In this video, Dr. Anthony Mato, M.D., Associate Professor of Medicine and Director, CLL Program at Memorial Sloan Kettering Comprehensive Cancer Center, in New York City, is interviewed by CLL Society founder and Chief Medical Officer, Dr. Brian Koffman, M.D., a retired family physician and a CLL patient. This video was recorded at the 61st Annual Meeting of the American Society of Hematology, in 2019, in Orlando, Florida.. Dr. Mato, also serves on the Medical Advisory Board of the CLL Society, Inc.
In this interview, Dr. Mato discusses a Phase Ia/Ib Study Exploring the Synthetic Lethality of the Orally Administered Novel Bruton’s Tyrosine Kinase Inhibitor; DTRMWXHS-12 (DTRM-12), in combination with Everolimus (Afinitor®) and Pomalidomide (Pomalyst®) in Patients with Relapsed/Refractory CLL, DLBCL or Other B-Cell Lymphomas.
This study is based on the concept of “synthetic lethality” where multiple targeted agents are used at low doses to block different pathways and to achieve the ability to kill cancer cells without the associated toxicities of putting three drugs together at customary doses. The concept of synthetic lethality is not new, in that it was first proposed in 1922. However, the application of this concept is relatively new and an outgrowth of expanding knowledge of the pathways within cancer cells that either promote proliferation or retard cell death. See https://www.future-science.com/doi/full/10.4155/fmc-2018-0227 for more background information.
- Pre-clinically, researchers worked in studies in mice to attempt to find optimal “low” dosing schemes for blocking multiple parallel pathways and lower the toxicities associated with the treatment of CLL. They studied two-drug and three drug combinations. Pre-clinical work led to finding that these three specific pathways, in combination, would yield the most effective way kill cancer cells in lymphoma or CLL.
- This pre-clinical work led to the selection of DTRM-12, Everolimus and Pomalidomide to study in patients “clinical-trial”. Like other Phase I trials, this trial assessed optimizing effectiveness and safety by selecting the lowest doses possible.
- DTRMWXHS-12 (DTRM-12) is a new Bruton’s Tyrosine Kinase Inhibitor https://www.cancer.gov/publications/dictionaries/cancer-drug/def/btk-inhibitor-dtrmwxhs-12, developed by Zhejiang DTRM Biopharma Company, Ltd of China. This drug serves as the backbone of therapy and is given at a “low dose” within this regimen, below the dose if it was used a single agent.
- Pomalidomide, is an oral thalidomide analogue, similar to lenalidomide that is currently approved in combination with dexamethasone in multiple myeloma patients. This drug is classified as an immunomodulatory imide drug (IMID) https://cllsociety.org/2015/06/biologic-or-immunotherapy-in-cll-or-chronic-lymphocytic-leukemia/, which affects the “micro-environment” of the cancer cell “making the neighborhood unfriendly. In addition, this drug blocks the NF-KB (nuclear factor kappa chain enhancer of activated B-Cells) pathway which plays a role in inflammatory responses as well as, cancer, arthritis and asthma. This drug is given at an “extremely low” dose within this study, when compared to its other uses. For more on the NF-KB pathway see: https://www.mechanobio.info/what-is-mechanosignaling/signaling-pathways/what-is-the-nf-%CE%BAb-pathway/
- Everolimus, is a derivative of sirolimus and is used as an immunosuppressant to prevent rejection of organ transplants as well as several advanced solid tumor cancers. This drug works by blocking the MTOR (mammalian target of rapamycin) pathway which is a component of the phosphatidylinositol 3-kinase (PI3K) cell survival pathway that monitors the availability of nutrients, mitogenic signals and cellular energy and oxygen levels, and therefore is significant in the regulation of cell growth and proliferation. PI3K inhibitors such as idelalisib https://cllsociety.org/2018/03/things-to-know-about-idelalisib/, umbralisib and duvelisib currently used in r/r CLL/SLL. Everolimus also is dosed at “extremely low” level, compared to other indications for this medication.
The Phase I trial was exciting and promising. In mouse studies, they found that this combination resulted in faster and deeper remissions. Although, by nature, Phase I trials are small in number (N=33) this combination appears to be promising, in humans for multi-refractory CLL, diffuse large B-cell lymphomas (DLBCL and for patients who’s CLL transforms to a more aggressive lymphoma in what is known as Richter’s Transformation. Like the mouse studies, humans who responded to this combination saw fast and deep remission of their disease. Of the six Richter’s patients enrolled, two remain in remission 14-months on this combination after multiple prior therapy failures.
Phase II studies involving larger numbers of patients are now enrolling patients at multiple sites. Patients with known Richter’s Transformation (RT) should consider this trial as there are not many options for trials in RT, at present.
The exciting aspect of this clinical trial is that if successful in larger numbers of patients in Phase II and Phase III studies, it gives CLL providers one more option to deal with the variability of patient’s disease and response to various therapies.
The link to find out where this clinical is available and more information is: https://clinicaltrials.gov/ct2/show/NCT02900716. To learn more about clinical trials, in general, go to https://cllsociety.org/clinical-trials/
The abstract for the original Phase I study can be found at: https://doi.org/10.1182/blood-2019-126192
Thanks for reading and viewing this interview.
Stay strong, we are all in this together.
Thomas. E. Henry III, MBA, RPh, CPh