Influence of Ketoconazole on the Pharmacokinetics of Romidepsin in Patients With Advanced Cancer

Inclusion criteria

• Males and females 18 years of age or older at the time of signing the informed consent document.
• Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted.
• Able to adhere to the study visit schedule and other protocol requirements.
• Must have diagnosis of advanced malignancy and must have failed other available therapies considered standard of care for their disease.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Negative urine or serum pregnancy test on females of childbearing potential; and
• All females of childbearing potential must use an effective barrier method of contraception (either an intrauterine contraceptive device [IUCD] or double barrier method using condoms or a diaphragm plus spermicide) during the treatment period and for at least 1 month thereafter. Male subjects should use a barrier method of contraception during the treatment period and for at least 3 months thereafter. Female subjects should avoid the use of estrogen-containing contraceptives, since romidepsin may reduce the effectiveness of estrogen-containing contraceptives. An in vitro binding assay determined that romidepsin competes with β-estradiol for binding to estrogen receptors.

Exclusion criteria

• Any significant medical condition or psychiatric illness that would prevent the subject from participating in the study.
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
• Subjects with significant gastrointestinal disease that may impair drug absorption, such as subjects with a history of Cohn's disease, colectomy, gastrectomy, celiac disease, or other diseases with known malabsorption.
• Serum potassium < 3.8 mmol/L or serum magnesium < 0.85 mmol/L (magnesium converts to 2.1 mg/dl or 1.7 mEq/L) (electrolyte abnormalities can be corrected with supplementation to meet inclusion criteria).
• Concomitant use of drugs that may cause a significant prolongation of the corrected measurement of the time between the start of the cardiac Q wave and the end of the T wave (QTc).
• Concomitant use of Cytochrome P 450 3A4 (CYP3A4) strong inhibitors within 1 week of trial medications.
• Concomitant use of CYP3A4 strong inducers within 2 weeks of trial medications.
• Concomitant use of therapeutic warfarin due to a potential drug interaction. Use of a low dose of warfarin or another anticoagulant to maintain patency of venous access port and cannulas is permitted.
• Clinically significant active infection.
• Known infection with Human Immunodeficiency Virus (HIV), hepatitis B, or hepatitis C.
• Inadequate bone marrow or other organ function as evidenced by:

• Hemoglobin < 9 g/dL (transfusions and/or erythropoietin are permitted);
• Absolute neutrophil count (ANC) ≤ 1.0 * 10^9 cells/L [subjects with neutropenia (ANC 1-1.5) as a function of their disease may be supported with granulocyte-colony stimulating factor (G-CSF)];
• Platelet count < 100 * 10^9 cells/L or platelet count < 75 * 10^9 cells/L if bone marrow disease involvement is documented;
• Total bilirubin > 1.5 * upper limit of normal (ULN) or > 2.0 * ULN in the presence of demonstrable liver metastases;
• Serum aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) > 1.5 * ULN or > 2.0 * ULN in the presence of demonstrable liver metastases; or
• Serum creatinine > 2.0 * ULN;
• Prior chemotherapy treatment within 3 weeks prior to the first day of romidepsin treatment (6 weeks for nitrosoureas) or prior treatment with an investigational agent within 4 weeks prior to the first day of romidepsin treatment.
• Prior radiotherapy within 4 weeks prior to the first day of treatment. Subjects who have not fully recovered or whose acute toxicity related to prior radiotherapy has not returned to baseline are ineligible.
• Major surgery within 2 weeks of study entry (day 1).
• Concomitant use of any other anti-cancer therapy.
• Concomitant use of any investigational agent.
• Prior exposure to romidepsin (other histone deacetylase[HDAC] inhibitors are allowed).
• Any known cardiac abnormalities, such as:

• Congenital long measure of the time between the start of the Q wave and the end of the T wave (QT) syndrome;
• . Mean QTc formula (QTcF) interval > 450 msec;
• A myocardial infarction within 12 months of study entry;
• A history of coronary artery disease (CAD), e.g., angina Canadian Class II-IV. A stress imaging study should be performed for any subject whose cardiac status is uncertain. If abnormal, an angiography should be completed to define whether or not CAD is present.
• An electrocardiogram (ECG) recorded at screening showing evidence of cardiac ischemia (ST depression of ≥ 2 mm, measured from isoelectric line to ST segment). A stress imaging study should be performed for any subject whose cardiac status is uncertain. If abnormal, an angiography should be completed to define whether or not CAD is present.
• Congestive Heart Failure (CHF) that meets the New York Heart Association (NYHA) Class II to IV definitions (see Appendix F) and/or ejection fraction < 40% by multi gated acquisition (MUGA) scan or < 50% by echocardiogram and/or magnetic resonance imaging (MRI);
• A known history of sustained ventricular tachycardia(VT), ventricular fibrillation (VF), torsades de pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD);
• Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes (if in doubt, see ejection fraction criteria above);
• Uncontrolled hypertension, i.e., blood pressure (BP) of ≥ 160/95; or
• Any cardiac arrhythmia requiring anti-arrhythmic medication
• Subjects who are pregnant or breast-feeding.