TGR-1202, ublituximab and ibrutinib combination for advanced CLL and NHL

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Published: 24 Jun 2017
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Dr Loretta Nastoupil - MD Anderson Cancer Center, Houston, USA

Dr Nastoupil talks with ecancer at EHA 2017 about the phase 1 trial that evaluates the safety/efficacy of the triplet combination of a novel anti-CD20 mAb PI3Kδ BTK inhibitor (ibrutinib) in pts with B-cell malignancies.

This is the first known triplet combination of an anti-CD20 mAb PI3Kδ BTK inhibitor. The combination of UTX, TGR-1202, and ibrutinib has been well tolerated with activity observed across heavily pre-treated and high-risk B-cell malignancies.

ecancer's filming has been kindly supported by Amgen through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.

I’m presenting a novel phase I combination of ublituximab, which is a novel CD20 antibody that binds a different epitope in comparison to rituximab. Similar to the other novel CD20 antibodies it’s glycoengineered to enhance ADCC but it still maintains its CDC activity since it’s a type 1 CD20 antibody. It’s being combined with umbralisib, which is a novel PI3 kinase delta inhibitor, and ibrutinib, which is a BTK inhibitor in relapsed refractory non-Hodgkin lymphoma and CLL. This novel combination was rationally combined to overcome some of the resistance mechanisms that are emerging through targeting the B-cell receptor signalling pathway. With the addition of the CD20 antibody we hope to enhance some of the ADCC, therefore the immune therapy approach as well.

We enrolled patients with CLL that were both treatment naïve and relapsed refractory. Those comprised most of the patients that were enrolled on this phase I study, so 20 of the 38 that were evaluable for toxicity. Important to note, at least half of those patients had high risk features, either 17p and/or 11q. With regards to the NHL cohort all of those patients were relapsed or refractory and had a median of four prior lines of therapy, so a heavily pre-treated patient population. This was a standard 3 3 phase I design with dose escalation of umbralisib, this PI3 kinase delta inhibitor, but it was dose escalated whether patients were of NHL subtype or CLL. So there were two ongoing dose escalations. Ibrutinib was maintained at either 420mg daily for patients with CLL or 560mg for NHL. The ublituximab had a flat dose of 900mg. Patients received up to twelve cycles of ublituximab; they continued the umbralisib or the ibrutinib daily until they had disease progression or intolerance.

This is a novel phase I study so we had approximately eight months of follow-up. With this we had 38 evaluable for safety and 36 for efficacy. It’s important to note that with other PI3 kinase delta inhibitors that some of the safety profiles have been seen with longer drug exposure so at least half the patients had had over six months of therapy. 81% had a median of approximately eleven months of follow-up.

With this the combination appears to be well tolerated. In regards to efficacy 100% of CLL patients, mantle cell and marginal zone lymphoma, had responded with an overall response rate of approximately 83% for the total cohort.

You mentioned the pre-treatment there, was there any analysis of whether pre-treatment was predisposing some of the responses that you saw?

For the treatment naïve we saw partial responses. There were only three patients with CLL that were treatment naïve, of those the majority had high risk features. Those that had had prior therapies, again at least half had poor risk features and at least two patients had had both PI3 kinase and BTK prior exposure. Of those one patient achieved a complete response that was durable for at least 1½ years. So this suggests the combination may overcome some mechanisms of resistance, albeit it’s a small phase I study with dose escalation and the follow-up is still relatively short. It will be interesting to see with longer follow-up if the favourable efficacy and toxicity holds up

Any plans to analyse pharmacokinetics of how these may be acting synergistically to overcome that resistance?

That’s a great question. That was not planned initially with the study. Given the efficacy that we’re seeing those studies are now being launched. It’s not uniformly being done across the study but centres such as MD Anderson are actively exploring whether this is synergism or just a well-tolerated combination that’s leading to efficacy.

You mentioned some follow-up trials, are there any names or doctors that we should be in touch with if we want to chase it up, say, in the near future, come ASH perhaps?

This is an ongoing study, there are other several ongoing studies with particularly umbralisib and ublituximab, including registration studies in CLL and non-Hodgkin lymphoma. So we’re hoping to see some of that data emerging. So those are larger either phase II or phase III studies with randomisation. In regards to this novel phase I concept there is a dose expansion that is planned, it has not quite launched so it will probably be longer than ASH before we see any additional updates.