You go to the maximum. There’s a scientific analysis that the inventor has gone through whereby there are some mechanistic reasons when you get to a certain level, as you know, is a topoisomerase to poison, there appears to be the potential for a point of diminishing returns where you simply can’t get any more cell kill benefit out of increasing the dosage, but you can actually start to have some sort of counter-effective results. And we don’t have the specific mechanism data to support that argument, but it’s a theory. But there is a theory out there that says there’s a point where you can go too far with TopII poison and not get any additional benefit out of it. Paul, do you want to add anything to that?
Paul Waymack: Let me just add just the indications. You are correct, and that’s a good point. The 330 we’re doing for soft tissue sarcoma is actually lower than the 230 we’re doing for AML because the 230 is for three straight days, which becomes 690. If you look at the soft tissue sarcoma, our number one by far adverse event is low blood counts, especially platelets. That forces us at times to stop. We could go up to 390. We didn’t have a DLT, but we had to delay therapy because of the low platelet counts, because it was hitting the bone marrow. Well, with AML, that’s where you’ve got to hit. That’s where the cancer is. It is the blood cells in the bone marrow. You’ve got to blast the hell out of them, essentially, and wipe them out for a while.
So the toxicity that is forcing us to hold and delay dosing in soft tissue sarcoma if we go too high, that’s not an issue with AML because in AML, here, the safety location is also the efficacy location. So it’s just with an adverse event for one indication for the other, that’s efficacy. So I think that’s the primary reason for the difference in why we’re keeping it a little lower than soft tissue sarcoma than in AML. If that makes sense to you.
Jason McCarthy: Got it. Last question. You had mentioned potentially selecting another indication next year. Can you provide a little bit more detail as to what you may be thinking, perhaps, along the lines of where an anthracycline may be a key therapy or a go-to therapy, kind of what the PFSOS might look like in whatever said indication?
Paul Waymack: Yes. I mean, we can’t speak to speculating on what the human PFSOS implications of this would be, but we’ve got very compelling data in a number of indications. For example, triple negative breast cancer metastatal lungs. Also, renal cell carcinoma metastatal lungs. But the one that probably gets the most excitement out there is pancreatic cancer and specifically pancreatic cancer met for the liver. And as I’m sure, Jason, most pancreatic cancer patients present with liver mets. And so it’s the most common site of metastasis. And we’ve talked for now a long time about the fact that we can hyperaccumulate in the lungs. It turns out we also hyperaccumulate in the liver as compared to doxorubicin. I think the ratio is like six to nine times more than doxorubicin.
So it might be the first opportunity to actually bring an anthracycline to the table in pancreatic cancer. So if we were to kind of pick and choose and say, what investigator funded study would we be most enthusiastic about? It’s probably that one.
Jason McCarthy: Okay. Just to follow up to that then, because you’re accumulating in the liver, does that reduce the potential for healthy tissue talks in the liver? Because a lot of chemotherapies are just not used in the liver because the liver is already weak. Because it has either liver mets or primary tumors there.
Walter Klemp: Well, I mean, what we know from the animal data is that we don’t see any disproportionate increase in liver toxicity in animals vis-a-vis doxorubicin, even though we appear to accumulate it nine times the level. Paul, you’ve been monitoring liver toxicities in human patients. What’s your perspective there?
Paul Waymack: To date, we have seen no indication of liver toxicity. You look for liver toxicity based on what’s called High’s criteria. That’s [Indiscernible]. He’s a famous physician in liver disease. We’ve seen that. We have not seen Billy Rubin go up. We have seen liver enzymes fluctuate a little, but they never go up to a clinically significant degree. As of now, I guess we’re approaching 70 patients being treated in all of our studies. We don’t have evidence of liver toxicity.
Jason McCarthy: Great. Thank you, guys.
Paul Waymack: Thanks, Jason.
Operator: Thank you. Our next questions come from the line of Jeff Jones with Oppenheimer. Please proceed with your question.
Jeff Jones: Thanks for taking the question, guys. Congrats on the quarter and the updated data. A couple of questions. Following on from what’s been discussed already, my understanding of your path forward in STS lung mets is that you’re looking at, similar to Trabectedin, a PFS endpoint for approval. Is that correct?
Walter Klemp: Well, I think we would modify that to say we really think that we’ve got a shot at moving the needle materially on OS. So, correct me if I’m wrong, Paul, but I think of our window of opportunity here to be the combination of both PFS and, for the first time ever, PFS that actually translated into increased OS.
Paul Waymack: Again, from a regulatory standpoint, we would, in any clinical trial, would be measuring both variables, PFS and OS. We would prefer to have PFS since it would be quicker approval, obviously, but as Wally said, the data are becoming very impressive for OS. So, we would probably, at an end of Phase 2 meeting, propose to the FDA initial approval on PFS and then add OS into the product labeling just for better marketing opportunities.
Jeff Jones: Okay. That makes sense. And then, I guess, as I look at the PFS data across the subgroups that you’ve provided, while it’s 3.4 in the 330 mg per meter squared with less than two prior lines of therapy, it’s in the two to two and a half range when you look at the more intent-to-treat populations for both the Phase 1b and 2. And, Trabectedin, the PFS, was somewhere on the order of two and a half months. So, even taking the 3.4 months, you’re adding a month, a month and a half to PFS. And so, it goes to the question of clinical meaningfulness. And, as you probably know, there was a company that just dropped a trial or dropped a program with the PFS of 3.6 months. So, they just abandoned the product with the 3.6 month PFS. So, that overall…
Walter Klemp: So, Jeff, one thing I would point out that I think is a point of difference is, first of all, it’s not greater than a first-line therapy. It’s two or fewer prior therapies in that right-hand column. But, it’s important to note that we chose the most difficult subset of patients in our inclusion-exclusion criteria here. So, we’re not taking all advanced. This was not an all-comers trial. This is not all advanced soft tissue sarcoma. This was only lung mets. And, in every trial we’ve ever seen published, while no one actually gives specific data for the subgroup of lung mets, most of those trials will somewhere in their text acknowledge that the lung mets subgroup underperformed vis-a-vis the overall population. So, because we accumulated in the lungs the way we do, we deliberately chose this worst possible selection criteria.
