed. A repeat CT in January 2010 showed a reduction in the size of some masses, an increase in size in other areas, and stable disease elsewhere, and the sorafenib dose was increased to 600 mg in the morning and 400 mg in the evening. In April 2010 the sorafenib dose was further increased to 600 mg twice daily due to progressive disease in the liver. Whereas stable disease was documented on CT scans of June and September 2010, a new lesion involving the caudate lobe of the liver was noted on a CT of December 2010. The patient currently feels well and, although not currently employed, has a performance status of zero.

Past Medical History is notable for a deep venous thrombosis involving common iliac vein diagnosed at the time of his diagnostic imaging in 2002 and treated with a 3-month course of warfarin.

Thoughts/questions:

1. Does the patient have a documented c-kit mutation? History makes c-kit mutation very likely, but if wildtype, need to check for PDGFRA and BRAF mutations.

What is the current status of c-kit?

2. Is the tumor still ETV1 dependent?

Does the region of tumor that is growing have higher levels of ETV1 protein and more of an ETV1-associated transcriptional program than regions of the tumor that are not growing?

Can we measure ETV1 levels in various regions of the tumor by Western as was done in Chi et al., Nature. 2010 Oct 14;467(7317):849-53 ?

3. MAPK pathway members as potential targets.

If I understand the above referenced Chi et al., paper correctly, it suggests that “leak through” MAPK induction of the ETV1 program may be the downstream mediator of imatinib resistance in GIST.

Is it possible to assess MEK/ERK signaling in various regions of the tumor? It is my understanding from Frank McCormick that these studies are unreliable unless the MAPK pathway is “on fire”, as occurs with BRAF mutations (see “dynamic case report” at http://personaloncology.org/education-consultation.php).

4. PI3K/AKT/mTOR pathway members as potential targets.

There is also a substantial literature that suggests that AKT signaling can drive imatinib resistance (see Wang et al., J Cancer Res Clin Oncol. 2010 Jul;136(7):1065-71, Bauer et al., Oncogene 2007 Nov 29;26(54):7560-8, Ikezoe et al., Cancer Sci. 2006 Sep;97(9):945-51).

How common are PI3KCA mutations in GIST? (There are no Pubmed hits when I search PI3KCA and GIST).

Can do IHC to check for P-AKT, P-S6, PHAS, 4E-BP-1 and PTEN.

Consider contacting Gordon Mills at MDACC (see “dynamic case report” at http://personaloncology.org/education-consultation.php).

These papers seem to suggest that perhaps we should go after AKT. However, I don’t think that AKT was mentioned as an effector of the ETV1 induced transcriptional program.

Important foundational paper for signaling in GIST is Duensing et al., Oncogene. 2004 May 13;23(22):3999-4006.

There are precedents for combining mTOR inhibition with sorafenib.

Everolimus plus sorafenib

See the following: Ruangkanchanasetr et al., Nephrology (Carlton). 2011 Jan;16(1):118-9. doi: 10.1111/j.1440-1797.2010.01346.x (http://www.ncbi.nlm.nih.gov/pubmed?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=21177421),

Oudard S. Anticancer Res. 2010 Dec;30(12):5223-5 (More Than 4 Years of Progression-free Survival in a Patient with Metastatic Renal Cell Carcinoma Treated Sequentially with Sunitinib, Everolimus, Sorafenib, and Temsirolimus.), http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=52754,

http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=34991,

http://ash.confex.com/ash/2010/webprogram/Paper29061.html,

http://www.springerlink.com/content/0440823w62886820/.

Lack of additional suppressive effect on lymphocytes suggested by: www.aapsj.org/abstracts/AM_2010/T2376.pdf

See also the very interesting case report by Bhoori et al., Journal of Hepatology Volume 52, Issue 5, pages 771-775 (May 2010).

Note from Wikipedia: In a fashion similar to other mTOR inhibitors the effect of everolimus is solely on the mTORC1 protein and not on the mTORC2 protein. This can lead to a hyper-activation of the kinase AKT via inhibition on the mTORC1 negative feedback loop while not inhibiting the mTORC2 positive feedback to AKT. This AKT elevation can lead to longer survival in some cell types.

