But is also to remark is that a dose and schedule that was used to treat as a tier two positive neuroendocrine tumors, which is a indolent disease, was then in its key element applied to treat metastatic castration-resistant prostate cancer and then further moved into earlier lines of therapies. As the field grows and as we continue to develop novel radiopharmaceutical therapies, the question is, how can we be more thoughtful and more intentional about how we optimally dose these therapies?
One of the key advantages of theranostics is the ability to image the drug, and I'm sharing here some of my prior experience with first-in-human imaging trials, which are a great tool for rapid translation into the clinic. But we can also derive critical information about the distribution of the drug in tumors in normal organs. The dosimetry that we can derive from these images can support a starting dose selection for a formal dose escalation, potentially better than extrapolation from rodent or non-human primates.
At AdvanCell, we are developing a lead-based PSMA targeting alpha therapy that is currently in phase-two clinical development, and we have incorporated into our trial routine PSMA PET imaging at baseline and turn follow-up, as well as routine biodistribution imaging and dosimetry during dose escalation. What you see in the middle four images here is our multi-time point SPECT/CT acquisition from the gamma rays that are emitted from Lead-212 directly. Over in approximately 24 hours, we can derive a full biodistribution that covers over 2.5 times the half-life of Lead-212. These real-time feedback loops on imaging have supported us streamlining our dose escalation and potentially avoiding futile doses with the benefit for the enrolled patients as well as accelerating the trial.
But how do we ultimately select a dose after escalation? Now, that depends well on the specific dose-effect curve of the specific radiopharmaceutical. But what we may observe similar to other targeted therapies is a curve that plateaus out. With incremental dosage or activity levels, the added toxicity may outweigh the incremental efficacy gain. Activity in dose level, however, is only one component of a dose regimen in radiopharmaceuticals. The total number of doses, as well as the dose schedule, all these variables combined define the dose density of the treatment as well as the cumulative exposure to the normal organs as well as to the tumors.
The FDA has provided recently a guidance for a radiopharmaceuticals dose optimization supporting how an optimized dosage that maximizes the benefit-risk profile of the drug can be evaluated and assessed during development. The agency stated clearly that dosage optimization includes both the dose and the schedule, meaning the recommended interval between doses as well as the duration of treatment.
When we look at current treatment regimens in prostate cancer with current approved drugs, we see that we observe across all treatments a fixed dose density with often continuous treatment up until disease progression if the drug is well-tolerated or kept dosing due to cumulative toxicity concerns.
When we look at learnings from other cancer treatments, for example, in colorectal cancer or bladder cancer, we see additional strategies that are employed. Often treatment regimen include a treatment-intense induction designed to gain rapid disease control upfront, and then a de-escalated maintenance therapy to prolong response with a lower toxicity strategy. The question is, can this be applied to radioligand therapies? We have seen some variations to lutetium PSMA dosing strategies in trials thus far. I want to highlight the work by Oliver Sartor and Scott Tagawa, where they explored in a phase-one, -two trial a single fractionation of a very high dose of Pluvicto. Notably, the authors observed comparable time-to-event outcomes with this single fractionation regimen 15 days apart compared to the six-times-six schedule, despite not selecting for PSMA positivity.
Louise Emmett has taken this concept further with her current enrolling phase-two optimal trial, where she includes an even more intense induction of day one, day three, and day 15, followed by maintenance dosing up to six cycles. Nick has presented yesterday on the STAMPEDE trial that also proposes a more intense schedule in the hormone-sensitive space.
At AdvanCell, we have invested early in our development into dose optimization, as you see in our dose escalation schema here. We have explored or have explored pre-specified dose schedule cohorts escalating both the activity level as well as the dose intensities, and our most dose-dense scores were up to weekly dosing for up to six cycles. We have presented the initial results from this trial at ESMO last year. It was notable that we have not seen any dose-limiting toxicities in any of the dose schedule cohorts, nor have we seen any dose modifications or dose reductions or any delayed adverse radiation events to date.
Other learnings from this trial were looking at the PSA kinetics and patterns of response and progression. I want to share with you what I have not shared publicly thus far: from observing these PSA kinetics, we saw that the deepest and most rapid responses were observed in the dose-dense schedules, supporting that a dose-dense schedule may achieve tumor control rapidly and elicit a deeper response. What we've also seen in some patients, what I call a bit the bending of the curve, is that we may overcome resistance potentially due to cell repopulation that may occur at less frequent dose schedules. What we also know with metastatic prostate cancer is that progression is almost inevitable as treatment or as treatment disease due to persistent disease. We have seen patterns of progression after treatment cessation, sustaining or supporting the argument for prolonged duration on therapy to extend time on active therapy and prolonged duration.
All these learnings from phase-one in the totality of the data from clinical data, the symmetry, PK, metabolites analysis all concluded or drove our phase two design. This trial is currently enrolling where we evaluate the safety and efficacy of a dose-optimized or novel dosing schedule consistent of an intense induction therapy followed by maintenance therapy across two randomized dose schedules. I also want to note, since the majority of this trial is enrolling in Australia, we were very fortunate to include baseline PSMA PET, as well as every eight week PSMA PET for up to 24 months in addition to conventional imaging into this trial. I'm very curious about the learnings that we will have about the correlation of conventional imaging and PSMA PET across the different enrolled cohorts.
Can we treat infinitely with radioligand therapy as some of the other therapies are until progression? No, we can't due to cumulative radiation exposures to normal organs, but we may have strategies to optimize the timing and duration of active treatment, especially during maintenance therapy. I do think biomarker-driven adaptive dosing is a risk mitigation strategy for patient safety, preventing potentially unnecessarily high cumulative doses, allowing for treatment holidays and saving therapy potentially for later. Our trial incorporates aspects of adaptive dosing into maintenance as well as to other trials. Some of them have been mentioned from the first Enza-P and LuParp, but also now the FLEX-MRT and other studies underway by Tom Hope and Jeremie Calais.
In conclusion, dose optimization for RPT consists of several key considerations that influence a dosing regimen, certainly the disease biology, understanding of tumor doubling times and specific disease settings, radiosensitivity, target expression, all these things are taken into consideration. As well as the therapeutic agent factors, which includes the payload characteristics, the half-life of the isotope, the plasma half-life of the ligand, uptake in normal organs, metabolites, all these are considerations for cumulative radiation exposure. Data have shown that dose, dose intensity, and duration of active treatment matter, and learnings from the past have shown us that investing early into dose optimization pre-phase-three trials is the foundation for a successful development program.