Cure Alveolar Soft Part Sarcoma International (iCureASPS)

I'll post our update to 'K''s personal pages when I get a chance, but 'K' began ARQ 197 this week.

We love the group at Premiere Oncology. We had to apply for an age waiver because 'K' is only 11 years old (youngest age is 13 for trial). Also when her latest Chest CT showed lung nodules that were too small for the study (smaller than 1 cm), the team applied for another waiver and 'K' was able to be accepted as a "non-evaluable patient" - meaning they will not be able to use her results for their studies, but she can still receive the drug.

We were also able to waive pharmacokinetics blood draws (required by study for all subjects less than 20 years old) and allow MRI scans to be substituted for CTs and PETs.

'K' has had no side effects, but just started 2 days ago. She has also been allowed to continue on Celebrex.

I have been corresponding with Karen Imm, but cannot relay what she told me about her results on the trial (private email). Hopefully she will be able to update herself soon. Apparently we have heard from the oncologist that there is some anti-tumor effect of ARQ197 in ASPS. We heard the best response is 30% shrinkage by RECIST, but it is more commonly found to stabilize or shrink some, but not all tumors. It might be because of the clonal variation problem, this is the best result to hope for with medical therapy in ASPS - try to stabilize or kill off some clones / tumors, and surgically remove others if they don't respond or become dangerous. There has been relatively low toxicity, although there may be more risk to the liver (all have been reversible) in children.

They are actively recruiting for this study still. They will pay for hotel, but not airfare. We are amassing frequent flyer miles and flying down to LA once a week for 5 weeks. This will shift to once a month thereafter, however long we choose to stay on the drug.

Dear 'F',
Thank you for your thoughtful update and all of the valuable information. We will continue to closely follow 'K''s and the other ASPS patients' experiences and outcomes with ARQ-197 , and will be holding very tight to Hope that this promising new treatment will prove to be the effective systemic treatment that we are all so desperately seeking. Is there a maximum number of patients who can be enrolled in the Clinical Trial, and how long is the Trial scheduled to last before it is concluded and the results are published? I hope that the other ASPS patients who are participating in the Trial will also update their experiences and outcomes on this Forum because through our almost seven year experience of fighting this very challenging disease we have found that shared anecdotal information is truly one of our most powerful weapons. Our most special thoughts and best wishes for a very successful outcome to the Clinical Trial will be with dear 'K' and your family as she undergoes this new treatment, and we will be anxiously awaiting your next update. Thank you again for your very dedicated and gracious sharing of information.
With special caring thoughts and continued Hope,
Bonni

In terms of the size of the trial, this is what I found: "The total enrollment will be 45 patients. This trial is taking place at Premiere Oncology, Santa Monica, California, Dana Farber Cancer Institute (not yet recruiting), Boston, Massachusetts, Texas Children's Cancer Center (not yet recruiting) Houston, Texas, and Mary Crowley Cancer Research Center (not yet recruiting) Dallas, Texas."

To my knowledge the Santa Monica site has recruited less than a dozen patients. The longest anyone (not ASPS) has been on the drug has been since 2006.

The data from Ladanyi's lab suggests a key role for met in ASPS pathogenesis, and Vistica told me that 4 out of 4 metastatic samples he had of ASPS were IHC-positive for met and had met by quantitative PCR.

'K''s primary was very met positive by IHC, but 1 lung nodule at least was negative (did not test others).

XL880 is a combined met inhibitor + VEGF, but it may be more cardiotoxic, perhaps especially with prior anti-angiogenesis use. They would not let 'K' in the trial under age waiver at Dana Farber.

ARQ 197 seems to be well tolerated at least in adults, but with aggressive disease, it's possible one might need to combine it with other agents. There are 2 combination trials with ARQ197 and other drugs, but I don't think those combos are suitable for ASPS (e.g. ASPS is EGFR negative).

We had to apply for a waiver, but the whole process from approval to drug took about 2-3 weeks. We were happy with this. ARQ197 may inhibit new metastases and spread of metastases - and that is particularly our interest as at least at present it looks as if we may be able to resect all her metastases and the primary is gone. Fritz told us, it's the mets we don't see that may be more dangerous than any of the ones we do.

