AI
| Followers | 55 |
| Posts | 2312 |
| Boards Moderated | 0 |
| Alias Born | 06/28/2012 |
Sunday, October 27, 2013 2:23:18 PM
Reaching cohort 9 could really show some stellar results, IMO. But, I agree BK - one thing at a time, let's get through cohort 6 safely. To get to cohort 9 - the dosing would still need to more than triple to get there. Still, 110mg/m2 is nothing to dismiss given the very early optimistic signs/indications that were noted at 20-30mg/m2 at R&R. But it is fun to speculate about those dream scenarios. 
Still, let's remain grounded and also remember another key point : compared to the high expectations of many here for Kevetrin (myself included!), the bar for actual marketable 'success' is relatively low compared to what is regularly discussed here.
While we speculate about shrinking tumors, which of course would be the big grand slam, let's not lose sight of what is considered success in the current scenario at DF.
They are treating stage 4 patients. All stage 4 cancer diagnoses are not created equal. There are fraction of folks out there who are diagnosed at stage 4 and can be treated successfully with existing treatments.
The Kevetrin trial is treating stage 4 patients that even the best treatments in market today cannot effectively treat. These folks are in the K trial because nothing else works. So any kind of effectiveness, any sign of improvement in several possible ways is breaking new therapeutic ground.
So when you think about that, it really makes you realize this is the most difficult set of circumstances that Kevetrin could go up against for a phase 1 trial. And I think to this point, we've seen the challenges that come with treating these aggressive stage 4 patients with a completely novel compound for the first time. It is time consuming, and great care must be taken to properly care for every individual patient and to determine properly if dosing can be escalated safely for the next cohort. Every AE is cautiously scrutinized, even if it has nothing to do with Kevetrin itself, these are very sick patients.
But when we think about what defines success in the Dana Farber trial, it is easy and tempting to get caught up in efficacy discussions and the speculation that comes with it. For us investors, its exciting to think of the possibilities, certainly.
But what truly defines success from a phase 1 clinical trial standpoint? I think this is where it's important to take a step back and think about what phase 1 success means from a minimalist perspective. And it all comes down to one word : SAFETY.
SAFETY, SAFETY, SAFETY. This hugely important centerpiece and primary endpoint of this trial is so easy to overlook and gloss over when talking about efficacy is so much more exciting and sexier. But really, the fact that they are safely increasing human dosing with a completely new and unique chemical compound is a big win in itself. And with dosing levels now reaching 110mg/m2, the possible pathways to success from a purely minimalist point of view are possibly multiplying. A solid safety profile in phase 1 buys a ticket to explore many possible routes to move forward to reach the market.
Let me explain what I mean by that. Let's say for the sake of discussion, When all the dust settles from the DF trial, there are no significant signs of efficacy. (I know, i know - we've already seen initial clues/signs that were reported at R&R - just bare with me here) But let's assume all we get is confirmation of P21 activation across the board, but nothing overly significant in terms of secondary efficacy endpoints. (Scans, serum marker, etc)
If that were somehow the case, how can Kevetrin advance forward in a minimalist way to be a marketable success? If all we know is that Kevetrin is safe up to MTD after phase 1, how will advancing the compound in further trials prove it can be effective in some capacity?
Here are the possible avenues for "success" I see, again from a minimalist point of view:
1. Kevetrin as a stand alone treatment at this point may prove to be more effective with a change in dosing frequency. Don't forget, right now the dosing regimen consists of dosing once a week for three weeks, then one week off. Looking at the slide from R&R, this is a very important point, IMO:
"Pharmacokinetic profiles and parameters show no evidence of accumulation in plasma
• This points to possibility to increase dose and frequency"
Key word to me there aside from the obvious dose increase is FREQUENCY. With that in mind, again we refer to this statement from another slide from the R&R presentation :
"• Evidence of stable disease by radiological examination in 6 cases, which includes head and neck cancer, ovarian cancer, liposarcoma and clear cell carcinoma
• Disease progression occurred following stabilization of disease in some cases"
My interpretation of the statement above, I think it is reasonable to speculate that even at the low doses being referred to here, an increase in the frequency of dosing to 2x per week may help to stop/delay the following : "disease progression occurred following stabilization of disease in some cases"
If kevetrin had an initial minimal effect in potentially slowing growth or stabilizing disease as stated, perhaps a more continuous 2x per week infusion of kevetrin will be that much effective in keeping disease progression at bay. Again this is a minimalist view, i think purely in terms of increasing progression free survival and/or overall survival, that in itself has significant value in the marketplace. Time is a precious commodity to those suffering with an advanced stage of disease, and even a few months or more of time is obviously important and valuable given the circumstances.
