RE:RE:RE:RE:RE:RE:RE:RE:RE:Interview with Dr. Shah I am not sure but I would guess generally speaking the demographics will also be considered during clinical trials as per the MTD it seems they will be trying to find it for few cancers. From the trial design:
“Part 1 (dose escalation): will comprise patients with recurrent advanced solid tumors (all comers) that have relapsed or are refractory to standard chemotherapy, surgery, radiation therapy, and for which no known effective therapies exist.
The PK profiles of TH1902 and free docetaxel will be evaluated for all patients in Parts 1 and 2. Once the MTD has been reached in Part 1, patients with TNBC, gynecological cancer (epithelial ovarian or endometrial cancer), colorectal cancer and pancreatic cancer (10 patients per cancer type) will be enrolled in Part 2 and treated at the MTD or RP2D to further assess the safety and tolerability of TH1902. The preliminary anti-tumor activity of TH1902 will be evaluated for all patients as per the response evaluation criteria in solid tumors.
Once the MTD has been defined, patients with TNBC, gynecological cancer (epithelial ovarian or endometrial cancer) colorectal cancer and pancreatic cancer may be treated at the MTD or Recommended Phase 2 Dose (RP2D), to further assess the safety and tolerability of TH1902, and the preliminary anti-tumor activity of TH1902.”
palinc2000 wrote:
yes I know that the technology needs to work .... but would they necessarily consider the MTD as one size fits all for all the 4-5 different cancers and for all the patients or would /could they make ajustments per type of cancer, patient age and sex and weight etc....I am really trying to see if the duration of the trial can be easily predictable or not
scarlet1967 wrote:
The way I understand it the short answer is yes but for the technology to work there other pieces which needs to come together, obviously the whole PDC has to be stable in the blood for long time enough before it gets internalize into cancer cells otherwise there is high chance of toxicity and chemotherapeutic agent can induce neutropenia (lower blood cell and risk for infections), the other important factor is how selective the PDC is for instance whether it targets the cancer cells only or healthy cells also which is a relative ratio(not absolute) with other words the amount of off target delivery decides the dosing the more off target the higher dosing needed having said that again the off target delivery has to be in acceptable range for minimum damages to healthy cells. All that worked well in mice now they need to prove it in humans, CFO???
Peptide
A homing peptide is a selected peptide that is chosen for its specific targeting capabilities of protein receptors found overexpressed at tumour tissues. In the case of PDCs, the homing peptide will direct the whole PDC construct to the targeted cell and limit off-target delivery.
Linker
Various linker technologies have been used depending on the desired PDC mechanism of action. The linker must demonstrate stability within the circulation in order to prevent the premature and unspecific release of the drug. Pre-release is a cause for concern for PDCs as the build-up of cytotoxins can lead to dangerous or even fatal side effects. It is also important to consider the fate of the linker when it is metabolised within the body, and hence the resulting toxicity of the products formed.
There are several chemical motifs under the umbrella of chemically cleavable linkers including acid cleavable, reducible disulfides and linkers which are cleaved by exogenous stimuli.
There are a range of cytotoxic drugs available for cancer treatment, but often with each drug comes a range of limitations including poor PK properties. However, the most limiting aspect is the unselective manner of the drug to target cancer cells, causing harm to healthy cells and resulting in severe side effects.
Payload
The use of a peptide allows for specific targeted therapy, consequently resulting in the enhancement of several properties for example the therapeutic window. As a result of the cytotoxin being attached to a peptide, the dose of the cytotoxin will be reduced as a greater proportion is reaching the target – typically an increased dose is needed to compensate for the off-site delivery. There are several criteria that determine which cytotoxic payload to use in PDCs including stability within circulation, the demonstration of high potency, its release through the cleavage of the linker, and there must be a viable attachment point for the connectivity to the linker.
palinc2000 wrote: thx a lot.... very clear.... Is it 100% certain that the higher the MTD the higher the efficacy ? Or are there other factors to consider?
scarlet1967 wrote:
I am hoping they would announce more details as the trial progresses for instance each escalation sequence and results etc.… I am not a clinical trial expert so I asked Spartrap about the timing going forward, it seems ideally(if everything goes fine) it can take about 6 months before a good number(highest possible dosage with no adverse effects as per planned) for the MTD is known so the longer it takes the better if they choose to announce the final result(which at the time they definitely should issue a PR with all the details which is the bare minimum of information they should share with the investors/market imo) that’s why I believe they also should feed the market with any progress along the process.
This was Spartrap’s response and after that some information about traditional 3+3 escalation design.
“well if it's a classic 3+3 escalation design as I suppose, you have cohorts of 3 pts per dose, and they continue on that dose up to the end until toxicity or other withdrawal (so, one cycle every 3 weeks, following the usual docetaxel posology). After the first cycle, a new cohort of 3 pts is started, either at the next dose or at the same dose if there was a toxicity observed in the previous level. There might be a few days of delay between the assessment of cohort 1 and starting of cohort 2, depending on trial organization, availability of pts, etc. So here we have 7 doses to test. 30, 60, 120 and then 4 Fibonacci. In the ideal case where no toxicity is found, we will end up with 7 cohorts treated with at least one cycle in a time span of, say, (21+2)*7=161 days (5.5 months)”
“Traditional 3+3 Design
The traditional 3+3 design remains the prevailing method for conducting phase I cancer clinical trials (7). It requires no modeling of the dose–toxicity curve beyond the classical assumption for cytotoxic drugs that toxicity increases with dose. This rule-based design proceeds with cohorts of three patients; the first cohort is treated at a starting dose that is considered to be safe based on extrapolation from animal toxicological data, and the subsequent cohorts are treated at increasing dose levels that have been fixed in advance (Figure 2, B). Historically, dose escalation has followed a modified Fibonacci sequence in which the dose increments become smaller as the dose increases (eg, the dose first increases by 100% of the preceding dose, and thereafter by 67%, 50%, 40%, and 30%–35% of the preceding doses). In most cases, the prespecified dose levels do not fit the exact Fibonacci sequence as described in the 12th century (5). If none of the three patients in a cohort experiences a dose-limiting toxicity, another three patients will be treated at the next higher dose level. However, if one of the first three patients experiences a dose-limiting toxicity, three more patients will be treated at the same dose level. The dose escalation continues until at least two patients among a cohort of three to six patients experience dose-limiting toxicities (ie, ≥33% of patients with a dose-limiting toxicity at that dose level). The recommended dose for phase II trials is conventionally defined as the dose level just below this toxic dose level.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2684552/
palinc2000 wrote: Very interesting interview!
Will there be a PR or similar when the MTD will have been determined and will they share what the actual dose will be?