Oops, looks like I posted old site news. Here is more current:

" United States, California
Premiere Oncology Recruiting
Santa Monica, California, United States, 90404
Contact: Isett Laux 310-633-8400
Principal Investigator: Lee S. Rosen
UCSF Medical Center Not yet recruiting
San Francisco, California, United States, 94143
Principal Investigator: Steven DuBois, MD
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Principal Investigator: John Goldberg, MD
Principal Investigator: Andrew Wagner, MD, PhD
Sub-Investigator: George Demetri, MD, PhD
United States, Texas
Texas Children's Cancer Center Recruiting
Houston, Texas, United States, 77030
Principal Investigator: Alberto S Pappo, MD
Mary Crowley Cancer Research Center Recruiting
Dallas, Texas, United States, 75201
Principal Investigator: Neil Senzer "

http://clinicaltrials.gov/ct2/show/NCT0 ... %22&rank=2

We're just completing our first cycle on ARQ197 and starting our second. We aren't due to check scans until the beginning of July. 'K' tells us she feels a little tired on the medication (vs. no medication), but this hasn't slowed her up at all. She was able to spend 6 1/2 hrs at Disneyland just fine (with all that walking) and has had several sleepovers with friends and grandma since school got out. She is also back to riding her bike and running. She is also on Celebrex 200 BID and green tea.

I thought I would post additional info I got from the clinical coordinator. The teen girl who briefly stopped ARQ197 because of mild LFT rise has resumed it. She is feeling fine and is due to have her scans checked in the next few weeks. She is finishing her 2nd cycle.

There is a 40's year old with ASPS who has elected to continue with ARQ197 and is now in his 8th month with stable disease. He has had no new metastases, but some progression of some existing nodules. The growth over 8 months has been below the 20% increase that would take him out of the study.

I also did get more information about what the conditions would be for staying on ARQ197. Apparently recent data have suggested that ARQ197 may inhibit the develop of new metastases. This is backed up by animal data in at least 2 cancer models, but of course not ASPS (colon CA, breast CA). The discovery of antimetastatic effect for ARQ197 was also seen in solid tumor patients (below), but from analysis of existing data, and not a planned testable goal of an ongoing trial...as a result, it is possible for a patient on trial to have an antimetastatic effect of ARQ 197, but have growth in 1 nodule over 20% and leave the study. Existing criteria say that if tumor growth is over 20%, patients will not remain in the study. This may be a point that an oncologist could appeal, however. Apparently different clinical trials are planned to look at the antimetastatic effect.

The data I found on this:
Eighteen of 19 (94.7 percent) of patients treated with ARQ 197 for 12 weeks or longer did not develop detectable new metastatic lesions. Five of 7 (71.4 percent) patients treated for 7 to 12 weeks did not develop detectable new metastatic lesions. In contrast, eleven of 19 (57.9 percent) patients treated for 6 weeks or less developed new metastatic lesions. All new metastatic lesions occurred only in organs with documented pre-existing metastatic disease, except in two patients.

Hi there, just posting our update from our first set of scans. 'K' finished her 2nd cycle of ARQ197 and we will go back down to LA after the holiday weekend. The CT looked fairly stable, although some growth in existing nodules. No definite new nodules - this with me pouring over her scans. Her largest is still only about 5 or 6 mm. We will check MRIs down in LA next week.

All that being said, the appearance of what looked like new nodules at first glance made me go back to her scans 2 months ago, and it was only then I found nodules were there before (often present on just 1 section). This really told me how easy it is to miss nodules - sometimes you can only tell they are there when they grow. Our total number now - 12 on right, 2 on left (had thoracotomy that removed 11 a few months ago).

So not a slam dunk (tumor shrinkage, etc.), but we are relieved there aren't new ones (the first scan in 9 months where there haven't been new ones), and it is possible shrinkage may occur later (this is what they have seen in other patients). We were also somewhat expecting this, as it seemed from the sketchy literature that there was more evidence of an antimetastatic effect (ie prevent new mets) than antitumor (kill existing tumors), but still we're disappointed. Apparently the biggest antitumor effect with ARQ has been in a gastric CA patient who showed tumor shrinkage in just 6 weeks.

