Similar in concept to Abraxane, paclitaxel poliglumex (PPX, or Xyotax) is another novel formulation of paclitaxel in which the taxane is bound to a biodegradeable polymer utilizing a polyglutamate drug delivery system. As with Abraxane, this allows administration without solvents over a recommended infusion time of 10-20 minutes and potentially allowing for improved delivery of the agent to the tumor target with a greater relative sparing of normal tissues. The idea is that the release of the paclitaxel molecule from the polymer backbone by lysosomal proteases (enzymes that cut apart proteins), some of which are overexpressed by tumor cells.
(click to enlarge)
Xyotax has been studied in several phase III randomized trials in the performance status 2 (PS2) patient population . In the STELLAR 3 trial (abstract here), the combination of carboplatin/PPX was compared with carboplatin/paclitaxel q3weeks, while the STELLAR 4 trial compared single-agent PPX to gemcitabine or vinorelbine as a single-agent (abstract here).
Each of these first-line trials demonstrated no significant differences in survival or other efficacy endpoints favoring the Xyotax arm in either trial, but an exploratory analysis of the female patients in both of these trials revealed a markedly superior survival in recipients of PPX.
Subsequent careful assessment for a potential explanation for this gender-based difference may be due to the finding that the release of the paclitaxel molecule from the polymer backbone of PPX requires intracellular cleavage by lysosomal proteases, particularly a lysosomal protein called cathepsin B, which is upregulated by estrogen. Therefore, it was thought that Xyotax may be more active in a high estrogen environment. Based on these results, a follow-up randomized phase III trial of women with PS 2, known as PIONEER, was initiated to compare xyotax to standard paclitaxel:
. This trial was discontinued recently, apparently due in part to higher survival than expected on the control arm. The company has also decided to focus exclusively on premenopausal women, as further analysis of the work in their STELLAR trials demonstrated that the improvement in survival seen with Xyotax was limited to women under 55:
The company is planning a trial of carboplatin/paclitaxel vs. carboplatin/Xyotax in approximately 300 premenopausal women with a marginal performance status.
This is a remarkable strategy in trying to bring a new drug to market. I do believe that the new era of lung cancer will bring more individualized therapies, but it remains to be seen whether the company can run a large trial looking for such a limited population. It costs money for cancer centers to open clinical trials, and my institution would not be inclined to invest the funds to open a trial that would be limited just to pre-menopausal women who have a poor performance status. Other people have dismissed this approach, wondering when trials will be targeted only to dark-haired, left-handed men. The flip-side of running trials for specifically targeted populations is that it can be hard to find enough of these patients to complete the trials, and even if they are successful, can a company succeed if their drug is indicated for such a very narrow indication? Lung cancer is a big problem, but the focus for Xyotax right now is on a very small proportion of that population. But it represents the first major industry-funded research on sex-based treatments for lung cancer, and the company has been able to move forward some of the questions of how men and women may respond differently to the same drug.
posted by Dr. West @ 9:52 pm link to this post
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April 2nd, 2007 at 5:52 pm
Dr. West,
“another novel formulation of paclitaxel”
If a patient once exibited allergic reaction to Taxol, what are the chances they would be allergic to other formulations of paclitaxel.
I heard that some clinics routinely run Pre-Treatment tests to determine if a patient has developed an allergy or resistance to a particular chemical treatment.
I think Taxol is one of the drugs that has a higher tendancy to present an allergic reaction. Is that because it is derived from a natural source (the bark of the Pacific Yew tree)? Many people have seasonal allergies to trees and grasses etc. Is it the same thing?
Do you know if they actually still have to have the tree to make Taxol?
So, if a woman was already taking ERT (forced menopause) they would be excluded from taking Xyotax?
Thanks - Chanwit
April 3rd, 2007 at 8:54 am
Chanwit,
Most of the reactions to taxol are from the solvent it’s dissolved in, not from the taxol itself. Abraxane or xyotax would be an option for patients who developed a hypersensitivity reaction to taxol, since these don’t require that solvent. It’s still possible to get a reaction, but it’s considerably less common with these “next generation” taxanes. Of note, they still include the taxol molecule itself, but it’s packaged differently. And that’s stil derived from the Pacific yew tree. Taxotere is a semisynthetic taxane similar to taxol, but it’s associated with a lower risk of reactions, but still requires its own solvent and needs premedication with steroids, which neither Abraxane nor Xyotax do.
