Romidepsin (Istodax brand in the US). Romidepsin is also known as FK228, FR901228, or Depsipeptide; Abraxane is the branded name of Nab-Paclitaxel, a nanoparticle form of Paclitaxel
Purpose of Trial:
The phase 1 portion of this study is to find the maximum tolerated dose of the drug Romidepsin in combination with Abraxane. The phase 2 portion aims to evaluate the activity of this combination in metastatic IBC. Romidepsin is an epigenetic drug that targets the structure of DNA via enzymes called histone deacetylases. Histone deacetylases normally silence genes, some of which are aberrantly turned off in cancer. By turning these genes back on, cell death may be induced. Abraxane is a form of chemotherapy that is related to taxol. It functions to block cell division.
Why this study is relevant for IBC patients:
There is preclinical data that the HDAC inhibitor Romidepsin has induces synergistic destruction of tumor emboli in IBC models in combination with taxanes. In this study, the authors also noted that the tumor lymphatic vessels were damaged by this drug combination.
Romidepsin is a very potent class 1 HDAC inhibitor that is FDA approved in several types of lymphomas. HDAC stands for histone deacetyltransferase – which literally means “removal of acetyl groups”. HDAC inhibitors block this function both in chromatin as well as other non-histone proteins, therefore keeping the DNA in an open, active conformation. This makes Romidepsin a pseudo-targeted drug as it works by multiple mechanisms. For information regarding the toxicities experienced in the clinical trials and in current practice in lymphoma patients, see the second half of this review paper (open access). One of the unique features of IBC biology that differs from other breast cancers is that despite the highly invasive and stem-cell-like nature of the tumor cells, E-cadherin remains highly expressed, whereas it is normally silenced during the progression from local disease to metastatic disease. It is thought that the function of this E-cadherin in IBC is to help the tumor cells remain connected to each other and migrate as clumps rather than single cells. HDAC inhibitors disrupt this collective migration capability, as well as blocking the metastatic ability of IBC preclinical models.
This 2-phase trial is for HER2 negative (ie TNBC or ER+) metastatic IBC patients. For the phase 1 dose-escalation portion, eligible patients are those who have had 0 or 1 line of chemotherapy in the metastatic setting, and not received Abraxane or Romidepsin previously. The phase 2 portion is aimed at newly diagnosed metastatic patients who have not received other therapy previously.
Romidepsin and abraxane are both IV infusions you will receive every week on day 1, 8, 15 of a 28 day cycle. The infusion will take a total of 1.5 hours each week. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 2 years, and then annually thereafter.
Location of Trial:
Thomas Jefferson University, Philadelphia, Pennsylvania, United States, 19107
For more information:
Contact the principal investigator, Dr Laura Austin at 215-955-8874, or the Clinical Research Management Office at 215-955-1661.