Title of the Research Project:
“Venetoclax and Obinutuzumab in Combination with Roginolisib in CLL / SLL Patients After Bruton Tyrosine Kinase (BTK) Inhibitor Failure”
Research Project Summary:
For those with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) who have been previously treated with a covalent BTK inhibitor medication (such as ibrutinib, acalabrutinib, and zanubrutinib) but then experience relapse after being on these drugs, the remaining treatment options are limited. The standard next line of treatment for these individuals has been venetoclax. But the duration of benefit for patients with this sequencing of therapy is only two years (compared to about five years for patients who were treated with venetoclax prior to receiving a BTK inhibitor). The goal of this study is to test if combining venetoclax and obinutuzumab with a first in class selective phosphoinositide 3-kinase (PI3K) delta inhibitor called roginolisib will significantly improve the depth and duration of remission in those whose disease has relapsed after being on a BTK inhibitor, while also making sure that the burden of treatment (adverse side effects) is acceptable.
About the Award Recipient, Dr. Jennifer Brown:
Jennifer Brown, MD, PhD is currently the Director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute in Boston, Massachusetts, as well as the Worthington Margaret Collette Professor of Medicine at Harvard Medical School. She grew up on Long Island, New York, and earned her bachelor’s and master’s degrees simultaneously at Yale in molecular biophysics and biochemistry. Dr. Brown then received her MD and PhD in molecular genetics at the Harvard Medical School, followed by completion of her Internal Medicine residency at Massachusetts General Hospital and a fellowship in Hematology and Medical Oncology at Dana-Farber. After her training, Dr. Brown joined the faculty of Dana-Farber and Harvard Medical School where she currently has an active research program dedicated to CLL / SLL and is highly regarded worldwide as an expert in the field. Her research interests have included the development of novel targeted therapies, and she was instrumental in the clinical development and FDA approval of idelalisib and ibrutinib. She also has a longstanding research interest in the inherited predisposition to CLL / SLL.
Why Is Research on Roginolisib Needed for CLL / SLL?
More treatment options are needed for CLL / SLL as it remains incurable. Roginolisib is a new PI3K delta (Pi3Kδ) inhibitor that is showing promise and seems to have minimal side effects compared to previous PI3K inhibitors that have been developed to treat the disease.
What Kind of Drug is Roginolisib and How Does It Work?
It is a very selective PI3K delta (Pi3Kδ) inhibitor that binds to PI3K in CLL / SLL cells. Roginolisib is considered a new drug class, because even though it targets the PI3 kinase pathway it works much differently than its predecessors. While idelalisib and duvelisib directly block the PI3K target, roginolisib binds to the PI3K target which results in different downstream effects (less toxicities). Data from phase one studies in Europe indicate there is a synergistic effect when roginolisib is combined with obinutuzumab and venetoclax.
How Does Roginolisib Differ from Previous PI3K Inhibitors Used to Treat CLL / SLL?
Roginolisib has a very different, improved safety profile compared to the older PI3K inhibitors. The use of PI3K inhibitors has historically been troubled by severe and unpredictable drug toxicities (side effects) that can occur. Roginolisib acts differently within the body and doesn’t get broken down (metabolized) in the same way that previous PI3K inhibitors do. For example, when the body metabolizes idelalisib and duvelisib, it turns the molecule into other substances that can result in serious side effects. Roginolisib does not turn into other substances and has a very clean metabolism in the body. Also, in contrast to idelalisib and duvelisib, the safety profile of roginolisib showed no major toxicities in the early phase one studies and there were no autoimmune toxicities that occur with the earlier generation of PI3 kinase inhibitors.
Who Is Eligible for This Study?
Individuals living with CLL / SLL who have been previously treated with a covalent BTK inhibitor medication (such as ibrutinib, acalabrutinib, and zanubrutinib), but have experienced relapse during or after being on these drugs, are eligible for this study.
What Interventions Will Be Used?
Participants will either receive the two-drug combination of obinutuzumab and venetoclax, or they will be given the three-drug combination of obinutuzumab, venetoclax, and roginolisib.
What is the Design of the Study?
The study is designed to be a two-arm, randomized trial comparing the results of those who are given the two-drug combination versus those who are given the three-drug combination. The primary outcome that will be measured at the end of the study (also called the endpoint) is the percentage of patients who do not have any detectable CLL / SLL cells using measurable residual disease (MRD) testing after one year of therapy is complete. Dr. Brown has hypothesized that both arms of the study will have better results than what has been previously demonstrated in the relapsed CLL / SLL setting when using venetoclax alone.
How Will the Findings Be Used?
If the results of combining venetoclax and obinutuzumab in those with relapsed CLL / SLL are superior to the results of using venetoclax alone in relapsed patients, the practice of combining venetoclax and obinutuzumab can be immediately implemented for treating patients since both drugs are already FDA approved. Additionally, if the results of adding roginolisib to the venetoclax and obinutuzumab combination are significant, the data could serve as justification to then perform a phase three trial, potentially leading to this drug combination being a valuable new treatment option for those living with the disease. Dr. Brown is hopeful that roginolisib will further increase the proportion of CLL / SLL patients who can achieve complete disease clearance (undetectable measurable residual disease) and that the risk of subsequent relapse will be reduced.
Please watch the interview between CLL Society’s Director of Scientific Affairs and Research, Robyn Brumble, RN, MSN and Jennifer Brown, MD, PhD.
What Is the Goal of CLL Society’s Clinical Scholar Award?
This research award is dedicated to supporting exceptional physician researchers who have already established themselves in the field of CLL / SLL. It is designed to fund the research efforts of an advanced physician-scientist who is engaged in independent clinical research and has demonstrated outstanding leadership, scholarship, and academic success. The Clinical Scholar Award is intended to advance the development of treatments and/or preventative options for those living with the disease.
CLL Society invites you to read more about CLL Society’s Research Program. The 2024 Clinical Scholar Award was made possible through generous donations from those in our community. CLL Society is one of the only blood cancer organizations whose research program is dedicated solely to funding CLL / SLL research. CLL Society relies on generous donations from our community to fund this important work.