Combination of Perifosine (a novel AKT inhibitor) plus sorafenib: http://seekingalpha.com/news-article/178733-aeterna-zentaris-phase-2-data-demonstrate-perifosine-s-promising-efficacy-in-the-treatment-of-advanced-leukemia-lymphoma-and-multiple-myeloma

Another option would be MK2206 plus sorafenib, but I don’t see evidence that this has been tried to date.

5. Other thoughts regarding sorafenib.

What is being inhibited by sorafenib? VEGF receptors, PDGFR, FLT3, RET, BRAF, KIT. What are the major differences between sunitinib and sorafenib? Why do we think sorafenib is working where sunitinib failed? Does sunitinib work less well for gatekeeper mutations? What is the IC50 of sorafenib for the various c-kit mutations? Sorafenib efficiently inhibited gatekeeper mutants of KIT and PDGFRβ (IC50 for KIT T670I, 60 nmol/L; IC50 for PDGFRβ T681I, 110 nmol/L). Instead, it was less active against activation loop mutants of the two receptors (IC50 for KIT D816V, 3.8 μmol/L; IC50 for PDGFRβ D850V, 1.17 μmol/L) that are also imatinib-resistant. Sorafenib blocked receptor autophosphorylation and signaling of KIT and PDGFRβ gatekeeper mutants in intact cells as well as activation of AP1-responsive and cyclin D1 gene promoters, respectively. Finally, the compound inhibited KIT-dependent proliferation of Ba/F3 cells expressing the oncogenic KIT mutant carrying the T670I mutation. From Guida et al., 2007: clincancerres.aacrjournals.org/content/13/11/3363.full. See also Guo et al., Clin Cancer Res 2007;13(16) August15, 2007. Looking at exon 11 mutation combined with different secondary mutations.

Other thought regarding sorafenib resistance – Consider having patient eat broccoli. See: Rausch et al., Cancer Res. 2010 Jun 15;70(12):5004-13.

6. Other therapeutic considerations:

Does the patient have an c-kit activating loop mutation? If so, then consider AP23464 (Corbin et al., Blood, 1 July 2005, Vol. 106, No. 1, pp. 227-234). Also consider dasatinib (Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Schittenhelm et al., Cancer Res. 2006;66:473-81).

In the unlikely event that the patient’s mutational analysis is negative (wildtype c-kit, PDGFRA, BRAF) consider IGF1R inhibitor.

Consider HSP90 inhibitors, ZTA-9090, SNX-5422, 17-AAG. See Bauer et al., Cancer Res 2006;66:9153–61. Clinical trial at: http://clinicaltrials.gov/ct2/show/NCT01039519

Consider protein kinase C theta (PKCθ) (Ou et al., Oncogene. 2008 Sep 18;27(42):5624-34, http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&DbFrom=pmc&Cmd=Link&LinkName=pmc_pubmed&LinkReadableName=PubMed&IdsFromResult=2811224&ordinalpos=1&itool=PPMCLayout.PPMCAppController.PPMCArticlePage.PPMCDiscoveryDbLinks). However, from Skvara et al., JCI 2008, PKCθ plays an essential role in T cell activation.

7. On January 17, 2011 I learned of another new Phase III trial using a multiple tyrosine kinase inhibitor called regorafenib. http://www.webwire.com/ViewPressRel.asp?aId=129842

EMAIL CORRESPONDENCE WITH ROBERT MAKI AND PING CHI, MEMORIAL SLOAN KETTERING CANCER CENTER, NEW YORK, NEW YORK

From: C. Anthony Blau [mailto:tblau@u.washington.edu] 

