Deacetylase inhibitor therapy
Inventors
McCulloch, William • Piekarz, Richard L. • Bates, Susan E.
Assignees
Celgene Corp • US Department of Health and Human Services
Publication Number
US-8957027-B2
Publication Date
2015-02-17
Expiration Date
2027-06-07
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Abstract
The present invention relates to deacetylase inhibitor (e.g., histone deacetylase inhibitor) therapies and demonstrates that individuals with low electrolyte levels may have increased susceptibility to certain unwanted side effects such as cardiac side effects. In some embodiments, the invention provides methods of administering DAC or DAC inhibitor therapy that includes electrolyte supplementation.
Core Innovation
The present invention relates to deacetylase inhibitor therapies, particularly histone deacetylase inhibitors (HDAC inhibitors), and reveals that individuals with low electrolyte levels, especially potassium and magnesium, may have increased susceptibility to certain unwanted side effects such as cardiac side effects during such therapy. The invention provides methods of administering deacetylase (DAC) inhibitor therapy that incorporate assessment of electrolyte levels and optionally include electrolyte supplementation prior to, concurrently with, and/or sequentially with DAC inhibitor treatment.
The problem being solved is minimizing potential side effects, especially cardiac side effects, associated with deacetylase inhibitor therapy. It has been found that individuals with low potassium and/or magnesium levels are susceptible to development of cardiac repolarization abnormalities including QTc prolongation and dysrhythmias when undergoing DAC inhibitor therapy. This presents a need for improved administration methods that reduce these risks by managing electrolyte levels.
The invention encompasses methods of assessing serum potassium and magnesium levels in individuals scheduled to receive or receiving DAC inhibitor therapy, and administering electrolyte supplementation if these levels are below certain thresholds to mitigate cardiac and other side effects. Electrolyte supplementation may include potassium and magnesium, administered prior to, concurrently with, or after DAC inhibitor therapy initiation. The therapy can be used with various DAC inhibitors, including romidepsin, and is intended to improve the safety profile of DAC inhibitor treatment in diseases such as cancers and other cell proliferative disorders.
Claims Coverage
The claims define eight main inventive features covering methods of treating hematological malignancies with romidepsin and integrating electrolyte monitoring and supplementation to mitigate side effects.
Administering romidepsin over controlled infusion time
Intravenous administration of romidepsin over a time period of over 30 to 60 minutes, including specific durations such as over 30 to 50 or 30 to 40 minutes, with unit doses ranging from 0.5 to 28 mg/m2; dosing schedules optionally include administration on days 1, 8, and 15 of a 28-day cycle, repeated multiple times.
Assessing and correcting electrolyte levels prior to or during therapy
Assessing serum potassium and magnesium levels in patients undergoing romidepsin therapy, and administering potassium if serum potassium concentration is below 3.5 mEq/L and magnesium if serum magnesium concentration is below 1.9 mEq/L to achieve target levels prior to or concomitantly with initiation of therapy.
Mitigating cardiac toxicities by electrolyte supplementation
Using potassium and/or magnesium supplementation during romidepsin therapy to reduce toxicities associated with therapy, where toxicity includes cardiac toxicity such as QTc prolongation or arrhythmias.
The claims focus on methods of administering romidepsin with specific dosing regimens combined with electrolyte level assessment and supplementation to reduce cardiac side effects, establishing protocols for safe and effective treatment of certain hematological disorders.
Stated Advantages
Electrolyte supplementation prior to, concurrently with, or sequentially with DAC inhibitor therapy mitigates cardiac side effects associated with such treatment.
Maintaining serum potassium and magnesium within or at the higher end of normal ranges prior to and during therapy reduces risks of cardiac repolarization effects and dysrhythmias.
The methods provide improved safety profiles for DAC inhibitor therapies by reducing side effects including nausea, vomiting, fatigue, cardiac toxicities, and other related adverse events.
Documented Applications
Treatment of hematological malignancies including Hodgkin lymphoma, myeloma, myelodysplastic syndromes, leukemias such as chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), and adult T cell leukemia/lymphoma.
Treatment of lymphomas including Hodgkin's and non-Hodgkin's lymphomas such as peripheral and cutaneous T-cell lymphomas.
Treatment of solid tumors including lung, breast, colon, liver, pancreas, ovarian, prostate, kidney, sarcomas, brain tumors, and childhood solid tumors.
Treatment of immune-mediated disorders such as graft-versus-host disease, transplant rejection, autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus, psoriasis, Crohn's disease, ulcerative colitis, and multiple sclerosis.
Treatment of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and Huntington's disease.
Use of electrolyte supplementation in combination with DAC inhibitor therapy to reduce cardiac and other toxicities during treatment of DAC-mediated diseases.
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