Umbralisib, Ublituximab, Ibrutinib Triplet Reaches 100% Response in CLL

Angelica Welch

Loretta J. Nastoupil, MD
Loretta J. Nastoupil, MD
The first known triplet regimen of a CD20 monoclonal antibody plus a PI3K-delta inhibitor and a BTK inhibitor demonstrated clinical activity and tolerability in patients with advanced chronic lymphocytic leukemia (CLL), among other subsets of non-Hodgkin lymphoma (NHL), according to phase I findings.

Results from the study of the triplet of ublituximab, umbralisib (TGR-1202) and ibrutinib were presented at the 2017 ASCO Annual Meeting1 and subsequently at the 2017 European Hematology Association Congress.2 Among 36 evaluable patients with various subtypes of NHL, the objective response rate (ORR) was 83%.

The evaluable population included 19 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. In this group, the ORR with the triplet was 100%, including 6 complete responses and 13 partial responses.

In an interview with OncLive at ASCO, lead investigator Loretta J. Nastoupil, MD, an associate professor in the Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the findings of this phase I trial.

OncLive: Can you provide an overview of this study?

Nastoupil: We presented a phase I study with a novel 3-drug combination of ublituximab, which is a glycoengineered chimeric CD20 antibody that binds to a unique epitope, in combination with TGR-1202, or umbralisib, and the BTK inhibitor ibrutinib. Ublituximab is a novel CD20 antibody that is currently under investigation primarily in CLL and in phase II studies in indolent NHL. TGR-1202, or umbralisib, is a novel PI3K inhibitor that we think has more selectivity for the PI3K-delta isoform of the PI3K enzymes.

Ibrutinib is a BTK inhibitor, and from what we know primarily from B-cell malignancies, the B-cell receptor signaling pathway is overutilized by many B-cell malignancies to their survival advantage and targeting it with tyrosine kinase inhibitors has been highly effective across many B-cell malignancies. However, we also see more partial responses than complete responses, and the durability of response is of concern.

The rationale behind this combination is that by targeting multiple enzymes in the B-cell receptor signaling pathway, you may overcome some of the mechanisms of resistance. The primary endpoint of this study is the safety of the combination. Therefore, the primary endpoint is identifying the maximum-tolerated dose (MTD). The target population was relapsed/refractory NHL or CLL. This was amended to include patients with treatment-naïve CLL. 

We presented the results of approximately 38 patients—38 were evaluable for safety and 36 were evaluable for efficacy. Of those, this did include 3 patients with CLL who were treatment naïve. The median number of prior therapies for the group was 3, with more than half of the patients having 3 or more prior therapies.

The largest proportion of patients consisted of patients with CLL, which was approximately 20 patients, but there was a vast variety of other NHL subtypes such as large cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal cell lymphoma. What we have learned with this novel triplet combination is that it does appear to be tolerated in patients, with most adverse events (AEs) being grade 1 or 2, [and there were] infrequent grade 3 or higher AEs. What was notable of the grade 3/4 AEs was a neutropenia rate of 18%, a colitis or diarrhea rate of 3%, and a pneumonia rate of about 11%. 

We have not reached an MTD, and it is important to note that the ublituximab dose was maintained at 900 mg, the ibrutinib was dosed according to the subtype—in CLL it was 420 mg, and in NHL is was 560 mg—and there was dose escalation of the umbralisib to a target of 800 mg. 

Although the primary endpoint was assessing the safety, it is important to note that there was a very high ORR. In the total population, it was 83%. For the CLL subgroup, it was 100%, with 6 patients achieving a CR…We did see efficacy across all the subtypes, including 1 patient with a partial response in large cell lymphoma. Of the 6 patients with large cell lymphoma, 4 were of the non-germinal center subtype.

We have seen durable responses as well, with the median time on therapy of 11 months or longer. We have also not seen an increase in toxicity with longer drug exposure. This appears to be a safe and highly effective combination.

Is there anything else you would like to note about these findings?

This is a phase I study with a small cohort of patients. What is notable about the study is we do have a meaningful duration of drug exposure. What we have learned from prior PI3K-delta inhibitors is that there are unique side effects, particularly colitis, transaminitis, pneumonitis or infection, that have impeded patients’ ability to stay on the drug. This may have a differentiated safety profile, and we have at least 80% of patients over 11 months of drug exposure with the PI3K-delta inhibitor TGR-1202. We have not seen the same rates of AEs associated with drugs such as idelalisib (Zydelig) or duvelisib.

Again, notable is the colitis rate of 3%. We did not have a significant rate of transaminitis. Now, there was a high rate of neutropenia of 18%, albeit that compares favorably with chemotherapy, particularly in a patient population that has [received] numerous therapies. The pneumonia rate of 11% seems to be favorable cross-comparison with other PI3K-delta inhibitors. We think that this may speak to the selectivity of the PI3k-delta inhibitor umbralisib. However, a longer follow-up and more patient exposure will be needed to be comfortable in that conclusion.

What are the next steps following these findings?

This is a very novel, interesting combination that may lead to deeper responses; the response does appear to be durable and the combination does appear to be safe with at least the 38 patients who were evaluable for safety. The next step for this combination is to examine if this should be available for all patients with B-cell lymphomas, or should it be specific to CLL—where we know that targeting the B-cell receptor signaling pathway may be more favorable.

Studies are planned or ongoing to identify a specific population where this novel combination may be expanded upon. We also feel that this PI3K-delta inhibitor (umbralisib), because it may have a differentiated safety profile, may be a favorable agent to combine with agents with the role of synergism. 


  1. Nastoupil L, Lunning MA, Vose JM, et al. Tolerability and activity of chemo-free triplet combination of TGR-1202, ublituximab, and ibrutinib in patients with advanced CLL and NHL. J Clin Oncol 35, 2017 (suppl; abstr 7511).
  2. Nastoupil L, Lunning MA, Vose JM, et al. Chemo-free triplet combination of TGR-1202, ublituximab, and ibrutinib is well tolerated and highly active in patients with advanced CLL and NHL. In: Proceedings from the 2017 EHA Congress; June 22-25, 2017; Madrid, Spain. Abstract S772.
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