Sent: Tuesday, January 04, 2011 11:21 AM

To: Sawyers, Charles/HOPP

Cc: SIBEL BLAU

Subject: your advice

Dear Professor Sawyers,

I am a hematologist at the University of Washington and my wife, Sibel Blau, is an oncologist in Puyallup, Washington. I recently co-founded a not-for-profit organization called Partners in Personal Oncology (www.personaloncology.org). Sibel asked that I help assist in the case of a 52 year old man with advanced GIST, originally diagnosed in 2002, who has been treated over the years with imatinib, sunitinib, nilotinib, and most recently, sorafenib. The patient initially responded to treatment with imatinib for a period of approximately 4 years. He was then switched to sunitinib which provided a response lasting at most 6 months. He subsequently received nilotinib on a clinical trial out of UCLA, and while this appeared to slow down the progression of his disease, he eventually developed very advanced disease resulting in a brief transition to hospice care in August 2009. Around the same time, he was able to receive sorafenib, which produced a marked improvement in his overall state of well being, although he continues to have a very large pelvic mass, a second stable lesion in the right anterior abdominal wall, and the appearance of a new lesion in the caudate lobe of the liver. His clinical condition is excellent on a sorafenib dose of 600 mg twice daily.

Sibel is planning to have the region of progressive disease excised, and I am wondering whether one might be able to use this as an opportunity to learn about GIST and simultaneously to potentially help this patient. In particular, I read your recent Nature paper with great interest, and wonder whether studies comparing the region of progressive disease with a region which seems to be held in check by sorafenib might be informative. While we will clearly check for the emergence of new c-kit mutations, I wonder about your thoughts in particular regarding the following questions:

1. Do you think it would be worthwhile to measure ETV1 levels in sorafenib responsive versus resistant bits of the patient’s tumor by Western blotting or IHC? Would it be possible for your lab to do this?

2. It is my understanding from your Chi et al., paper that the ETV1 transcriptional program in imatinib resistant tumors might occur via persistent, leaky MAPK signaling. While I recognize that this is counterintuitive, do you think this might suggest that it would be useful to combine sorafenib with a MEK inhibitor (provided we could get the drug)?

3. As you know, there is a substantial literature on AKT signaling as a mediator of imatinib resistance. Might persistence of the ETV1 program be mediated via AKT?

4. Do you know of anyone who is doing RNA-sequencing of clinical GIST specimens in this setting?

I would of course greatly appreciate any additional comments or advice you might have. Thanks very much for considering these questions.

With best regards,

Tony Blau

From: makir@MSKCC.ORG
Subject: RE: your advice
Date: January 5, 2011 2:30:12 PM PST
To: tblau@u.washington.edu
Cc: chip@mskcc.org, sawyersc@mskcc.org

Dear Dr. Blau,

I am the clinician who has worked with Ping Chi and Charles Sawyers on the GIST ETV1 project. You have asked some very important questions on the issues outlines in the paper.

The response rate in 3rd and 4th line to sorafenib in GIST is ~15%, which interestingly is higher than the 8% on which sunitinib was approved in 2nd line.

It would be very reasonable to combine a KIT active tyrosine kinase inhibitor with a MEK inhibitor, but the latter are only in phase I trials / early phase II in humans right now, and so the hypothesis has not been tested (nor for AKT inhibitors + KIT inhibitors). A small study of TOR inhibitor everolimus in addition to imatinib in the imatinib-refractory setting showed little activity except for stabilization of disease for 3-6 months for a small proportion of patients. It is clear that there is KIT oncogene “addiction” (as described by Dr Sawyers initially for CML) going on in these tumors as indicated by signaling downstream of the multiply mutated KIT in the imatinib resistant setting, and there are usually many different secondary mutations in people who have imatinib resistant disease; it is no longer clonal, but polyclonal. The latest clinical research is on agents that may decrease KIT expression such as HDAC inhibitors or hsp90 inhibitors, one of the latter which failed badly in a phase III clinical trial as monotherapy.

Sam Singer at our center may be doing some total mRNA sequencing of GIST at our center, but I do not know the status of that work. The greatest amount of deep sequencing is probably being done by Mike Heinrich and Chris Corless at U Oregon Health Sciences Center. It may be possible to have your wife’s patient’s tumor sequenced.

If you needed to develop a clinical collaboration, an excellent resource will be Robin Jones, recently arrived from London to take over the adult medical oncology sarcoma program at UW / Fred Hutch. We’d be happy to help as well, but it may be easiest to reach out to him first.