I have never seen the protocol for the Xyotax trial that is coming out, and I’m not sure it’s completed yet, but I believe they’re checking blood estrogen levels and are probably excluding women on hormone replacement therapy, since many post-menopausal women are on hormone therapy, but the benefit they saw was in younger women, which they believe to be a surrogate for pre-menopausal status.
-Dr. West
April 13th, 2007 at 5:49 pm
Hi everybody:
Cell Therapeutics announced that they will be launching a Phase III clinical
trial of Xyotax that seems different from the one discussed in this post
(which will be running too).
here is the link to the announcement:
http://www.cticseattle.com/investors_news.htm
Here is the description:
“The trial, PGT306, will focus exclusively on women with normal estrogen
levels, the subset where XYOTAX demonstrated the greatest survival advantage
in the STELLAR trials. The trial is expected to enroll 300 poor performance
status (PS2) women who have advanced stage non- small cell lung cancer
(NSCLC) and have not received prior chemotherapy. Only women with normal
estrogen levels either as a result of pre-menopausal age or hormone
replacement therapy will be randomized in the trial.”
So it seems that in this trial Xyotax will be used as a monotherapy,
although it does not say against which therapy they will compare it to
(Alimta, docetaxel?)
Carlos
April 17th, 2007 at 10:11 pm
Carlos, and others,
In researching this issue, I found press releases about a trial PGT306, which you note here, and another trial PGT307, which is the one I’m describing. It isn’t clear to me whether the plan changed from pursuing PGT306 to running PGT307 instead, or whether the plan is actually to conduct two separate trials. CTI has been modifying plans pretty quickly, and what is out in the public domain is pretty scant info. I think I’ll have the occasion to speak with someone from the company in the near future, and I’ll see if I can get more concrete information and relay it back to people here.
-Dr. West
May 11th, 2007 at 1:29 pm
Xyotax would appear to be of very limited application. 1rst line younger women. 2nd line patients will probably be postmenopausal whatever their age. I also wonder if Xyotax can be effective long as the chemo, probably a 2 or 3 drug combination, will likely itself induce menopause after 1 or 2 rounds. In other words the treatment will have a self limiting response. This drug seems like a desperate attempt to keep something alive that is questionable and essentially a me too product. There are a lot of variations on taxol in the works and without a clear advantage likely a waste of money and scarce clinical trials. I also think this approach is backwards as there is considerable research to support that estrogen promotes the growth of lung cancer and should be blocked or suppressed.
May 11th, 2007 at 2:53 pm
Hubbie,
In other settings, I have been critical of the product and the potential role it may have in lung cancer, more for very open question of how much value it adds compared with many other often well-tolerated chemo drugs, but even compared with other “next generation” taxanes like Abraxane that are already commercially available. Thus far, Abraxane has been approved for breast cancer but is not used especially commonly, even in breast cancer, largely because it is not yet perceived to have a substantial incremental benefit over other taxanes, but it does have a remarkably higher cost.
You are in good company as one of the people who perceives the development of Xyotax as a process in which the goal line keeps getting moved in order to salvage something positive out of a lot of negatives.
Have you ever heard the joke about the definition of an optimist as someone who steps into a room full of horse manure and immediately starts beaming with joy? It’s because they’re thinking about the pony that must be hidden nearby.
-Dr. West
September 27th, 2007 at 1:52 pm
Dr. West:
I just read that Cell Therapeutics announced the beginning of the PGT307 trial (combination chemotherapy for women with NSCLC) (CNN story here : http://money.cnn.com/news/newsfeeds/articles/
newstex/AFX-0013-19770456.htm ).
I could not find information on the specifics of the trial (who is eligible, etc.) except that it will target pre-menopausal women.
Carlos
September 28th, 2007 at 9:46 pm
I believe it’s also still limited to women with a marginal performance status, but I also don’t have any additional details.
-Dr. West