2. The safe max dose of kevetrin is applied in combination with other current drugs to increase their overall effectiveness. There could be immense value here. As we are going to find out at the cytarabine/kevetrin cocktail trial at the university of bologna, and will likely see in future trials with other potent compounds, even if kevetrin itself serves as a catalyst that increases the efficacy of other compounds, the possibilities here are really quite extensive.
Here once again we have seen some preclinical clues, most notably the past statement from the researchers at BIDMC:
"Research by BIDMC combined Kevetrin™ with sunitinib on cell line 786, a drug-resistant renal cancer. Cellceutix was advised by the researchers that “the Kevetrin/sunitinib combination is the first we’ve used in which actual tumor shrinkage is noted.”"
Also noteworthy, the following statement from the same PR :
"Per protocol, Cellceutix has formally notified BIDMC that it has a strong interest in further collaborative efforts to develop combination treatments with Kevetrin and multikinase VEGF receptor antagonists, particularly VEGFR2 inhibitors. Cellceutix has provided the requested information that will be used to investigate a Specialized Programs of Research Excellence (SPORE) grant for a phase 2 clinical study.
Renal cell carcinoma is the most common type of kidney cancer in adults. BIDMC is the lead recipient of the prestigious National Cancer Institute-funded kidney cancer SPORE grant."
And of course, not to be overlooked is the recent agreement with MD Anderson, and the robust plan of studies to determine which potential trials and drug combinations may be best to pursue in human clinical trials:
" MD Anderson intends to utilize in vivo and in vitro methods to research specific pathways, gene expression, mechanism of action and apoptotic activity of Kevetrin in a range of concentrations and time points in both mutant and wild-type p53 Myeloma and Lymphoma cell lines. Research is also planned to evaluate Kevetrin against models of Multiple Myeloma cell lines that are resistant to bortezomib, lenalidomide and other FDA-approved chemotherapies. Additional studies will be conducted evaluating the anti-tumor activity of Kevetrin when used as a combination therapy with several FDA-approved drugs. MD Anderson will provide funding for these studies of Kevetrin defined by the MTA."
Clearly, the possibilities of using Kevetrin as the "quarterback" for a number of potential combination therapies is something that the company is pursuing aggressively, and for good reason. Because once again, even in a minimal sense, if Kevetrin can help improve the effectiveness of existing treatments to give patients more time, then it is a viable way forward that Kevetrin becomes valuable in the market.
3. Finally, another not often discussed but IMO very relevant possibility is that Kevetrin also increases the effectiveness of radiation treatment for those cases in which radiation may be the only option. Again the preclinical data here is impressive :
https://docs.google.com/file/d/0BzCMnkQtKcypMjBlNmRiYjctNmZmMS00ZjZkLTkwZGUtOTI1OGRiYjEwMTRh/preview?pli=1&hl=en
From looking at this document, we can see the dramatic difference that kevetrin made ONLY when being administered BEFORE radiation, again showing preclinical proof that this could be another roadmap to success in the market. If Kevetrin can show to replicate even a fraction of the success in increasing the effectiveness of radiation in humans after administering of kevetrin, then this should have certain quantifiable value in the market.
So to me, those are 3 ways in which Kevetrin can achieve some degree of market penetration and a significant valuation:
1. Highest safe dose administered purely as a stand alone treatment, but with a dosing regimen that possibly includes increased dosing frequency
2. Highest safe dose administered as a combination therapy with other potent FDA approved drugs
3. Highest safe dose administered sequentially as number 1 in a potent 1-2 punch combination therapy when combined with radiation therapy
I think any of these 3 could bring significant market success to Kevetrin and CTIX. Of course, all of this is fine and dandy, but still will take time and plenty of testing to prove out.
However, I share BK's opinion that if dosing can reach a level of at least 365mg/m2 in cohort 9 as the best case "dream" scenario that was mentioned, then the results from this level of dosing will be quite impressive. Regardless of whether that cohort is reached, I believe that there should be a mountain of scans, serum readings, P21 confirmation, etc at the end of the trial to show clear signs of the big E just from phase 1 alone.