Bob Maki
makir@mskcc.org

Subject: Re: your advice
From: tblau@u.washington.edu
Date: January 5, 2011 3:13:54 PM PST
To: makir@MSKCC.ORG
Cc: chip@mskcc.org, sawyersc@mskcc.org, sibelblau@msn.com

Dear Bob,

Thanks so much for your very detailed reply. I wasnt aware of the failed Phase III clinical trial of a HSP90 inhibitor for GIST, so that information is helpful indeed. It is also extremely helpful to know of your sentiment that the region of progressive disease is still likely to be c-kit-driven. If I understand correctly, that would lead to the prediction that the region of disease progression likely has acquired a new kit mutation compared to the region that is stable on sorafenib. Does that sound right?

I have also emailed Dr. Heinrich at OHSU and am awaiting his response, and will certainly followup on your suggestion to contact Dr. Jones, who is in my own back yard!

My wife intends to send the patient for resection of the progressive disease in his liver, and so I have just a couple of remaining questions:

1. Might it be possible to send regions of progressive versus stable disease to you guys for testing of ETV1 expression by Western? The question would be whether disease progression is associated with higher levels of ETV1 expression.

2. In the same way, I wonder whether one could compare stable versus progressive bits of the tumor for intensity of PI3K signaling. In particular it is my understanding from correspondence with Frank McCormick (as described in a different case – please see attached) that P-AKT, P-S6, PHAS and 4E-BP-1 can be assessed by IHC fairly reliably, whereas reliable measures of the intensity of MAPK signaling are more challenging. Couldnt one compare the progressive versus stable bits of the tumor for these markers and conclude that if the intensity of PI3K signaling is greater in the progressive bit, then maybe targeting mTOR/AKT may be the way to go, whereas if there is no difference, then maybe one should go after a MEK inhibitor (trying to convince the company to give the drug on a compassionate use basis).

Again, thanks so much for your help.

Sincerely,

Tony

From: makir@MSKCC.ORG
Subject: RE: your advice
Date: January 6, 2011 5:14:37 AM PST
To: tblau@u.washington.edu
Cc: chip@mskcc.org, sawyersc@mskcc.org, sibelblau@msn.com

I am not sure it will be helpful to test tissue on a clinical sense, in particular since part (2) has already been well demonstrated for GIST resistant to imatinib or sunitinib. There is re-activation of the entire signaling pathway you mention in resistant GIST. We do need other ways of knocking down the signaling via KIT (and perhaps parallel pathways) besides just blocking the kinase domain, which is the focus of at least a fair amount of research at present. Since I am not in the lab Ping may be able to comment best on ETV1 testing as a potential biomarker for resistance to a given TKI.

Bob

Subject: Re: your advice
From: tblau@u.washington.edu
Date: January 6, 2011 8:08:09 AM PST
To: makir@MSKCC.ORG
Cc: chip@mskcc.org, sawyersc@mskcc.org, sibelblau@msn.com

Dear Bob,
Thanks very much for your input. Dr. Chi, I wonder whether it would be possible to have ETV1 testing performed?
Thanks a lot,
Tony

From: chip@mskcc.org
Subject: RE: your advice
Date: January 6, 2011 3:28:24 PM PST
To: tblau@u.washington.edu, makir@MSKCC.ORG
Cc: sawyersc@mskcc.org, sibelblau@msn.com

Dear Tony,

If you have fresh frozen samples, we can do ETV1 WB. We are still developing the antibodies for more reliable ETV1 testing on paraffin embedded samples. But as Bob mentioned, it is unlikely going to help guide clinical management at this stage. If he were to have surgery anyways, it would certainly make sense to bank fresh frozen tissue for RNA/DNA/proteins for future research.

Ping

Subject: Re: your advice
From: tblau@u.washington.edu
Date: January 6, 2011 6:52:58 PM PST
To: chip@mskcc.org
Cc: makir@MSKCC.ORG, sawyersc@mskcc.org, sibelblau@msn.com

Dear Ping,
Many thanks for your email and willingness to do this study. We will definitely make a point of collecting plenty of frozen tissue for these studies now and in the future.
Best,
Tony

EMAIL CORRESPONDENCE WITH GORDON B. MILLS, M.D. ANDERSON CANCER CENTER, HOUSTON, TEXAS

Subject: Could I please trouble you for MORE advice, this time for a patient with GIST
From: tblau@u.washington.edu
Date: January 6, 2011 8:43:22 AM PST
To: gmills@mdanderson.org
Cc: sibelblau@msn.com

Dear Professor Mills,

I am writing in hope of again enlisting your help, this time regarding a patient with GIST.

