EHA 2016

SL401 in patients with rare neoplasm

Prof Naveen Pemmaraju - The University of Texas MD Anderson Cancer Center, Houston, United States

I’m excited to be here at the European Haematology Association, or EHA, for presentation of a very rare tumour called blastic plasmacytoid dendritic cell neoplasm or shortly known as BPDCN. I’ll be presenting results from our ongoing phase II trial with a novel agent called SL401.

Can you give us a little bit of background about the disease?

BPDCN, or blastic plasmacytoid dendritic cell neoplasm, is an exceedingly rare hematologic malignancy. In fact, the name has changed many times over the past three decades which adds to the diagnostic confusion. The good thing is that in 2008 patients with this disease have since now had a reclassification and the World Health Organisation, or WHO, published a very nice reclassification or categorisation and placed BPDCN under the family of AML or acute myeloid leukaemia and related family of neoplasms. So since 2008 the combination of having a category as well as having a very clear diagnostic triad of CD4 positive, 56 positive and 123 positive with the addition of other markers has given rise to a uniform diagnosis for this historically very rare disease. Furthermore, if I may add, the disease has qualities of both leukaemias, lymphomas, but also skin disorders as well and because of that it presents in the clinic with very difficult and confusing ways. Lastly, because it has these protean manifestations, the diagnosis and therefore the treatment have been very difficult and there remains no standard of therapy for patients with BPDCN.

Which is where SL401 comes in.

Exactly right. So the results that we’ll be presenting here are a very novel agent, it’s SL401 which essentially consists of a truncated diphtheria toxin which is then fused to human IL3. The reason why that’s important is almost 100% of patients with BPDCN express or overexpress the IL3 receptor alpha known as CD123. So we have a rare disease with a possible target and we have a novel drug that hits said target. So the hypothesis was that if we expose patients on the clinical trial to this novel agent that we would hopefully have a high response rate and clinical benefit for these patients.

What sort of dosages are you looking at?

The dose is a very important question. It’s a phase I study in the first portion and it was a dose escalation. As we’ve presented before in other conferences and as we’ll show here, we started out at the low doses which was 7µg/kg/day and the drug is given over five days. It escalated up to 9µg and then ultimately culminated at the 12µg/kg/day dosing, again over five days. That dose, although there was not a formal maximum tolerated dose in the BPDCN cohort, it did result in early enough favourable activity where we were able to establish that as the dose and now that’s the dose that’s moving forward in the phase II portion.

When it came to responses to these doses what kind of results were you getting?

We’ve shown these results at ASCO last week and we’ll be updating them here at EHA this week. We report actually so far an 89% overall response rate in all lines and all doses treated in the BPDCN cohort, so those are very encouraging, exciting results thus far. Out of those 89% the majority of them are actually either complete remissions, CRs, or a designated term called CRC complete, or clinical complete remission.

When it comes to the administration of this, has it been as a single agent or in combination with anything else?

The administration of the drug in this clinical trial and thus far has only been with a single agent activity. Before this trial there was only one prior clinical experience, an experience that I was a part of, published by my colleague Dr Art Frankel. In that experience a single agent, the same drug, SL401, was given actually just as a single dose and in that study seven out of nine evaluable patients actually had major responses, including five complete remissions. So this study is the first ever multicentre study, prospective, dedicated to patients with BPDCN. The same drug, SL401, but given now over multiple repeated cycles. But your question is very good and very important which is it’s as a single agent we’re seeing these encouraging results.

These are significant results for a small phase I trial, what would the next step be?

The next steps for patients with this rare disease, BPDCN, is for us to continue the enrolment on this phase II portion now that we have identified a dose and this is ongoing. So the study is continuing to enrol at the multiple sites, it’s open in approximately seven sites right now in the United States and Canada and we hope to enrol more sites in both the States and Canada. So that’s the first item for patients with this rare disease is to continue enrolment. The second item for us to do is to then try to see if we can build on these data and use the results from this encouraging clinical trial to go for what’s called a registration study for patients with this rare disease.

You mentioned this was bound to a truncated diphtheria toxin and repurposing other infectious agents such as with the VTEC repurposing of viruses and all kinds of other re-engineering of pathogens has been generating a lot of interest. So any thoughts on that?

What a very good question. In general this field of immunotoxins is really expanding, as you said, nicely. This is a very important and new development for the field of oncology. You mentioned a few, I would also add to that list pseudomonas based toxins which have been used and other diphtheria toxin agents are used before such as the drug known as Ontak or denileukin diftitox which is used in cutaneous T-cell lymphoma. So in principle this is a very exciting field for oncology and as far as the science and for our patients is concerned we need to be keeping aware and studying the rare side effects that are sometimes only seen uniquely to this class of drugs. For example, there’s a side effect known as capillary leak syndrome which can be common in these bacteria or microbiological based approaches. We did see some occurrence of this capillary leak syndrome in our current trial and we’ve reported on this before. So the understanding that this is a completely new and exciting field of oncology, coupled with a cautious optimism and also vigilance and rigorous monitoring for these unique side effects that these agents may have really opens the door for a new way to treat cancer patients.

That’s all the questions I’ve got prepared, is there anything you’d like to add?

Basically the last thing I would add is that patients with rare cancers and rare diseases oftentimes have really a paucity of information out there. It’s important for patients to know that there are doctors, clinicians, researchers such as myself and my co-investigators who have dedicated their life and their careers to really finding out solutions and cures to these rare diseases. So I want to let folks know out there that there is a big movement in the cancer field to break down cancers into very specific unique subtypes, such as BPDCN, and to let folks know that there are those of us who are interested in patients and really looking for cures in these rare diseases. I think that social media, media such as yourselves and really all the internet media out there are actually really good sources. People have to be aware that there are pitfalls and there are misinformation out there but in general it’s important to know that, yes, there’s a lot of information and a lot of activity going on for patients with rare diseases such as BPDCN.