Systemic mastocytosis is an uncommon disease but patients really have a very difficult time specifically in the aggressive phenotype. There’s a specific mutation, this KIT D816V mutation. Unfortunately most tyrosine kinase inhibitors do not inhibit that particular mutation, midostaurin is one that does but has some limited efficacy and a lot of gastrointestinal toxicity; it’s still a big step forward. BLU-285 is a potent selective inhibitor of the mutant form of KIT, specifically targeting the D816V which is mutated in about 90% of patients with systemic mastocytosis. So it lends itself to try and see what the efficacy of this particular agent is in this disease. There are other diseases with the mutation but my focus was on systemic mastocytosis.
What did you do?
It’s a phase I study so the first thing we try to do is establish the maximum tolerated dose and establish a recommended phase II dose moving forward. We started at very low doses, 30mg/day, and the nice thing about this drug is it’s a single daily dose so very easy to administer. We started at 30mg and worked our way up to 400mg and we never established a maximum tolerated dose because the drug is very well tolerated but 300mg seemed to be well beyond what was needed to saturate and inhibit the mutant receptor so that was the dose that we went forward with.
How many people?
The phase I dose escalation is 32 patients. Right now we’re accruing into the part 2, the dose expansion cohorts in specific histologic subtypes of systemic mastocytosis. Systemic mastocytosis is a complicated disease, it represents a multitude of different histologic subtypes including aggressive systemic mastocytosis, systemic mastocytosis with associated other hematologic neoplasia and mast cell leukaemia. So we’re expanding cohorts of patients in each of those three disease sets.
What have you found so far?
The phase I, the part 1 of the dose escalation, which was really designed to find a dose, we were surprised that we had huge efficacy. First of all, of the 32 patients that enrolled on the study 30 patients remain on study, arguing that a) the drug is well tolerated, and b) it seems to be efficacious. In addition, all 32 patients have responded based on reduction in the serum tryptase. Of the 25 patients who went on study with a lot of bone marrow disease more than 60% of them have been able to establish a complete remission within the marrow cavity itself. So although the part 1 dose escalation was not designed for an efficacy endpoint, we saw huge amounts of efficacy in a very well tolerated fashion.
What about toxicities?
The toxicities of BLU-285 were very mild, most were what we call grade 1, grade 2 - mild GI, mild oedema. The most common non-haematological grade 3 toxicities were periorbital oedema, swelling around the eyes, as well as fatigue but that was mitigated by maybe a dose break and then reduction in the dose. No patient on the part 1 dose escalation of the study came off study for toxicity which is a little unusual, so just arguing how well tolerated it was.
So the conclusions so far?
So far we have a recommended phase II dose, we have established pharmacokinetic steady state data. We have established that the target is a valid target, the D816V; we have established that the dosing level that we’re at is able to inhibit the mutation form and we’ve established that there is huge efficacy in a variety of histologic subtypes of systemic mastocytosis. So the plan right now is to confirm that with the dose expansion at the very specific histologic subtypes and there are plans next year to more formally test the efficacy question in advanced systemic mastocytosis. But also, because this is a very tolerated agent, to look at more indolent forms – indolent systemic mastocytosis as well as something called smouldering – and that’s because the drug is very well tolerated.
You mentioned that this applies to 90% of the people with it.
90% of patients will have the D816V mutation, there are other mutations that are also inhibited by this particular molecule, the BLU-285. Because it’s so rare we don’t know all the mutations but most of the patients, 90% of them, will have this specific mutation .
Are people looking at the 10% at all?
Always looking at the 10%, there’s always the odd man out.
But no-one is looking into that?
It’s a rare subtype, so of the patients who do not have the D816V there are other mutations – D816Y and other things that are also inhibited by BLU-285. When it’s a one-off it’s harder to describe efficacy, it’s all one, one, one. Then there are those patients who have a wildtype, this drug also hits the wildtype form of KIT. But 90% versus 1-2%, it’s very hard to establish confidence intervals around the efficacy of that but we are looking into it as well as other mutations. So these are not isolated mutations, there’s a panoply of other mutations that also co-migrate with the KIT and looking at which of those mutations render efficacy or reduced efficacy is very important but those are ongoing clinical questions.