On another note, I have heard that recently researchers have seen greater efficacy in some patients at a higher dose, and the maximally tolerated dose has now been increased to 300 BID (we're on 120 BID), so the trials are in the process of ramping things up. She may not be allowed to try a higher dose though because she is already so young.

The nodule growth in this time interval was nothing like the explosive growth we saw soon after the primary was removed (she was also on no meds at the time), so we are very thankful for that. We are hoping that she is still completely resectable. By my eye, none of nodules is in an immediately dangerous place, so we may even be able do 1 or 2 more courses of ARQ197 if they let us before going to surgery. I'll let you guys know.

Virtually no side effects we can see, though our daughter says it makes her a little tired. She has been very motivated to exercise though, and so she manages to push through.

'F', hi, thank you for the update. I wanted to comment on the situation of the rather rapid growth of the lung mets after the primary removal. We had the same picture after Ivan's primary tumor resection - on the initial staging lung mets were not even visible on the CT scan but after the primary resection they started to pop up. I started to study if there is an effect in ASPS like in some other cancers, when there is a growth inhibition of remote metastases by a primary tumor, it is known as endogenous growth inhibition leading to dormancy of the metastases. I have seen other cases when after the removal of the primary tumor, especially bulky one, there was a growth of the metastases. The same sometimes happens with a bulky metastasis, when after its resection there are new small mets appear elsewhere. This effects is not seen after the lung surgery when multiple small mets removed and usually we even see a prolonged period of stability in the contra lateral site after the resection of the small mets which suggest some increase in immuno competency here, even debulking surgery to harvest tissue for the vaccine might have this effect. So my guess is that in ASPS a bulky primary or metastasis can have this growth inhibition of remote metastases and the rapid growth that you saw after the primary removal was the temporary effect of the withdraw of the inhibitory effect. This is just a speculation on my part and I share it with the attempt to show that there might be other explanation for slowing pace of growth in the remaining lung mets aside of ARQ 197, although the absence of the new mets is encouraging.

Just wanted to add here that we recently had good news from the path after 'K''s thoracotomy. I posted more on the Personal pages under 'K', but the quick news is that necrosis was seen in some (? most) lung nodules indicative of a treatment effect. Furthermore all of the smallest lung nodules were fibrotic, consistent with the possibility that ARQ197 might be able to inhibit the develop of new metastases.

I just wanted to add that Arqule has now announced a "clinical milestone" with ARQ197 and MiT study (ASPS is a MiT tumor). They have a total of 23 patients in the study, 14 evaluable for efficacy. Our daughter is one of the non-evaluable patients because she does not have a tumor that is at least 1 cm. It looks like out of the 14, 1 has met RECIST criteria for partial response (a clear cell sarcoma) and 10 have stable disease. It looks as if patients are stable first and then may start to shrink. In addition, a study from the Marsden group in UK showed that the dosing can be increased from 120 mg BID to 300 BID with no added toxicity and possible increased efficacy, so all on study will be increased on this.

Another encouraging note is that there are rumblings that ARQ197 may be licensed soon... possibly this year. That would be good news for people who couldn't make the study - the drug would have to be licensed before becoming commercially available. We had contacted David Vistica and asked about whether he knew about met expression in ASPS metastases - we know at least one ASPS met that was negative for c-met. He checked his samples from patients and told me at least 3 ASPS mets seen in different parts of the body were positive for c-met. C-met has been implicated in the growth, spread, and invasiveness of tumor metastases.

We also found out on our daughter's recent set of scans, no new tumors and MRI of the brain remains OK (praise God!).

I mentioned there was evidence of response in 'K''s resected lung nodules - we are arranging for the blocks to be transferred to UCLA and the pathologist has graciously offered to let me to see the slides with her once they have arrived. We were encouraged that there was evidence of a pathological response in her resected lung nodules after only 13 weeks on ARQ197 (and 5 weeks high dose Celebrex + green tea capsules).

