First, I want to thank members Jim (dadawg001) and Neil (neilb) for bringing up this topic in the Discussion/Q&A Forum yesterday. Amazingly, yesterday morning I happened to be reviewing slides in my collection on a novel agent and approach that I thought would make a good topic for a post here: the drug DMXAA, which is a “vascular disrupting agent”. Later that same day, Jim raised a question about a new agent, ASA404, which had promising results reported in a press release by its manufacturer, Antisoma, based in London. I noted that I was unfamiliar with the agent, which was only partly true. In fact, it has been known previously as AS1404 and DMXAA, so even though I was thinking about this agent for reasons other than the press release (which I’ll get to), we were all circling around the same drug yesterday. Definitely worthy of a full discusison now. (Antisoma also needs to work on it’s brand identity so that people can actually figure out that ASA404 is AS1404 and also DMXAA.)
Anti-angiogenic drugs like Avastin (bevacizumab) are felt to work largely by causing regression of new blood vessels to tumors as well as inhibition of a new blood supply to a tumor that would otherwise be growing and is now limited by an inability to receive nutrients and oxygen and also to dispose of waste products. In contrast, ASA404 is a vascular disrupting agent that works directly on the endothelial (blood vessel inner wall) cells to cause apoptosis (programmed cell death). In addition, it causes release of the glycoprotein Von Willebrand factor in blood that can lead to clotting of blood vessels (potentially a good feature, also potentially bad) and also a cascade of cytokines, basically proteins with hormonal activities that often contribte to making people with cancer feel terrrible, such as tumor necrosis factor, another focus of cancer treatment modalities. The end result is that this agent can cause the breakdown of existing (not just newly forming) blood vessels and destruction of cancer cells.
This year at ASCO, an early clinical trial that is known as a Phase Ib/II trial was conducted in which the novel agent was combined with the chemotherapy backbone carbo/taxol at escalating doses as the investigators looked for dose-limiting toxicities (DLTs) that would help define the maximum tolerated dose for ASA404 (referred to as DMXAA (AS1404) in their abstract and poster). After checking tolerability at lower doses of ASA404, they ended up proceeding with enrollment of about 70 patients who were randomized to either carbo/taxol alone or to a combination of carbo/taxol + ASA404 at 1200 mg/m2.
(These data have been presented at multiple meetings over the last year, so the numbers change slightly between their official poster and the slides — it’s a work in progress).
Though we’re talking about small numbers, the basic take-home message is that the results were encouraging. Compared to carbo/taxol alone, the same chemo with ASA404 was associated with a better progression-free survival, overall survival, and response rate:
The median overall survival of the chemo + ASA404 group is an impressive 14 months.
In terms of side effects, there were higher numbers of patients with both cardiac problems (of any nature) and infections in the group that had ASA404 added to chemo, but not obvious increases in toxicities overall:
Thus far, there apparently haven’t been life-threatening or fatal bleeding complications with this agent, as is rarely seen with agents like Avastin and some other anti-angiogenic drugs.
The update yesterday was a press release from Antisoma in which they announced that their new phase II trial of chemo with a higher dose of ASA404, 1800 mg/m2, also showed a favorable survival in keeping with the earlier trial I describe above. The actual data will be reported at the World Lung Conference in Korea that I’ll be attending and speaking at, and you can bet I’ll be there to learn what I can. They call it a “positive trial”, which is really a wording I’d reserve for a larger phase III trial that can actually detect differences between one treatment and another, and I would consider it rather aggressive to make an international declaration of the astounding benefit of their drug based on a phase II trial. Many new drugs and combinations show phenomenal results in small phase II trials reported early, and many don’t pan out. This doesn’t mean I don’t think the results are encouraging — I absolutely do, and I’d consider this agent on my “ones to watch” list for years to come. And it’s also shown some early but promising results in prostate cancer (abstract here), although a previously reported trial in ovarian cancer was looked decidedly unfavorable for ASA404, and the chemo alone arm actually appeared to do better (results described here). This was despite using the same combination and doses for ovarian cancer as for lung cancer. So there’s at least reason to be cautious in your optimism.
How are things moving forward? Antisoma is partnering with the larger company Novartis, and there is a plan to launch a phase III trial of chemo and ASA404 next year. One key issue that isn’t clear, at least not to me and at least not yet, is whether this will be a larger version of the smaller phase II work, comparing chemo alone to chemo with ASA404. If so, even a trial that shows an improvement over carbo/taxol alone would beg the question of whether carbo/taxol/ASA404 is better than carbo/taxol/Avastin, and also what the differences in side effects would be, for Avastin-eligible patients (a subset, but perhaps 40-50% of first-line patients). Thus far, the phase II trials have enrolled all NSCLC pathology subtypes, so for patients with squamous histology, who aren’t generally given Avastin, a benefit with ASA404 would make an easy choice. I’d probably recommend running a trial in which one arm gets carbo/taxol/ASA404, and the other arm gets carbo/taxol with or without Avastin at the discretion of the treating oncologist. This way, the company can look at the different subsets of those who got chemo alone, and also those who got it with Avastin, and see how carbo/taxol/ASA404 does against each. If it beats the alternatives on both counts, great. Maybe ASA404 will be an improvement for the Avastin-ineligible people but a lateral move for Avastin-eligible patients. We just don’t know.
