Cure Alveolar Soft Part Sarcoma International (iCureASPS)

FYI ASCO meeting is going on now and here are the results for 'alveolar soft part sarcoma'.

A continuation of the Sutent trial from Italy had the following (see below):

It was nice to see the high percentages of response - but of concern to me was the person who was responding for 17 months, then developed progressive disease. They stopped the Sutent, then the patient died 1 months later. I think it seems to be a dangerous time discontinuing anti-angiogenesis inhibitors and this is another case.

The other interesting mention in the abstracts was about a tubulin-liked drug (like Vinblastine). It really looks good - if it were closer to us and for kids, we would definitely try it - especially as there have been responders who have been on Vinblastine. The full abstract is below the Sutent one, but this is the interesting line: "one alveolar small part sarcoma patient, who had marked progression prior to enrollment, has received 21+ cycles of study drug with stable disease." I especially liked that the side effects seemed especially LOW.

It is put out by a little company though, so I do worry that it may take them a while to get to Phase II.

I also talked to Barbara Adam today about cryoablation. I'll add more general info for those who might consider that route.

'F'
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Abstract:

Background: ASPS is a rare soft tissue sarcoma, characterized by the t(X;17), resulting in the ASPL-TFE3 fusion protein. It carries a high metastatic potential with a typical indolent growth even in the advanced stages. ASPS is generally resistant to chemotherapy. We already reported on the activity of SM in 4 cases of ASPS. This series updates those results. Methods: Since July 2007, 10 patients (pts) with progressive metastatic ASPS (M/F 7/3; median age 24 yrs; site of primary: extremities 9, retroperitoneum 1; site of metastasis: lung 10, bone 3, liver 3, brain 2, other 4; pretreated pts: have been treated with continuous SM 37.5 mg/day, on name-use basis. Responses were evaluated after 2 months from baseline, then every 3 months by CT scan and/or MRI, according to RECIST criteria. PET responses were evaluated in 5 cases. Biochemical analysis by phospho-RTK arrays complemented by downstream signaling pathway analysis was performed on 5 pts whose cryopreserved material was available. Results: At the time of the present analysis 8/10 pts are evaluable for response (2 just started), 8 pts are still on treatment. Treatment was fairly well tolerated (no G3-4 toxicity). After 3 months of treatment, 5 pts had RECIST PR, along with subjective improvement in symptoms, 1 SD, 2 PD. PR/SD were confirmed in all cases after 6 months. PET was consistent with response/progression. One patient had a secondary PD after 17 months of treatment and died one month later. Responses seemed to be long-lasting (>9 months in all cases), with one patient still responsive after 28 months. In 2 cases treatment interruptions lead to tumor progression. Response was re- established when restarting SM. Biochemical analysis showed good correlation between RTK activation profile and SM targets, and a uniform activation of AKT, ERK1-2, mTOR downstream pathways. Notably, a particularly strong activation of EGFR was evident in the case with SD. RET-mediated activation might be responsible of the 2 progressive cases. Conclusions: SM confirmed to be active in ASPS. Long- lasting dimensional responses were obtained. Interval disease progressions were recorded in case of treatment interruptions. Molecular analysis supported SM activity.

Background: ALB 109564(a) [ALB] is a vinca alkaloid, which functions as a tubulin inhibitor, interfering with microtubule polymerization resulting in metaphase arrest. In preclinical studies, ALB was active in a wide variety of tumor types (e.g., colon, NSCLC, prostate) at concentrations comparable to those of approved vinca alkaloids. Methods: This study sought to determine the maximum tolerated dose based upon first cycle toxicity in 3-6 patients at each dose level, as well as to evaluate the pharmacokinetics of ALB when administered intravenously every three weeks. The starting dose was 1.2 mg/m2, and escalation proceeded according to a modified Fibonacci scheme. Results: 28 patients have been administered ALB across eight dose levels (1.2 to 12 mg/m2). No dose-limiting toxicities as well as no serious adverse events specifically attributed to ALB were observed. Through seven cohorts, adverse events reported to be at least possibly related to study drug were constipation (n=5), anemia (n=2), fatigue (n=2), blurred vision (n=1), decreased appetite (n=1), flushing (n=1), paresthesia (n=1), and rash (n=1); all were either grade 1 or 2. The overall half-life of ALB was 19.05 ± 8.80 hours, which is comparable to that of approved vinca alkaloids. Of 21 patients evaluable for clinical activity, one alveolar small part sarcoma patient, who had marked progression prior to enrollment, has received 21+ cycles of study drug with stable disease. An additional four patients have had stable disease after two or more cycles; one anal (7+ cycles), one pancreatic (5+ cycles), one colon (4 cycles), and one NSCLC (4 cycles). Conclusions: ALB is well tolerated and has shown preliminary activity in disease types not typically associated with approved vinca alkaloids. Further trials in soft tissue sarcoma are in development.