We stopped all meds with the recent lung surgery, but are back on (currently 15wks ARQ197 8wks high dose Celebrex). 'K' is back at school and looking forward to being able to do PE next week (we are told to wait on sports until 6 wks after surgery). We are having her walk a mile on the treadmill every day though. As far as we can tell there are no side effects from the medication. We are still on the 120 BID dose - maybe they will increase us at our next visit down to LA later this month. We are seeing slight growth in the lung nodules, but this may be hard to interpret because of all the lung changes (left side expanded more when she had surgery on the right) - we have been mapping nodules with fine cut CT...and it looks like possibly 1-2mm growth over 3 months between the scans.

We would like to hold off on surgery as much as possible now because we run the risk of getting kicked out of the ARQ197 trial if we leave for surgery.

Hi there. Just a quick update.

'K''s doing great on ARQ197 (plus high dose Celebrex + green tea), currently at almost 6 months on the trial (though interrupted by thoracotomy) and 4 months on 400 BID Celebrex. She continues to have no new lung nodules, but a least some of them seem larger (though fewer were growing in this last interval). The largest finally reached 1 cm. We are waiting to hear from Dr. Rolle about the timing of a redo on the left. Fortunately none of them look as if they are in dangerous locations. We think it looks like 2 on the right and 6-8 on the left. We can see how hard it is to follow these nodules. We are doing fine cut CTs (1.3 mm) - at small sizes they're hard to distinguish from little blood vessels etc. You have to wait until they grow to know that they are tumor.

We just received a CD of 'K''s slides from Germany reviewed at UCLA and the slides will also be sent for molecular profiling. I'll let you know when the results are back. From UCLA: 5 out of 31 showed no tumor and 2 out of 31 showed the treatment effect. We were happy to see that the treatment effect was not subtle - 40% necrosis and 80% necrosis in the nodules. The question is - what are the 5 without tumor - completely treated nodules or unrelated patches of fibrosis?

I'm going to attach an image of the findings if anyone would like to see. the top nodules is 100% tumor (purple), the lower two images show central necrosis of 80% and 40% according to the pathologist. It was interesting to see this as 'K' was only a 13 weeks ARQ197 and 5 weeks high dose Celebrex at his point. In the phase I data for ARQ, partial responses were only seen after 20 weeks on the drug. It was disappointing that more nodules weren't necrotic, but we realize this was early in the study and 'K' is now at triple the dose of ARQ197 (the path of 'K''s lung nodules after 6 months of Sutent showed no evidence of necrosis), and there is some suggestion of better tissue expression with the higher dose. Fortunately there are no side effects of her regimen as far as we can see. She in school, probably straight A's and enjoying PE.

The pathologist told us the size of the nodules that showed some treatment effect were estimated to be about 5 and 7 mm. One question we wondered about was whether the dying nodules actually presented as slightly enlarging nodules (and more irregularly shaped?) by CT because of the area seen by the necrotic debris. It can be difficult to tell.

Our best to you all. Hope you have a nice Thanksgiving holiday.

Hi everyone,

'K''s 8 months on ARQ197 and 6 months on high dose Celebrex. Not much to post, but we checked another chest CT at Rolle's request because he would like to redo the left (conventional thoracotomy done 10 months ago). Looks to us as if no new nodules and probably slight continued slow growth in at least some of the ones that are there. It looks as if no new nodules at least for the last 6 months - and we are one year out from having the primary removed. Also if it matters to anyone, it looks like growth is slower than say 5 months ago - that could be the result from thoracotomy though, or the fact that the most aggressive clones (fastest growing) would be expected to be seen first. From what I've heard there is a 14 or 15 year old girl with ASPS also at Premiere Oncology who continues to have stable lung disease now at 9 or 10 months on ARQ.

We fedex'ed scans off to Rolle yesterday and will wait to hear from him. We would proceed with surgery if he agrees - because they think there is the possibility all tumors can be cleared completely (that being said -there are some missed on the right, so we would also have to redo the right at some time in the future).