The bigger but related question is whether vascular disrupting agents like ASA404 are really significantly different from “anti-angiogenic” agents that inhibit the activity of the Vascular Endothelial Growth Factor (VEGF) axis, which have a related but not identical mechanism of action. We all hope it will be more than just a variant on what we already have in the clinic or late testing. The stock market is optimistic — the stock price for Antisoma did well, I understand. It would be great to have another effective agent to try in lung cancer, especially one that might be helpful for a broader range of histologic types. I’m encouraged, but at this point these data are early enough that I don’t want to feed any irrational exuberance. But I wish them luck with the larger study.
posted by Dr. West @ 4:44 pm link to this post
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August 23rd, 2007 at 6:26 pm
Dr. West:
I noticed that in one of the slides of your note there appear other “vascular disrupting agents” besides ASA404 (CAP4, Exherin, AVE8062A). How advanced and or promising are these other agents compared to ASA404?
The second question is that the same slide seems to imply (but correct me if I am wrong) that vascular disrupting agents work best for large solid tumors with established vessels and that the angiogenesis inhibitors work best in small tumors that are creating new blood vessels. If true, wouldn’t this create a different niches for each one of these types of drug depending on the size of the tumor?
Cheers and have a nice & safe trip.
Carlos
August 23rd, 2007 at 7:10 pm
Dr. West: Thanks for the lengthy post on this. I knew there was a reason we pay you the big money!
One thing still puzzles me that I mentioned in the forum. The effective disease control rates of 91% for the ASA404 group and 75% for the control group are very high (even for first-line chemotherapy). The six-week interval struck me as a logical explanation (maybe people who are progressing only show 15-20% progression in 6 weeks, which qualifies for “stable”, but they might have gone over the threshold if the first scan were after 8 weeks). Is there a standard for these things? It seems like a lot of studies use 8 weeks. Obviously, this only matters if you’re comparing disease control rates (it would have the opposite effect if the measure you were interested in was response rate), but I’m curious about the level of standardization and how much difference it makes in results (as well as how different the protocols are in New Zealand vs. the US; it seemed that they reported adverse events in a somewhat different fashion).
Just curious, but also hopeful that ASA404 and I will both do well enough that I may meet up with it some day!–Neil
August 24th, 2007 at 9:28 am
I haven’t seen any clinical data with any of the other agents mentioned on the first slide figure, so I would say that they’re not as far along and that we may or may not ever see them in clinical trials. That will depend on some favorable early studies in animals and then humans, but also on whether they are developed by their companies, which may or may not have adequate resources and interest in developing these.
I’d also say that while there may be some distinction in having vascular disrupting agents work for larger tumors and that anti-angiogenic agents are theoretically more effective for smaller tumors, my emphasis would be on the word theoretically. We don’t restrict our use of Avastin (or other anti-angiogenic drugs) to smaller cancers, and there’s no evidence yet to suggest that patients with a smaller tumor burden or smaller individual lesions do better, or even that in patients with a wide range of tumor sizes that anti-angiogenic drugs work better for smaller lesions than for larger ones. We don’t have any suggestion of a size difference for lung cancer or any other cancer right now, so I really would say that this is a conceptual idea that doesn’t have any practical implication at the present time.
With regard to Neil’s question about disease control rate (DCR), we pretty standardly check a repeat scan after 6 weeks on therapy, or two cycles of a three week regimen. I think that with only a few dozen patients per arm, I wouldn’t read much into it. The fact that the DCR is so high with carbo/taxol alone illustrates the ability of small trials to mislead. If you flip a coin 4 times, you may come up with heads each time and conclude it’s a two-headed coin. That won’t happen if you flip it 50 times. If the DCR is 91% in a phase III trial, I’ll be writing that this approach is going to be my new standard of care if I can get it. Until then, I’m skeptical it’ll hold up but still hopeful there’s something to this agent.
-Dr. West
August 27th, 2007 at 3:24 pm
Dr. West:
You stated-
I haven’t seen any clinical data with any of the other agents mentioned on the first slide figure, so I would say that they’re not as far along and that we may or may not ever see them in clinical trials. That will depend on some favorable early studies in animals and then humans, but also on whether they are developed by their companies, which may or may not have adequate resources and interest in developing these.
