"dose-finding was one of the more interesting aspects of the webcast"
I suspect Project Optimus may have something to do with it. This is a rather new FDA initiative (2022) that emphasizes dose-optimization early in the trial process, in Phase 1 and 2 primarily. I missed the first ten minutes of the CC so I don't know if it was mentioned. Anyway, here is the first paragraph from the FDA website:
"The Oncology Center of Excellence (OCE) Project Optimus is an initiative to reform the dose optimization and dose selection paradigm in oncology drug development. Too often, the current paradigm for dose selection—based on cytotoxic chemotherapeutics—leads to doses and schedules of molecularly targeted therapies that are inadequately characterized before initiating registration trials."
Project Optimus begs the question--what if your drug is exceedingly safe, like leronlimab? The examples they provide--"severe toxicities that require a high rate of dose reductions, intolerable toxicities that lead to premature discontinuation and missed opportunity for continued benefit from the drug, and potentially persistent or irreversible toxicities..." that limit options for further therapies--simply do not apply to leronlimab. Doubling the 350mg dose does not increase toxicity, and will likely help reset the immune system and treat the patient, not just the disease (thank you Geoffrey Fourqurean). On the other hand, if the drug has different effects in various indications or with different drug combinations, as we seem to be seeing in mCRC compared to TNBC, perhaps there is some validity here. But whatever we might think, the FDA is serious about this. I found the following on the website of a CRO called Novotech:
"What Does Project Optimus Mean For Clinical Trials?
1. Early Investment in Dose Exploration--Sponsors must now incorporate comprehensive dose-finding and dose-ranging studies into Phase 1 and Phase 2 trials—not just Phase 3.
2. Redesign of Trial Protocols--Protocols will require additional cohorts and arms, along with PK/PD modeling and patient-reported outcomes to assess tolerability.
3. Greater Regulatory Expectations--The FDA will expect sponsors to justify the selected dose with robust evidence—not simply based on tolerability or historical precedent.
4. Longer Timelines, Higher Costs (Initially)--The early-stage trial burden may increase, but long-term benefits include more effective drugs, fewer dose modifications, and smoother regulatory reviews."
With all the measurements they are taking and have built into the protocols, the mCRC trial seems to be meeting the Project Optimus expectations, even though I didn't hear Dr Lalezari mention PO. I suspect the 700mg dose will separate itself from the 350mg dose in boosting PDL-1, and where prime and pair is the desired outcome, the 700mg dose will become standard. And if the best result of the 350mg dose in the mCRC trial turns out to be stable disease, and/or partial responses that eventually progress, then prime and pair with 700mg should seal the deal and save the day... and save lives in the trial. Let us hope. However, we probably won't know the outcome of that scenario until, say, early-mid 2027. But I would be very surprised if we didn't have a partner way before then. Like, way way way before then! And then the partner will have to deal with the vagaries of Project Optimus.
(The Novotech piece is the better read... from the industry's point of view. But the FDA piece reveals how the powers-that-be frame it.)
https://www.fda.gov/about-fda/oncology-center...ct-optimus
https://novotech-cro.com/blog/what-fdas-proje...cal-trials
I suspect Project Optimus may have something to do with it. This is a rather new FDA initiative (2022) that emphasizes dose-optimization early in the trial process, in Phase 1 and 2 primarily. I missed the first ten minutes of the CC so I don't know if it was mentioned. Anyway, here is the first paragraph from the FDA website:
"The Oncology Center of Excellence (OCE) Project Optimus is an initiative to reform the dose optimization and dose selection paradigm in oncology drug development. Too often, the current paradigm for dose selection—based on cytotoxic chemotherapeutics—leads to doses and schedules of molecularly targeted therapies that are inadequately characterized before initiating registration trials."
Project Optimus begs the question--what if your drug is exceedingly safe, like leronlimab? The examples they provide--"severe toxicities that require a high rate of dose reductions, intolerable toxicities that lead to premature discontinuation and missed opportunity for continued benefit from the drug, and potentially persistent or irreversible toxicities..." that limit options for further therapies--simply do not apply to leronlimab. Doubling the 350mg dose does not increase toxicity, and will likely help reset the immune system and treat the patient, not just the disease (thank you Geoffrey Fourqurean). On the other hand, if the drug has different effects in various indications or with different drug combinations, as we seem to be seeing in mCRC compared to TNBC, perhaps there is some validity here. But whatever we might think, the FDA is serious about this. I found the following on the website of a CRO called Novotech:
"What Does Project Optimus Mean For Clinical Trials?
1. Early Investment in Dose Exploration--Sponsors must now incorporate comprehensive dose-finding and dose-ranging studies into Phase 1 and Phase 2 trials—not just Phase 3.
2. Redesign of Trial Protocols--Protocols will require additional cohorts and arms, along with PK/PD modeling and patient-reported outcomes to assess tolerability.
3. Greater Regulatory Expectations--The FDA will expect sponsors to justify the selected dose with robust evidence—not simply based on tolerability or historical precedent.
4. Longer Timelines, Higher Costs (Initially)--The early-stage trial burden may increase, but long-term benefits include more effective drugs, fewer dose modifications, and smoother regulatory reviews."
With all the measurements they are taking and have built into the protocols, the mCRC trial seems to be meeting the Project Optimus expectations, even though I didn't hear Dr Lalezari mention PO. I suspect the 700mg dose will separate itself from the 350mg dose in boosting PDL-1, and where prime and pair is the desired outcome, the 700mg dose will become standard. And if the best result of the 350mg dose in the mCRC trial turns out to be stable disease, and/or partial responses that eventually progress, then prime and pair with 700mg should seal the deal and save the day... and save lives in the trial. Let us hope. However, we probably won't know the outcome of that scenario until, say, early-mid 2027. But I would be very surprised if we didn't have a partner way before then. Like, way way way before then! And then the partner will have to deal with the vagaries of Project Optimus.
(The Novotech piece is the better read... from the industry's point of view. But the FDA piece reveals how the powers-that-be frame it.)
https://www.fda.gov/about-fda/oncology-center...ct-optimus
https://novotech-cro.com/blog/what-fdas-proje...cal-trials
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