All that being said, it is a difficult thing knowing when to operate. With fine cuts, we often trace back tumors to a little dot / blood vessel appearing thing - the only way to know that it is tumor is to see if it grows. Because metastases can occur long after the primary is removed, it is difficult to know when to wait and when to proceed. If we go now, for instance, what about new little cancer deposits that are non-detectable now, but may be detectable in a few months?

We have opted to continue ARQ197 because of the high met expression by 'K''s primary , the role of met is known to have in in vitro and in vivo models re: spread of cancer and invasiveness, and the early clinical observations that suggest it could inhibit spread of metastases to new organs. With Olga's latest library-added case report about the 11 year old who took cytoxan and vinblastine, though - we think we might have a backup plan if we get kicked out of the ARQ study for leaving to have surgery again. Our onc thinks there would be a good chance we could go back on though if we wanted - we would have to appeal. I am going to email the article of the case report and see if that boy had visible sub centimeter nodules on chest CT that resolved on cytoxan + vinblastine, or whether he had no visible disease and simply none recurred after surgery. The report is kind of vague.

Dear 'F',
Thank you for sharing this continued very encouraging information with all of us. It is interesting that the younger patients like 'K' and the 14 year old girl who you mentioned that has had ten months of disease stability seem to have had a more successful response to the ARQ-197 than Brittany or the two other adult patients who we are familiar with that heartbreakingly had unsuccessful responses. Our observations as lay persons during our challenging seven and a half year journey with this poorly understood disease has been that the younger patients seem to have less extensive metastasis and slower progression of the disease with better and more sustained treatment response. It would be very interesting to find out if there is any research that has been done or published data to substantiate our observations. Perhaps the younger patients have stronger less compromised immune systems which are better able to fight the disease. Our best wishes and greatest Hope will be with 'K' for a continued successful treatment response and disease stabilization, and we will be anxiously awaiting your next update. Thank you for being so faithful in your sharing.
With special caring thoughts and continued Hope,
Bonni

Ugg. Perhaps I spoke too soon. The report came back and they said at least 1 tiny new nodule on the right and 1 tiny new nodule on the left. So I went back diving through the scans. Also I learned that although we ask for fine cuts (1.2 mm cuts), they will only send the 5 mm cuts to the radiologists to read (I guess it takes them too long).

So I looked at these two "new" nodules and sure enough I found them back at least 4 months and sometimes longer (6+ months). So I really began pouring through all through the scans (fine cuts) with a fine tooth comb. We unfortunately see more than these 2, so we are thinking we want to boost our medical regimen. Some of them really haven't grown - and some minimally. But it was discouraging finding them. But this data is hard to interpret too.

We had stopped ARQ to have the right thoracotomy (about 4 weeks - had her surgery end of August) - so if the clock has to start all over again (12 weeks to have no new metastases), we haven't proved that ARQ isn't working, and maybe if we stopped the drug now, it would just be before the time we would see more of an effect (partial remissions only occurred after 3 months). It looks pretty clear that lung growth has slowed compared to what was happening earlier in the year. I would say about half of the nodules on the left aren't growing (this is definitely better than early last year - but who knows, could it be the natural course of disease?), but 2 definitely are. I could not definitely find any new nodule that has appeared in the past 4 months...but when they are slow growing, it takes time to find them. Now we are not certain what to think.

We are still waiting for Rolle's opinion and 'K' and Brock will be going down next week for the ARQ visit. They will also want to talk to Lee Rosen.

I would like to get in touch with the Minderleins to ask them - did they ever see lung nodules disappear with Vinblastine and Celebrex, or was it just stabilization? And why did they do 3 rounds of AIM at the end of the Celebrex? Were nodules starting to grow again? I found an old hotmail address for Janette. Let me know if any of you know how to reach her or Amanda.

It would be fairly easy for us to add on Vinblastine - especially with the latest case report Olga added to the library. I am also planning to email on of the authors to get more detail. I am also emailing George Ladas - UK surgeon who did CTOS presentation on redo thoracotomy. I don't know whether he will answer, but I wonder what his criteria were for redo thoracotomy. Did he want no new nodules - and if so, how long? I know ASPS can continue to have metastases 5+ or much longer out from the primary being removed. Was there a certain size that prompted him to do a redo? I know some doctors don't think lung metastases in ASPS predispose to other tumors (the argument is that the vessels are end vessels - so can't spread elsewhere), but I am not so sure. Because of their vascularity and ASPS tumors to break off early and metastasize, that would be what I would worry about when they get to a certain size.

