"I don't get why EVERYONE isn't given 700mg at this point."
The simple answer, Cardamine, is the FDA and their recent "Project Optimus" initiative (August 2024). Now you and I--if we had a choice--would insist on 700mg. But this is a relatively new drug without a lot of testing in oncology... and the FDA is conservative on this. I think Lalezari and Cytodyn are being very proactive here, trying to get ahead of any potential squabbles. Yes it's frustrating... but most of the members of this board likely know more about leronlimab than the FDA. So it's probably necessary to keep the FDA overlords happy.
"Project Optimus, spearheaded by the FDA’s Oncology Center of Excellence, aims to modernize dose selection and optimization in oncology drug development. Traditionally, dose selection focused on finding the Maximum Tolerated Dose, often without considering whether this dose provided the best therapeutic balance. This approach, rooted in the era of cytotoxic chemotherapies, often led to unnecessary toxicity in patients taking modern targeted therapies or immunotherapies."
That's from a CRO publication I didn't bother to footnote. AI--not AI SLOP, but AI YUM, the kind that makes you want a second helping--made these points:
[color=var(--text)]--Early Dose-Ranging Studies: The FDA now expects companies to conduct randomized trials to evaluate multiple dosages early in development (Phase I/II) rather than waiting for Phase III.[/color]
--Integration of Data: Project Optimus emphasizes using pharmacokinetic (PK) and pharmacodynamic (PD) data—how the drug interacts with the body—to select the best dose.
--Finalized Guidance: In August 2024, the FDA finalized guidance, Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases, formally outlining these expectations.
--Compliance Approach: While guidance documents are not legally binding regulations, they represent the FDA’s current thinking. Non-compliance often leads to the FDA requiring post-marketing dose optimization studies, which can delay commercialization.
Plotinus gave us a clue a couple weeks ago when he noted, and explained in some detail, the protocol changes in the mCRC trial that had to do with "Pharmacokinetic Parameters." Cytodyn is now documenting Cmax, Tmax, trough concentrations, half-life, and all the other relevant indicators--so that we don't have to later on! I think it is valuable to do, now, early in the game. And at least patients in this trial have the safety net of 700mg if they don't respond to the 350 dose... (DSMB willing).
One way to look at this is it should put the 350 vs 700mg debate to rest. On the other hand... if the 350mg dose outperforms expectations, as I suspect it might do in the mCRC indication, it might just confuse things! 2 out of 4 patients in the MTNBC trials saw their PDL-1 numbers rise, if you recall. And leronlimab has never been studied before with TAS-102 and Avastin... All this happy talk about good results in early patients--where 7 out of the first 10 or 11 patients were on 350mg--makes me wonder if that dose actually does have some clinical relevance in mCRC. We will see. But they are documenting so many biomarkers and variables in this trial I would be surprised if they didn't come up with overwhelming evidence for the utility of 700mg.
Shoutout to Plotinus for the pharmacokinetics post.
The simple answer, Cardamine, is the FDA and their recent "Project Optimus" initiative (August 2024). Now you and I--if we had a choice--would insist on 700mg. But this is a relatively new drug without a lot of testing in oncology... and the FDA is conservative on this. I think Lalezari and Cytodyn are being very proactive here, trying to get ahead of any potential squabbles. Yes it's frustrating... but most of the members of this board likely know more about leronlimab than the FDA. So it's probably necessary to keep the FDA overlords happy.
"Project Optimus, spearheaded by the FDA’s Oncology Center of Excellence, aims to modernize dose selection and optimization in oncology drug development. Traditionally, dose selection focused on finding the Maximum Tolerated Dose, often without considering whether this dose provided the best therapeutic balance. This approach, rooted in the era of cytotoxic chemotherapies, often led to unnecessary toxicity in patients taking modern targeted therapies or immunotherapies."
That's from a CRO publication I didn't bother to footnote. AI--not AI SLOP, but AI YUM, the kind that makes you want a second helping--made these points:
[color=var(--text)]--Early Dose-Ranging Studies: The FDA now expects companies to conduct randomized trials to evaluate multiple dosages early in development (Phase I/II) rather than waiting for Phase III.[/color]
--Integration of Data: Project Optimus emphasizes using pharmacokinetic (PK) and pharmacodynamic (PD) data—how the drug interacts with the body—to select the best dose.
--Finalized Guidance: In August 2024, the FDA finalized guidance, Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases, formally outlining these expectations.
--Compliance Approach: While guidance documents are not legally binding regulations, they represent the FDA’s current thinking. Non-compliance often leads to the FDA requiring post-marketing dose optimization studies, which can delay commercialization.
Plotinus gave us a clue a couple weeks ago when he noted, and explained in some detail, the protocol changes in the mCRC trial that had to do with "Pharmacokinetic Parameters." Cytodyn is now documenting Cmax, Tmax, trough concentrations, half-life, and all the other relevant indicators--so that we don't have to later on! I think it is valuable to do, now, early in the game. And at least patients in this trial have the safety net of 700mg if they don't respond to the 350 dose... (DSMB willing).
One way to look at this is it should put the 350 vs 700mg debate to rest. On the other hand... if the 350mg dose outperforms expectations, as I suspect it might do in the mCRC indication, it might just confuse things! 2 out of 4 patients in the MTNBC trials saw their PDL-1 numbers rise, if you recall. And leronlimab has never been studied before with TAS-102 and Avastin... All this happy talk about good results in early patients--where 7 out of the first 10 or 11 patients were on 350mg--makes me wonder if that dose actually does have some clinical relevance in mCRC. We will see. But they are documenting so many biomarkers and variables in this trial I would be surprised if they didn't come up with overwhelming evidence for the utility of 700mg.
Shoutout to Plotinus for the pharmacokinetics post.
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