Please visit the Oxigene website
http://www.oxigene.com/home.asp?sf=f
Their pipeline
http://www.oxigene.com/vascular/pipeline.asp
First link
http://www.drugresearcher.com/news/ng.asp?id=77125-oxigene-novartis-antisoma-vascular-disrupting-agent-zybrestat
Second link
The product of research by Oxigene, a biotechnology company focusing on small-molecule therapeutics to treat cancer and ophthalmic diseases, Zybrestat is a Vascular Disrupting Agent (VDA) indicated for the treatment of anaplastic thyroid cancer and, potentially, other solid tumours. A member of a new class of anti-cancer drugs, Zybrestat is poised to enter pivotal phase II/III registration trials under a special protocol assessment agreement with the US FDA. It will be evaluated in combination with paclitaxel and carboplatin and its effectiveness compared to treatment with paclitaxel and carboplatin alone. VDAs
TARGET ESTABLISHED TUMOUR VASCULATURE
The concept of attacking tumours by cutting off their blood supply was first described in the early 1970s and subsequently led to the development of a new class of anti-cancer drugs called angiogenesis inhibitors. These drugs, which are now in clinical use, work by preventing tumours from developing a blood supply, a pre-requisite for tumour growth and metastasis (tumour spreading). “VDAs differ from angiogenesis inhibitors in that they are designed to attack the established blood vessel network within a tumour.” VDAs differ from angiogenesis inhibitors in that they are designed to attack the established blood vessel network within a tumour rather than preventing the growth of new blood vessels from the viable tumour rim. Zybrestat (combretastatin A4 phosphate) is a prodrug that is converted to combretastatin inside the endothelial cells that line blood vessels. Combretastatin has a dual-mode of action, targeting both VE-cadherin, a junction protein that is important for endothelial cell survival, and the associated beta-catenin/AKT signalling pathway. Once activated within the endothelial cell, it causes rapid collapse and necrosis of the tumour&squo;s vascular structure. As a reversible tubulin depolymerizing agent, combretastatin also causes tumour-associated endothelial cells to change from a flat to a round shape. This has the effect of plugging the blood vessels so depriving the tumour of the oxygen and nutrients it needs to survive. Because the endothelial cells of tumours are immature they are much more sensitive to the effects of combretastatin than the endothelial cells of normal tissue.
ZYBRESTAT SHOWS EVIDENCE OF ANTI-TUMOUR ACTIVITY
Data from a phase II study, in which the clinical effects of Zybrestat in combination with paclitaxel and carboplatin were studied in 13 patients with advanced malignancies including anaplastic thyroid cancer, suggest that Zybrestat possesses potent anti-tumour activity. Patients in this study received one of two dose regimens of Zybrestat, both of which reduced tumour blood flow as measured by Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI). The most marked reductions in tumour blood flow (70%) were seen in the patients with anaplastic thyroid cancer.
COMBINING VDAs WITH ANGIOGENESIS INHIBITORS The potential to use VDAs in combination with angiogenic inhibitors is a concept that is attracting considerable interest among scientists. Targeting different aspects of a tumour&squo;s blood supply, sequential use of VDAs and angiogenic inhibitors could lead to massive tumour necrosis and destruction. While a VDA such as Zybrestat could be used to destroy the established blood supply feeding the tumour, the subsequent addition of an angiogenic inhibitor could prevent the regrowth of blood vessels (neovascularisation) which allows a tumour to survive and proliferate following initial therapy. Preventing the regrowth of blood vessels from the viable tumour rim could help stop tumours from spreading.
http://www.jordomedia.com/RSS/l_op=viewrss/lid=2334.html
Best regards,
Cirkus
August 27th, 2007 at 7:10 pm
Cirkus,
I admit that I don’t know about every drug being developed in every cancer setting around the world. Combretastatin (Zybrastat) is an agent that I have heard of but really am not familiar with, largely because there hasn’t been a reported study in lung cancer yet. I’m happy to follow it but am not focusing on anaplastic thyroid cancer.
I edited your post, just slightly, and less than I’m tempted to do, because I’m happy to have new information added but don’t want the editorializing about OXiGENE being the world leader in this work. The public relations puff pieces can go on they company brochures, but this isn’t the advertising section for OXiGENE.
I’ll be happy to review actual clinical data on combretastatin when there are some dedicated clinical studies in lung cancer, but I’d still stand by my comment that there isn’t a critical mass of clinical data on this agent in lung cancer yet.
-Dr. West
August 29th, 2007 at 7:39 am
Dr. West:
Thanks for your response.
I admit that was a tactless remark from my side.
I apologize that.
Best Regards,
Cirkus
August 29th, 2007 at 10:24 pm
I got the sense that much of the entry was cut and pasted from a marketing/PR piece. I think those are fine on a company website, but I’d like to focus on what the data show and try to keep the editorials pretty circumspect, including my own. As I say, I’ll be happy to review this agent separately when there are lung cancer data to talk about.
-Dr. West