A key part of City of Hope's mission is our determination to leverage world-class research into leading-edge therapies and make them available to patients as rapidly as possible. Clinical trials play a vital role in this work.
The Kenneth Goldman and Briskin Family Clinical Trials Program manages and coordinates all trials related to the treatment of multiple myeloma, as part of the Judy and Bernard Briskin Center for Multiple Myeloma Research.
Our clinical trial portfolio is constantly changing as we seek the best agents. These include drugs targeting high-risk myeloma, bispecific antibodies and immune checkpoint inhibitors.
Several trials, currently in active development, demonstrate the breadth of our efforts:
Leflunomide – A drug approved to treat arthritis
For more than a decade, leflunomide, an immunosuppressant, has been used to treat rheumatoid and psoriatic arthritis.
Leflunomide works by blocking an enzyme necessary for synthesis of DNA and RNA, thereby inhibiting the production of rapidly dividing cells.
Recent laboratory studies of leflunomide have demonstrated significant cancer activity in myeloma, showing it has the ability to inhibit cell growth and induce cell death in common myeloma cell types and to do so at clinically achievable concentrations of the drug.
The drug is also showing promise in two significant areas in laboratory studies: effectiveness on steroid-resistant myeloma cells; and an ability to enhance the effectiveness of several established myeloma drugs such as melphalan, doxorubicin, dexamethasone and bortezomib.
Leflunomide also has minimal toxicity, is well-tolerated and has a unique mechanism of action. This makes it potentially very important for elderly patients as well as patients whose myeloma has recurred.
We are testing leflunomide in patients with myeloma who have relapsed after receiving available standard therapies.
Metformin and Ritonavir – A drug approved to treat diabetes and one to treat HIV
Cancer cells need glucose to keep growing. This is why PET scans, which can measure glucose activity, are often used to track a cancer's progress in the body.
Stopping cancer by cutting off its glucose supply may be an attractive and less toxic treatment option when standard treatments fail or the patient develops resistance.
Metformin is a first-line treatment for type 2 diabetes and one of the most widely used pharmaceuticals in the world. It suppresses glucose production by the liver.
Metformin's potential as an anti-cancer drug has been studied since 2005 when it was shown that diabetes patients taking metformin had a lower cancer rate than patients on other drugs. Metformin has been shown to inhibit proliferation of several cancer cell lines, including breast, colon, ovarian, pancreatic, lung and prostate cancer.
Our multiple myeloma researchers are investigating the use of metformin in combination with ritonavir, an antiretroviral protease inhibitor used to treat HIV.
Numerous studies have shown ritonavir to possess cancer-fighting properties separate from inhibition of HIV protease. In fact, ritonavir is already being used in combination with the myeloma drug bortezomib to fight renal cancer, so the prospect of employing it against multiple myeloma is especially attractive.
While there is extensive clinical experience with both metformin and ritonavir, this is the first trial in which they are being combined.
Ibrutinib and Pomalidomide
Pomalidomide has been approved for relapsed myeloma, however we seek to make it more effective by combining it with newer agents. The Judy and Bernard Briskin Center for Multiple Myeloma Research led a multicenter clinical trial evaluating the combination of Pomalidomide and Ixazomib, and recently opened a new study of Pomalidomide plus Ibrutinib. Additionally, we seek to understand why these drugs work for some patients and not others by studying individual patient samples in our research labs.
We believe we can enhance the effectiveness of Pomalidomide by combining it with other novel drugs that are better tolerated.
Ibrutinib, an inhibitor of Bruton’s tyrosine kinase, has recently been Food and Drug Administration-approved for certain subtypes of leukemia and lymphoma. It has also been studied as a single agent in relapsed/refractory multiple myeloma where it was 30 percent effective and well-tolerated at low doses.
Therefore we are studying the combination of Ibrutinib and Pomalidomide and their effectiveness in patients.
T Cell Immunotherapy
Truly the new frontier in cancer treatment, T cell immunotherapy utilizes the patient’s own immune system, genetically engineering immune T cells to be more specific and efficient at killing myeloma cancer cells. These modified T cells will replicate inside the body, hunting down and killing cancer cells, and are designed with the intention of providing long-term cancer surveillance.
T cell immunotherapy is showing tremendous promise in leukemia and lymphoma patients in the last five years, in diseases that target the CD19 tumor marker. Research in City of Hope’s Cancer Immunotherapeutics Program has yielded a growing portfolio of active clinical trials for targeting new tumor markers and a variety of blood and solid organ cancers, including glioma, lymphoma, childhood neuroblastoma, colorectal, breast and prostate cancers. Additional protocols for lung cancer, ovarian cancer, leukemias and pediatric/neonatal brain tumors are being added.
In addition, preclinical studies at City of Hope have investigated the optimal multiple myeloma tumor markers to target T cell immunotherapy. Based on laboratory studies, the CS-1 protein has been selected as a promising target and the first to advance to clinical trials of T cell immunotherapy for myeloma. CS-1 (also known as SLAMF-7) is an ideal target as it is universally expressed on myeloma cells but not on normal cells. We plan to open a phase I trial evaluating the safety and tolerability of modified T cells targeting CS-1 in late 2016, for patients with advanced myeloma. Meanwhile we continue to study additional myeloma targets for T cell immunotherapy to address the fact that myeloma between patients and even within an individual patient is very heterogeneous, possibly requiring targeting of multiple tumor makers for complete eradication. City of Hope is one of only a few centers in the U.S. where modified T cells are being used for treatment of advanced myeloma. Now we are embarking on the first of a series of planned trials to employ genetically-engineered T cells that recognize and destroy myeloma cells bearing selected tumor markers on their cell surfaces.