Just my opinions and an attempt to call out what I think are the many ways that Kevetrin can succeed in achieving monetization for CTIX and bring value to shareholders.
Still, let's remain grounded and also remember another key point : compared to the high expectations of many here for Kevetrin (myself included!), the bar for actual marketable 'success' is relatively low compared to what is regularly discussed here.
While we speculate about shrinking tumors, which of course would be the big grand slam, let's not lose sight of what is considered success in the current scenario at DF.
They are treating stage 4 patients. All stage 4 cancer diagnoses are not created equal. There are fraction of folks out there who are diagnosed at stage 4 and can be treated successfully with existing treatments.
The Kevetrin trial is treating stage 4 patients that even the best treatments in market today cannot effectively treat. These folks are in the K trial because nothing else works. So any kind of effectiveness, any sign of improvement in several possible ways is breaking new therapeutic ground.
So when you think about that, it really makes you realize this is the most difficult set of circumstances that Kevetrin could go up against for a phase 1 trial. And I think to this point, we've seen the challenges that come with treating these aggressive stage 4 patients with a completely novel compound for the first time. It is time consuming, and great care must be taken to properly care for every individual patient and to determine properly if dosing can be escalated safely for the next cohort. Every AE is cautiously scrutinized, even if it has nothing to do with Kevetrin itself, these are very sick patients.
But when we think about what defines success in the Dana Farber trial, it is easy and tempting to get caught up in efficacy discussions and the speculation that comes with it. For us investors, its exciting to think of the possibilities, certainly.
But what truly defines success from a phase 1 clinical trial standpoint? I think this is where it's important to take a step back and think about what phase 1 success means from a minimalist perspective. And it all comes down to one word : SAFETY.
SAFETY, SAFETY, SAFETY. This hugely important centerpiece and primary endpoint of this trial is so easy to overlook and gloss over when talking about efficacy is so much more exciting and sexier. But really, the fact that they are safely increasing human dosing with a completely new and unique chemical compound is a big win in itself. And with dosing levels now reaching 110mg/m2, the possible pathways to success from a purely minimalist point of view are possibly multiplying. A solid safety profile in phase 1 buys a ticket to explore many possible routes to move forward to reach the market.
Let me explain what I mean by that. Let's say for the sake of discussion, When all the dust settles from the DF trial, there are no significant signs of efficacy. (I know, i know - we've already seen initial clues/signs that were reported at R&R - just bare with me here) But let's assume all we get is confirmation of P21 activation across the board, but nothing overly significant in terms of secondary efficacy endpoints. (Scans, serum marker, etc)
If that were somehow the case, how can Kevetrin advance forward in a minimalist way to be a marketable success? If all we know is that Kevetrin is safe up to MTD after phase 1, how will advancing the compound in further trials prove it can be effective in some capacity?
Here are the possible avenues for "success" I see, again from a minimalist point of view:
1. Kevetrin as a stand alone treatment at this point may prove to be more effective with a change in dosing frequency. Don't forget, right now the dosing regimen consists of dosing once a week for three weeks, then one week off. Looking at the slide from R&R, this is a very important point, IMO:
"Pharmacokinetic profiles and parameters show no evidence of accumulation in plasma
• This points to possibility to increase dose and frequency"
Key word to me there aside from the obvious dose increase is FREQUENCY. With that in mind, again we refer to this statement from another slide from the R&R presentation :
"• Evidence of stable disease by radiological examination in 6 cases, which includes head and neck cancer, ovarian cancer, liposarcoma and clear cell carcinoma
• Disease progression occurred following stabilization of disease in some cases"
My interpretation of the statement above, I think it is reasonable to speculate that even at the low doses being referred to here, an increase in the frequency of dosing to 2x per week may help to stop/delay the following : "disease progression occurred following stabilization of disease in some cases"
If kevetrin had an initial minimal effect in potentially slowing growth or stabilizing disease as stated, perhaps a more continuous 2x per week infusion of kevetrin will be that much effective in keeping disease progression at bay. Again this is a minimalist view, i think purely in terms of increasing progression free survival and/or overall survival, that in itself has significant value in the marketplace. Time is a precious commodity to those suffering with an advanced stage of disease, and even a few months or more of time is obviously important and valuable given the circumstances.
