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Tolerability and Activity of Chemo-free Triplet Combination of TGR-1202 (Ublituximab) and Ibrutinib in Advanced CLL and NHL
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Dr. Loretta Nastoupil discusses Tolerability and Activity of Chemo-free Triplet Combination of TGR-1202 (Ublituximab) and Ibrutinib in Advanced CLL and NHL at ASCO 2017. For the ability to view on your mobile phone please visit us at

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On behalf of my co-authors, I'm Lauretta Nastoupil from the University of Texas in the Anderson Cancer Center and I am presenting the results of the phase one novel combination of ublituximab umbralisib which is a PI3 kinase delta inhibitor and ibrutinib in relapsed refractory non-Hodgkin Lymphoma or CLL at the 2017 annual ASCO meeting. This is a multicenter standard phase 1 study with the primary objective to identify the safety of this novel combination. As I mentioned ublituximab is a chimeric anti-CD20 antibody that binds a unique epitope on CD20 is being combined with umbralisib which is a more selective PI3 kinase delta inhibitor. And ibrutinib which is a BTK inhibitor in relapsed refractory non-Hodgkin Lymphoma and CLL. It's important to note that the study was also amended to include treatment naïve CLL patients.

This was a standard three plus three design. It's also important to note that the ublituximab had a flat dose of 900 milligrams. The umbralisib was dose-escalated starting 400 milligrams up to 800 milligrams. And the ibrutinib was standard dosed according to histology. For instance, for CLL it was dosed at 420 milligrams. And for non-Hodgkin Lymphoma 560 milligrams. It's also important to note according to the study schema that ublituximab continued up to 12 months and then stopped. But umbralisib and ibrutinib continued as tolerated or until disease progression. As mentioned the primary objectives were to determine the safety as defined by the maximum tolerated dose of the combination.

With secondary objectives to assess the ethicacy including overall response rate, time to response, duration of response, and progress free survival. The key eligibility criteria again included patients with relapsed or refractory non-Hodgkin Lymphoma subtypes. We had had at least one prior line of therapy and CLL patients including those who were treatment naïve. In regards to the results, the demographics demonstrate that we have 38 patients evaluable for safety, 36 evaluable for ethicacy, with the median age of 65. There were more male patients of 29 versus nine females. There were more CLL patients included with 20 CLL or SLL patients. Six large cell, six follicular, four Mantle Cell Lymphoma, and two Marginal Zone Lymphoma patients. ECOG performance was most commonly zero or one but we did include three patients with an ECOG of two. The median prior lines of therapy were three with a range of zero to six.

And more than half of patients had had at least three or more lines of therapy. And 39% of patients were refractory to rituximab. Again with the primary end point being examination of safety. We have listed out the most common adverse events occurring in at least 20% of patients. Most of which were grade one or two. Common adverse events included diarrhea, fatigue, nausea, and cough. It's important to note that the grade three or higher adverse events were infrequent as outlined in the table, but notable that 18% of patients had grade three or higher neutropenia. 8% thrombocytopenia. And 11% pneumonia. One patient discontinued therapy early as a result of sepsis. The median duration of therapy is 11.1 months with more than 80% of patients being on drug beyond six months of therapy.

Thus far, the overall response rate for the entire cohort was 83% but also notable that 100% of patients with CLL, Marginal Zone, or Mantle Cell Lymphoma have responded with six of nineteen patients with CLL achieving a complete response. Also notable were the fact that one patient with Large Cell Lymphoma achieved a partial response. Four of six of the Large Cell Lymphoma patients were of the non-germinal center subtype. And 50% of the patients with CLL had either 17P or 11Q. In conclusion, this novel combination appears to be associated with a favorable toxicity profile. With more than 80% of patients having at least six months of drug exposure. 

The ethicacy also appears to be quite notable with CRs achieved in patients with CLL with this novel combination. The toxicity profile of the PI3 kinase delta appears to be one that will pair favorably with combination therapies and in an attempt to overcome mechanisms of resistance. And additional studies are planned to identify how this combination will move forward. We appreciate your time and attention on this interesting novel combination.