Massey researchers co-lead global breast cancer trials
Named KATHERINE and OlympiA, the phase 3 clinical trials test new treatments for HER2-positive and triple-negative breast cancers, respectively
Massey researchers are part of two international leadership teams recruiting subjects for phase 3 clinical trials testing novel breast cancer therapies. The first trial, known as KATHERINE, will test the efficacy and safety of a new antibody-drug conjugate, trastuzumab emtansine (T-DM1), in comparison to the standard FDA-approved drug Herceptin as post-operative, or “adjuvant”, therapy for early stage Human Epidermal Growth Factor Receptor 2-positive (HER2+) breast cancer patients. The second trial, OlympiA, will test the efficacy of the drug olaparib as adjuvant therapy for high risk, triple negative breast cancer patients with inherited loss of the BRCA1 or BRCA2 cancer suppressor genes.
One in six women with breast cancer are diagnosed as HER2-positive. The abnormal expression of the HER2 protein drives their tumor’s growth and makes the cancer cells more aggressive and less responsive to chemotherapy. Standard treatments for HER2-positive patients include chemotherapy and Herceptin, known generically as trastuzumab, either before or after surgery. Herceptin is a specially designed antibody that binds to the abnormal amounts of the HER2 protein present in these tumors. Blocking this protein improves the activity of chemotherapy. After patients complete preoperative chemotherapy with Herceptin, they undergo surgery to remove any remaining tumor in the breast or in the lymph nodes under the arm. If there is no residual cancer found in the breast or lymph nodes at surgery, patients typically do well with little chance for cancer recurrence. However, if cancer is still present, patients have an increased risk of recurrence.
In KATHERINE, researchers are testing whether adjuvant therapy with a drug known as TDM-1 is more effective than adjuvant therapy with Herceptin. Standard therapy for patients with HER-2+ breast cancer would be to complete one full year of Herceptin, regardless of whether there was residual cancer at surgery or not. T-DM1 is an antibody-drug conjugate because it is made of a highly active, but also highly toxic, drug known as emtansine combined with Herceptin. Antibodies, like Herceptin, bind only to a specific protein on the surface of a cell, such as HER2, and can be used to carry chemotherapy directly to those cells. T-DM1 uses the Herceptin to specifically target cancer cells overexpressing the HER2 protein. This allows for minimal toxic exposure of normal cells to emtansine. T-DM1 has been approved by the FDA for use in metastatic patients and has been shown to be very well tolerated by patients with HER2-positive breast cancer that is no longer controlled by Herceptin.
“The key to the success of T-DM1 is that the linker – the piece of the molecule that hooks the chemotherapy drug onto the antibody – is designed to come apart only when the molecule gets inside a cell. So, it doesn’t fall apart in your blood stream and harm healthy cells,” said Harry Bear, M.D., Ph.D., who is the local principal investigator for both trials at Massey. Medical director of the Massey Clinical Trials Office, Bear is also the Dr. Walter Lawrence, Jr., Chair in Surgical Oncology, director of the Breast Health Center and member of the Developmental Therapeutics research program at Massey as well as professor of surgery and professor of microbiology and immunology at the VCU School of Medicine. Additionally, Bear serves on the Board of Directors of the National Surgical Adjuvant Breast and Bowel Project (NSABP).
The KATHERINE trial randomizes patients with residual HER2 positive breast cancer to complete a year of adjuvant therapy with either Herceptin (the current standard) or T-DM1. Patient outcomes will be reported up to ten years following treatment in order to track recurrence rates. T-DM1 could substantially lower the risk for recurrence in women who have persisting HER2-positive breast cancer following neoadjuvant treatment.
“If patients receiving T-DM1 enjoy a lower rate of recurrence than patients receiving standard Herceptin, the results would be practice changing,” said Charles Geyer, M.D., global co-chair for the KATHERINE trial. The associate director for clinical research at Massey, Geyer is also the Harrigan, Haw, Luck Families Chair in Cancer Research and member of the Developmental Therapeutics research program at Massey as well as professor in the Division of Hematology, Oncology and Palliative Care at the VCU School of Medicine.
In addition to serving as the global co-chair the KATHERINE trial, Geyer is one of four global co-chairs for OlympiA. In OlympiA – a double-blind clinical trial, researchers are studying the efficacy of the drug olaparib (trade name Lynparza) to prevent disease recurrence when added to standard therapy for patients with triple-negative breast cancer who also have inherited loss of function of tumor suppressor genes BRCA1 or BRCA2 . BRCA1/2 function to help correct mistakes that can occur when DNA is being replicated. Patients who have inherited mutated BRCA1 or 2 genes are at a substantially increased risk of developing breast or ovarian cancer at an early age. When the second copy of the BRCA1 or BRCA2 gene is lost as a tumor is being formed, cancer cells become very dependent on another DNA repair pathway that uses an enzyme called poly ADP ribose polymerase (PARP). If this enzyme is blocked, the BRCA deficient cells may die. Olaparib was recently approved by the FDA based on activity in patients with advanced ovarian cancer with inherited BRCA functional deficiencies. Researchers hope to see similar success in the treatment of women with BRCA 1/2 inherited deficiencies and high risk triple-negative breast cancers.
OlympiA participants will need to have completed all standard treatments, including chemotherapy and surgery and, if needed, radiation therapy. Then they will receive olaparib or a placebo for a year. Since all standard therapy will have been completed by the time patients enter OlympiA, the placebo control design is both appropriate and necessary to understand the true benefits and side effects of olaparib in this potentially curative situation.
KATHERINE and OlympiA are being conducted globally in the hopes of finding a larger pool of eligible candidates regardless of their primary treatment location. Both trials are actively recruiting eligible patients. Those interested in enrolling in either trial, or one of more than eighteen other breast cancer trials at Massey, should contact the Massey Clinical Trials Office at (804) 628-4712. For information about KATHERINE, please reference clinical trial NSABP-B-55. For information about OlympiA, please reference clinical trial NSABP-B50-I.
KATHERINE is sponsored by Hoffman-La Roche and being led by the National Surgical Adjuvant Breast and Bowel Project Foundation, Inc., and the German Breast Group. OlympiA is sponsored by the olaparib drug developer Astra Zeneca and the National Cancer Institute and is being led by NRG Oncology and the Breast International Group.