RE:RE:RE:RE:RE:Covid implications for meetings with shareholdersIf I were holding a gun to your head right now and demanding you tell me where you thought TH is in their TH-1902 trial at this time and when you thought it would be ending, based on what you read about how these trials are done, how would you respond? It certainly appears to me like there is a wide range of possible options. Given how important a good phase 1a result is to TH on so many fronts, most notably including financing options, it would be nice to get your perspective on this issue. Hopefully, the company will say something about it before Ipull the trigger!
jfm1330 wrote: I found the reference used by Thera for the studu design on clinicaltrials.gov.
https://academic.oup.com/jnci/article/89/15/1138/2526338
Here are the most relevants parts to understand how the escalation works
In phase I trials of new drugs, the starting dose is usually one tenth of the LD 10 (i.e., the dose that is lethal to 10% of animals) in the most sensitive animal species in which toxicology studies have been performed. Dose steps are defined by a modified Fibonacci series in which the increments of dose for succeeding levels are 100%, 67%, 50%, and 40%, followed by 33% for all subsequent levels. Three patients are usually treated at a dose level and observed for acute toxicity for one course of treatment before any more patients are entered. If none of the three patients experience DLT, then the next cohort of three patients is treated at the next higher dose. If two or more of the three patients experience DLT, then three more patients are treated at the next lower dose unless six patients have already been treated at that dose. If one of three patients treated at a dose experiences DLT, then three more patients are treated at that same level. If the incidence of DLT among those six patients is one in six, then the next cohort is treated at the next higher dose. In general, if two or more of the six patients treated at a dose level experience DLT, then the MTD is considered to have been exceeded, and three more patients are treated at the next lower dose as described above. The MTD is defined as the highest dose studied for which the incidence of DLT was less than 33%. Usually dose escalation for subsequent courses in the same patient, intrapatient dose escalation, is not permitted. For the purposes of this article, we have related the toxicity experience to grading scales commonly used in oncology, such as the National Cancer Institute Common Toxicity Criteria, and have described the levels as follows: none-mild (grades 0–1), moderate (grade 2), dose limiting (grade 3), and unacceptable (grades 4–5). Consistent with recent practice, we have not considered grade 3 neutropenia unaccompanied by either fever or infection to be dose limiting. We have grouped no toxicity with grade 1 toxicity because of the difficulty of determining whether mild abnormalities are drug or illness related in patients with cancer. Design 2 treats one patient per dose level until one patient exhibits DLT or two patients exhibit grade 2 toxicity during their first course of treatment. At that time, the escalation plan switches to design 1. That is, two additional patients are accrued at the dose that triggered the switch, and three to six patients are treated in that and each subsequent cohort. This approach offers the possibility of speeding up the trial and reducing the number of patients assigned to low doses. It uses the first instance of first-course DLT to trigger the switch as proposed by Storer ( 4 ). It also uses first-course grade 2 toxicity to provide an added element of caution. We use the second instance of grade 2 toxicity for practical reasons, since it is often difficult to determine whether a grade 2 toxicity is drug related in a heterogeneous population of very ill patients. Designs 3 and 4 also use only one patient per cohort during the early stage of the trial, but they incorporate more rapid dose escalation by using double-dose steps during this stage. With design 3, the single-patient-cohort stage of the trial also terminates when one patient experiences first-course DLT or two patients experience first-course grade 2 toxicity. With design 4, this accelerated stage terminates when the first instance of DLT or the second instance of grade 2 toxicity is observed in any course of treatment. In either case, after the rapid escalation stage terminates, subsequent cohort sizes are three to six patients and single-dose escalation steps are used as in design 1.
So they treated one patient per dose until they got the first grade 2 toxicity. Then they added two or three patients at that dose. If none of these added patient got grade 2 toxicity or dose limiting toxicity (DLT or grade 3 toxicity), they moved up to the higher dose (560 mg/m2) with the same three patients and maybe three new ones (not clear). If there is at least 2 DLT out of six patients, they will go back at 420 mg/m2 to treat three more patient. If there is one or zero patient with DLT at 560 mg/m2, they will go to the next higher dose (740 mg/m2) and treat six patients, including those without DLT from the previous dose. They use mostly the same patients after the first toxicity event to see possible cumulative toxicity.
So up to the first grade 2 toxicity, only one patient per dose was treated, since then, it is three or six (not clear). To confirm the MTD, they need six patients treated at that dose with no more than one experiencing a DLT event. If you add the variability between patients due to sortilin expression levels. It is a complex process. I don't know if they can interact with the FDA during the trial to adjust some parameters if they see a real difference between patients according to the probability that their cancer type is expressing or overexpressing sortilin. Remember that trougout this process they monitor the levels of free docetaxel over time in the bloodstream, that and other PK parameters.
Wino115 wrote: I preface this by saying I am one of the people still confused by the dosage decision tree charts. But it dawned on me that if they are only enrolling one slot at a time, would that mean there are only two conclusions this data point would support?
1. They are still moving up the dosage scale by adding one patient at a new higher level.
or
2. The previously enrolled patients have been surviving, so there are 4-5 with stable or partial response at a minimum who can roll into the final MTD. If so, to do the final 6 person test with the MTD you only need 1 or 2 slots filled, but not 5 or 6.
I don't see how that data point, if right, could support a negative conclusion of either too low a dose to work, or current patients are not being helped at least enough to be stable and maybe more.
please shoot this down if my conjecture is not logical.