Bruton tyrosine kinase (BTK) inhibitors revolutionized the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). However, first-generation BTK inhibitors such as ibrutinib have some off-target effects, leading to undesirable cardiovascular side effects. Next-generation BTK inhibitors such as acalabrutinib and zanubrutinib still bind similarly to ibrutinib, but they are much more specific and hopefully safer.
At the American Society of Hematology (ASH) 2021, Dr. Alan Skarbnick, Director of the CLL program at Novant Health Cancer Institute in Charlotte, NC, interviewed Dr. Constantine Tam, a hematologist at the Peter McCallum Cancer Center in Melbourne, Australia. They discussed the results of a phase 1 clinical trial testing the combination of three different drugs:
- TG-1701 is an experimental next-generation BTK inhibitor, which is currently being tested for safety and efficacy in clinical trials.
- Umbralisib is an experimental PI3Kδ inhibitor. Current data suggest that it might be better tolerated than other drugs in this class, such as idelalisib or duvelisib.
- Ublituximab is an anti-CD20 antibody. These types of antibodies (i.e., rituximab, obinutuzimab) have been used with chemotherapy and targeted agents for enhanced efficacy.
* Since the time of this interview, the FDA has placed a partial clinical hold on trials using umbralisib and ublituximab in CLL and Non-Hodgkin lymphoma
- TG-1701 is a next-generation irreversible BTK inhibitor similar to acalabrutinib and zanubrutinib.
- In the phase 1 study, TG-1701 appears to perform similarly to other BTK inhibitors with no unexpected side effects.
- There have been no cases of significant bleeding or abnormal heart rhythms (atrial fibrillation, ventricular tachyarrhythmia).
- After the safety of TG-1701 alone was determined, another arm of the phase 1 study looked at TG-1701 in combination with the PI3Kδ inhibitor umbralisib and the anti-CD20 monoclonal antibody ublituximab (U2).
- The hypothesis here is that blocking the B-cell receptor pathway two different ways through the combination of TG-1701 with U2 may confer a greater depth of response compared to either regimen alone.
- Thus far, 36 patients have been treated with TG-1701 + U2, and 19 are far enough along in the trial to be evaluable.
- The triple combination of TG-1701 + U2 was very well-tolerated, and the side effect profile was not substantially different from that of U2 without TG-1701.
- The most common side effects were diarrhea (53%), bruising (42%), nausea (37%), high blood pressure (32%), changes in liver enzymes (32%), and fatigue (32%).
- The overall response rate (ORR) was 84% (4 Complete Remissions and 12 Partial Remissions) among 19 evaluable patients at the data cut-off.
- This was primarily a safety trial, so further studies would be needed to determine efficacy, especially compared to other available treatments.
These phase 1 safety results are encouraging, especially about the safety of using two different types of drugs (a BTKi and a PI3Kδi) to block the B-cell receptor (BCR) pathway. However, whether the triplet is better than the already very effective doublet is yet to be determined.
New developments of concern have largely overshadowed these positive results since the time of this interview. The FDA has put a partial hold on clinical trials using U2 in CLL and Non-Hodgkin Lymphoma due to concerns about a possible increased risk of death. This means that no new patients can be enrolled in ongoing trials, and current patients must re-consent to continue. The FDA is also looking into whether treatment with umbralisib alone results in an increased risk of death in patients with lymphomas. You can find more details about these new developments here. We hope to learn more about the findings of the FDA investigation in the near future.
CLL Society will present the patient’s perspective and needs to the FDA at the public part of their formal review as the FDA reassesses what they need to know to ensure the safety and efficacy of PI3Kδi for those with CLL and other lymphomas.
Please enjoy this interview with Dr. Tam from the ASH meeting held in December 2021 in Atlanta, GA, and virtually.
You can read the actual abstract here: The Selective Bruton Tyrosine Kinase (BTK) Inhibitor TG-1701 As Monotherapy and in Combination with Ublituximab and Umbralisib (U2) in Patients with B-Cell Malignancies
Take care of yourself first.
Ann Liu, PhD