2. The safe max dose of kevetrin is applied in combination with other current drugs to increase their overall effectiveness. There could be immense value here. As we are going to find out at the cytarabine/kevetrin cocktail trial at the university of bologna, and will likely see in future trials with other potent compounds, even if kevetrin itself serves as a catalyst that increases the efficacy of other compounds, the possibilities here are really quite extensive.
Here once again we have seen some preclinical clues, most notably the past statement from the researchers at BIDMC:
"Research by BIDMC combined Kevetrin™ with sunitinib on cell line 786, a drug-resistant renal cancer. Cellceutix was advised by the researchers that “the Kevetrin/sunitinib combination is the first we’ve used in which actual tumor shrinkage is noted.”"
Also noteworthy, the following statement from the same PR :
"Per protocol, Cellceutix has formally notified BIDMC that it has a strong interest in further collaborative efforts to develop combination treatments with Kevetrin and multikinase VEGF receptor antagonists, particularly VEGFR2 inhibitors. Cellceutix has provided the requested information that will be used to investigate a Specialized Programs of Research Excellence (SPORE) grant for a phase 2 clinical study.
Renal cell carcinoma is the most common type of kidney cancer in adults. BIDMC is the lead recipient of the prestigious National Cancer Institute-funded kidney cancer SPORE grant."
And of course, not to be overlooked is the recent agreement with MD Anderson, and the robust plan of studies to determine which potential trials and drug combinations may be best to pursue in human clinical trials:
" MD Anderson intends to utilize in vivo and in vitro methods to research specific pathways, gene expression, mechanism of action and apoptotic activity of Kevetrin in a range of concentrations and time points in both mutant and wild-type p53 Myeloma and Lymphoma cell lines. Research is also planned to evaluate Kevetrin against models of Multiple Myeloma cell lines that are resistant to bortezomib, lenalidomide and other FDA-approved chemotherapies. Additional studies will be conducted evaluating the anti-tumor activity of Kevetrin when used as a combination therapy with several FDA-approved drugs. MD Anderson will provide funding for these studies of Kevetrin defined by the MTA."
Clearly, the possibilities of using Kevetrin as the "quarterback" for a number of potential combination therapies is something that the company is pursuing aggressively, and for good reason. Because once again, even in a minimal sense, if Kevetrin can help improve the effectiveness of existing treatments to give patients more time, then it is a viable way forward that Kevetrin becomes valuable in the market.
3. Finally, another not often discussed but IMO very relevant possibility is that Kevetrin also increases the effectiveness of radiation treatment for those cases in which radiation may be the only option. Again the preclinical data here is impressive :
https://docs.google.com/file/d/0BzCMnkQtKcypMjBlNmRiYjctNmZmMS00ZjZkLTkwZGUtOTI1OGRiYjEwMTRh/preview?pli=1&hl=en
From looking at this document, we can see the dramatic difference that kevetrin made ONLY when being administered BEFORE radiation, again showing preclinical proof that this could be another roadmap to success in the market. If Kevetrin can show to replicate even a fraction of the success in increasing the effectiveness of radiation in humans after administering of kevetrin, then this should have certain quantifiable value in the market.
So to me, those are 3 ways in which Kevetrin can achieve some degree of market penetration and a significant valuation:
1. Highest safe dose administered purely as a stand alone treatment, but with a dosing regimen that possibly includes increased dosing frequency
2. Highest safe dose administered as a combination therapy with other potent FDA approved drugs
3. Highest safe dose administered sequentially as number 1 in a potent 1-2 punch combination therapy when combined with radiation therapy
I think any of these 3 could bring significant market success to Kevetrin and CTIX. Of course, all of this is fine and dandy, but still will take time and plenty of testing to prove out.
However, I share BK's opinion that if dosing can reach a level of at least 365mg/m2 in cohort 9 as the best case "dream" scenario that was mentioned, then the results from this level of dosing will be quite impressive.
Regardless of whether that cohort is reached, I believe that there should be a mountain of scans, serum readings, P21 confirmation, etc at the end of the trial to show clear signs of the big E just from phase 1 alone. Just my opinions and an attempt to call out what I think are the many ways that Kevetrin can succeed in achieving monetization for CTIX and bring value to shareholders.