My wife Sibel is an oncologist in Puyallup Washington and she asked that I help assist in the case of a 52 year old man with advanced GIST, originally diagnosed in 2002, who has been treated over the years with imatinib, sunitinib, nilotinib, and most recently, sorafenib. The patient initially responded to treatment with imatinib for a period of approximately 4 years. He was then switched to sunitinib which provided a response lasting at most 6 months. He subsequently received nilotinib on a clinical trial out of UCLA, and while this appeared to slow down the progression of his disease, he eventually developed very advanced disease resulting in a brief transition to hospice care in August 2009. Around the same time, he was able to receive sorafenib, which produced a marked improvement in his overall state of well being, although he continues to have a very large pelvic mass, a second stable lesion in the right anterior abdominal wall, and the appearance of a new lesion in the caudate lobe of the liver. His clinical condition is excellent on a sorafenib dose of 600 mg twice daily.
Unsurprisingly, enhanced signaling via PI3K/AKT/mTOR is well described in GIST resistant to RTK blockade. Sibel is planning to have the region of progressive disease excised as well as debulking of tumor elsewhere, and I am wondering whether one might be able to use this as an opportunity to compare PI3K/AKT/mTOR signaling in sorafenib-responsive versus sorafenib-resistant bits of the tumor. I am currently applying for expedited approval through our IRB to allow for these and other non-CLIA approved studies to be done. I recall from your previous email that MDACC does this type of testing on a research basis. Would be be possible for your lab to test this patient’s tumor?
Thanks very much for considering this.
With best regards,
Tony Blau

From: gmills@mdanderson.org
Subject: RE: Could I please trouble you for MORE advice, this time for a patient with GIST
Date: January 6, 2011 9:15:17 AM PST
To: tblau@u.washington.edu
Cc: sibelblau@msn.com

Tony: We woud be very interesting in working on this with you. We do this on a research basis and would be interested in this approach. We now have an ability to move some of this forward to CLIA ie we use the research data to drive which CLIA assays to run.

From: C. Anthony Blau [tblau@u.washington.edu]
Sent: Thursday, January 06, 2011 12:34 PM
To: Mills,Gordon B
Cc: SIBEL BLAU
Subject: Re: Could I please trouble you for MORE advice, this time for a patient with GIST

That’s terrific Gordon!
I am hoping that your findings may help guide which type of inhibitor we might try – ie PI3K vs AKT vs mTOR. Does this seem possible?

Best,
Tony

From: gmills@mdanderson.org
Subject: RE: Could I please trouble you for MORE advice, this time for a patient with GIST
Date: January 6, 2011 11:37:11 AM PST
To: tblau@u.washington.edu
Cc: sibelblau@msn.com

Maybe. At the moment, we are not sure why specific inhibitors work in specific patients. However, it is an emerging concept.

From: C. Anthony Blau [mailto:tblau@u.washington.edu]
Sent: Wednesday, January 26, 2011 07:13 AM
To: Mills,Gordon B
Cc: SIBEL BLAU
Subject: Re: Could I please trouble you for MORE advice, this time for a patient with GIST

Dear Gordon,

This patient is scheduled for surgery this coming Friday.

A colleague and I met with people at the Fred Hutchinson’s IRB and since we will use the information we get to guide clinical care of this patient, we will not consider this research but rather clinical care. We (more accurately, my colleague Debbie Nickerson in the genome sciences department) will be doing exome sequencing on the stable and progressing bits of tumor as well as on blood, and our lab medicine people will confirm any clinically actionable mutations we find in the tumor using CLIA certified tests (as you are planning to
do).

I will be in the OR this Friday to make sure that we are sending representative bits of the stable and growing tumor. How should this tissue be processed for your studies?

Thanks,
Tony

From: gmills@mdanderson.org
Subject: Re: Could I please trouble you for MORE advice, this time for a patient with GIST
Date: January 26, 2011 5:31:29 AM PST
To: tblau@u.washington.edu
Cc: sibelblau@msn.com

Flash frozen is best.