Dear 'F',
Thank you for sharing this very important information. The information provided about the Italian Sutent trial certainly validates the effectiveness of anti-angiogenic treatments like Sutent for ASPS patients, as well as the concerns about eventual developed resistance to the drug, and rebound when the drug is discontinued. It is certainly something that everyone who participates in an anti-angiogenic treatment needs to be aware of, and plans for an alternative treatment in the event of disease progression need to be in place and initiated immediately to try to prevent the rebound and rapid progression of the disease as so tragically happened with the patient discussed in this presentation. Switching to another anti-angiogenic medication as soon as resistance is developed to the first one has been suggested as a possible effective treatment plan to restore disease stability.
The data provided on the tubulin inhibitor sounds promising, but it seems that more extensive study is needed before any significant conclusions can be drawn. Hopefully future trials with this drug for soft tissue sarcoma will become available soon, and the drug will prove to be an effective treatment option for ASPS. I will be anxiously awaiting any further information that becomes available.
With deepest gratitude for your dedicated research and thoughtful sharing, and with continued Hope,
Bonni

Bonni,

Your comment reminds me - the commercially available anti-angiogenesis inhibitors that may be effective against ASPS is(besides Cediranib which is only available by trial and Sutent which is part of thisstudy): Pazopanib. Avastin does NOTseem especially effective in ASPS although there are trials to combine Avastin with Cediranib. Pazopanib resembles Cediranib in terms involving another VEGFR by in the dish tests, but it is much less potent than Cediranib. There are some cases where mTOR has had partial responses in ASPS (some of you remember Pamela Ham), but when Pam was on a trial of Ridaforolimus and her disease progressed, she was taken off the drug and I think she died I a few months later.

Re: the Tubulin drug. Yes definitely too soon to tell. But was encouraging to see that they were going to try more sarcoma. If they get to phase II, there may be a possibility of asking for an age waiver for kids for those of us who have to wait for pediatric availability.

Hello again 'F',
Thank you for the additional input regarding other possible anti-angiogenic drug options which I am well aware of already, but many may not be. In the heartbreaking event that Brittany eventually develops resistance to the Cediranib, it would be extremely important to be able to switch to another treatment immediately to prevent rebound, and there would not be time to wait to get enrolled in another Clinical Trial, so unless there is a better readily available new promising treatment, her Clinical Trial oncologist has recommended that Sutent would probably be a good option. We continue to hold VERY tight to Hope that the Cediranib will provide a continued and sustained response until a permanent ASPS cure can be found, and the decision to seek another treatment will not be necessary, but we remain vigilant in our research regarding this issue.
With special caring thoughts and continued Hope,
Bonni

Agree Sutent would be a great choice, Bonni.

The thing to look for when resistance is developing - is that you may notice a few tumors growing slightly whereas others had been shrinking or were absolutely stable. If the next scans may show even more that show slight growth, then that may lead to a decision to either leave trial or switch medications etc. I think you're following Lindsey's blog and it's possible her ASPS is developing some resistance to Sutent after 13 months. I hope not though.

The other interesting thing is that there have been some studies that show that if one anti-angiogenesis drug starts developing resistance, switching to another for a while stabilizes things again, and then if resistance develops to that one, switching back to the original drug helps again - I know this has been seen with Sutent for instance. Important to know as not all these drugs are commercially available - but it looks like some promising data, so hopefully more of these drugs will become available so docs have more flexibility prescribing them.

Also - another abstract I noted with interest was an ARQ197 + Gemzar study in advanced solid malignancies. There was much more of a response (partial responses etc.) to the combination of these drugs than ARQ197 alone. It made me think of Sarah Debolt and her excellent response to Gemzar only. As we are currently on a Met drug - if / when we come off study, we might go for the cryoablation on the left as soon as we're kicked out, but then if no compelling trial is available for her, try a course of Gemzar for the ones on the left. I don't know. We'll have to look into it more at least. There is an idea that sequential chemotherapy may be beneficial and less toxic than the combination types. The main downside to Gemzar it seemed was that it was really fatiguing, but Sarah could see results fairly quickly. At least during the summer, it is easy to sleep in.

(Olga - this may not have been put in the correct forum, but I always struggle figuring out where to put discussions in different topic areas...sorry and move if you'd prefer).

'F'