AIM would be a bigger deal. Ugg.

I also wish I knew more about the cases that seemed so stable on redo thoracotomies alone. Is 'K' just not like them? We're also doing very sensitive scans because we ask for them - and I don't know whether that makes it hard to compare.

'F',
in my firm believe the thoracotomy alone (citoreduction) can stabilize the growth of the ASPS lung metastases for a while because Ivan had stable disease for about 2 years after his surgeries and we know about other cases as well when it was happening with no other treatment, (including may be even Anthony as his mets were harvested for the vaccine trial and I guess they took the bigger ones and may be this citoreduction was able to induce the stable condition for a few years in his case). I do not see enough arguments to suspect that ARQ is working at all (well - this is what the clinical trial is for). Two of the nodules that were removed by Dr.Rolle from Ivan's lung last time in May were also fibrotic with no treatment. We also know first hands here about the cases of the spontaneous partial regression of the smaller lung metastases - Brittany Hess and Sean Anderson - so I guess that small mets at times can get fibrotic with no treatment and as the time goes they can be dissolved by the body esp. meaning that we are talking about the young people.
On the other hand we have some firm evidence that traditional chemotherapy is able to kill smaller lung mets or may be works at the certain period of time - soon after the surgery? - Dr.Nickerson report, Amanda case, Camilla case, Tammy case. We also know that chemotherapy is not able to kill the bigger ASPS lung mets (more then 5-8 mm?), so if there is a back up from the surgeon that he will expect to be able to resect bigger mets, may be it makes a sense to do two rounds of the chemotherapy before of the surgery and see the result. Generally, there is no proof that smaller ASPS lung mets are chemo-insensitive because chemotherapy treatment was almost never done before of the complete surgery to remove the bigger mets. If there is no surgery in planning, I would not go for the chemotherapy as it is already known that any high dose chemotherapy induces increased vascularization and as bigger mets are never 100 % they are destined to regrow at the faster rate after.
There is a members list in the right upper corner of this screen - look for Amanda's mom Janette Minderlein and Amanda's nickname is MichaelsMommy.
Her secondary (referral) oncologist was Dr.Pappo and he might be able to comment somehow, although he moved to US again from Canada and is an arrogant person I have to tell, unlike Dr.Nickerson who is one of the nicest caring doctors,
Regards,
Olga.

Thanks a lot, Olga. Well, I still am not so pessimistic about ARQ197. I hope it's not just being defensive - I know other people are considering the drug too. It acts in a very different way from chemo - I think its greatest benefit is likely to be antimetastatic rather than tumor kill. But that is not a trivial thing especially in ASPS. In the mouse models, ARQ reduced lung metastases to 10%. So the appearance of some tumors doesn't mean there is no effect - its effect may just not be complete. The question is would you have developed more if you hadn't been on the drug? Looking at cases it looked to me as if it wasn't uncommon to get new lung metastases for the first 2-3 years after the primary's been removed.

My personal suspicion is that ARQ does probably have at least a partial beneficial effect in ASPS. It may not be strong enough though. But because of its specificity, it would probably be able to be combined with lots of other drugs though too, and it doesn't have some of the risks of conventional chemo.

I also thought it was cool that 'K''s mets removed at thoracotomy are now met-negative (her primary was highly positive). In other cancers at least that correlates with a better profile (less invasive, less metastatic). All of David Vistica's samples for ASPS were met-positive.

There are probably lots of individual variations though.

Well, we are thinking of metronomic Vinblastine (once a week) and still pushing on with laser on the left if Rolle agrees. Of note, we did see a sizable new nodule with the first postop thoracotomy scan. This was not the case with the second thoracotomy (and on ARQ) - the first new hint of a new nodule was 5 months post surgery - and then just at the threshold of being seen.