Email correspondence regarding PKC theta

From: “C. Anthony Blau”
Date: December 29, 2010 00:14
To: “Thomas Jung” Subject: AEB071 and GIST?

Dear Dr. Jung

I am writing on behalf of a 52 year old patient with a gastrointestinal stromal tumor that has been treated with a variety of TKIs over the past 9 years, including imatinib, sutinib, nilotinib and currently, sorafenib. The tumor is slowly progressing despite sorafenib and several reviews have mentioned that possibility that inhibitors of PKC theta may impede c-kit mediated signaling. I note that you have been involved in the investigation of AEB071, and wonder
whether you know if this drug has been or is being tested in GIST. Thanks very much for any information you might regarding this issue.

Best wishes for the New Year.

Tony Blau

Partners in Personal Oncology
www.personaloncology.org

On Jan 1, 2011, at 6:28 AM, thomas.jung@novartis.com wrote:

Dear Dr Blau,

I am sorry to hear that your patient is not adequately treated with the kinase inhibitors you mentioned. Unfortunately, we have never tested AEB071 in GIST and we have no plans to run clinical trials for this indication.

I am terribly sorry that I don’t have a better response for you.
Best regards, Thomas

From: “C. Anthony Blau”
Date: January 1, 2011 23:40
To: “Thomas Jung” Subject: AEB071 and GIST?

Dear Thomas,

Thanks very much for your kind reply. If I understand correctly, any PKC theta inhibitor would be expected to cause T cell suppression. Is this correct?

Best wishes for the New Year!

Tony

From: thomas.jung@novartis.com
Subject: Re: AEB071 and GIST?
Date: January 2, 2011 7:46:21 AM PST
To: tblau@u.washington.edu

Dear Tony,

also for you all the best for the new year. You are right, a PKC theta inhibitor should act as strong T cell inhibitor.

Best regards, Thomas

UPDATE – January 30, 2011

The patient was seen for preoperative evaluation on January 25, 2011 by Dr. Raymond Yeung, Professor of Surgery at the University of Washington. At that time the patient discontinued sorafenib in anticipation of his upcoming surgery due to concern regarding potential adverse effects of sorafenib on wound healing. Therefore the patient did not take his evening dose of sorafenib on January 25 and missed both doses of sorafenib on January 26, 2011. Upon learning that the patient had discontinued sorafenib, Tony Blau raised concern that differences in cell signaling between sorafenib-responsive versus sorafenib-resistant tumor might be attenuated in the wake of sorafenib withdrawal. During extensive discussions a number of options were considered including postponement of the surgery. It was decided not to postpone surgery and that the patient would resume sorafenib on the day prior to surgery. Therefore, the patient received 600 mg of sorafenib both on the morning and the evening of January 27, the day prior to surgery. It was also thought the relatively long half life of sorafenib (25 to 48 hours) would mitigate the effects of having missed the 3 doses on January 25th and 26th.

Surgery took place on January 28, 2011. A resected peritoneal lymph node was found on frozen section to contain tumor cells consistent with GIST. One half of the lymph node was saved for pathological studies and the remaining half was divided into 4 sections and snap frozen. Due to logistical problems, approximately 30 minutes elapsed between the time the tumor was resected and the time it was snap frozen.

The liver lesion was visualized on intraoperative ultrasound and a portion was resected. Surprisingly, frozen section did not reveal evidence of tumor, and preliminary results suggest a focal region of fatty liver.

One of the 4 snap frozen portions of the involved peritoneal lymph node and a sample of peripheral blood were submitted for DNA extraction and exome sequencing. Results from these studies are pending.

Since the liver lesion was found not to contain tumor, it appears that the patient’s tumor is currently stable on sorafenib and this medication will be continued at the current dose of 600 mg twice daily.

Areas for improvement:

When feasible, continue drugs without interruption up until the time of surgery.

Try to better correlate CT findings with tissues that are obtained for analysis. Interventional radiology may provide greater flexibility than surgery.

Minimize time interval between when tissues are resected to when they are snap frozen.

Optimize imaging to reduce “false positives” as occurred here.

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