John Paul Waymack: And Jeff is I think you €“ Jeff as I think you might know already, by the time you get to fourth or fifth line in these patients, there really is no standard treatment. At that point, it’s like an investigator’s choice, and it’s a wide range of desperate experiments, if you will.
Jeff Jones: Fair enough.
Jonathan Foster: Hey, Jeff, this is Jon, we referenced that paper in the 10-K. I will be glad to send it to you. But we actually provide the paper reference on that placebo trial.
Jeff Jones: Okay. That’s great. On the AML side, now looking at plus Cytarabine, so you are doing a dose escalation to optimize dose, so I assume following that you would look at an expansion Phase 2. And then similarly, if that looks good move on to a pivotal study, am I thinking about that, right?
Walter Klemp: Yes. Let me sort of kick this off. And Paul and I will invite you to add whatever color you think is important. But Jeff, this is a really, I am really glad you asked this question in particular, because it gets down to when and how we might be generating truly pivotal data. We don’t want to get ahead of ourselves. And we want to be appropriately cautious here. But with an overview, umbrella of caution, when we think optimistically about what may happen in this trial, and that’s informed by the strong response we had as in the monotherapy trial. It’s entirely possible that we truncate the Phase 1b portion of this trial. In other words, if we start to see strong activity at the current 190 milligram dose level, it’s not out of the question that we call it and say, that’s good enough for an RP2D.
And if it is moved more quickly into Phase 2 and if we continue to see that, it’s that hoped for a level of response in the Phase 2 expansion phase, it may make sense for us to even truncate the expansion phase, and collect our data, go to the regulatory authorities and talk about the pivotal trial design more quickly than one might otherwise expect. So, again, we are not predicting that because it’s just too soon to make a prediction like that, but I want to make it clear to people that’s a possibility here, okay.
Jeff Jones: Appreciate that. And so
John Paul Waymack: And so if I could just add to what Wally said €“ if I could just add to what Wally said, that’s exactly what happened in our 105 study in that, as I mentioned, when we got to 240, we did not have DLTs. The protocol said we were allowed to dose escalate further, but we looked and said, look, we got efficacy four to five patients. We don’t have toxicity. We found a good recommended Phase 2 dose. We are now going to be doing the same thing with combination therapy and we picked side therapy because the current standard of care first line therapy is an anthracycline and Cytarabine. So, we are going to be doing this combination. And as Wally said, we will look at each dosing cohort for both safety and efficacy.
And when we think we have hit a dose that would be appropriate to expand, we will do it then and there whether or not we have a DLT problem. It’s a combination of safety and efficacy that will lead us to go forward. The nice thing about leukemia as opposed to solid tumors, solid tumors is a little bit more difficult efficacy, you are having to look at scan, see how much did it grow. Here, you do the bone marrow and say, is the cancer gone, yes or no based on the percentage of blast cells. So, it can move very quickly in leukemias as opposed to solid tumors where year-over time studying scans.
