Influence of Ketoconazole on the Pharmacokinetics of Romidepsin in Patients With Advanced Cancer
Condition: Hematologic Malignancy; Malignant Lymphoma
MeSH terms: Neoplasms; Hematologic Neoplasms; Lymphoma
Intervention: Romidepsin; Ketoconazole
Intervention description: Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 1 and Day 8.; Ketoconazole 400 mg oral once daily on Days 4-8
Intervention MeSH terms: Ketoconazole; Romidepsin
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: ROMI-001; romi; Romidepsin; Istodax; advanced malignancy; PK; pharmacokinetics

Summary:

      The purpose of this study is to evaluate the effect and safety of multiple doses of
      ketoconazole on the pharmacokinetics of romidepsin after a single intravenous (IV) infusion.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Males and females 18 years of age or older at the time of signing the informed consent
             document.

          2. Understand and voluntarily sign an informed consent document prior to any study
             related assessments/procedures are conducted.

          3. Able to adhere to the study visit schedule and other protocol requirements.

          4. Must have diagnosis of advanced malignancy and must have failed other available
             therapies considered standard of care for their disease.

          5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

          6. Negative urine or serum pregnancy test on females of childbearing potential; and

          7. 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:

          1. Any significant medical condition or psychiatric illness that would prevent the
             subject from participating in the study.

          2. Any condition, including the presence of laboratory abnormalities, which places the
             subject at unacceptable risk if he/she were to participate in the study.

          3. 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.

          4. 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).

          5. 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).

          6. Concomitant use of Cytochrome P 450 3A4 (CYP3A4) strong inhibitors within 1 week of
             trial medications.

          7. Concomitant use of CYP3A4 strong inducers within 2 weeks of trial medications.

          8. 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.

          9. Clinically significant active infection.

         10. Known infection with Human Immunodeficiency Virus (HIV), hepatitis B, or hepatitis C.

         11. 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;

         12. 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.

         13. 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.

         14. Major surgery within 2 weeks of study entry (day 1).

         15. Concomitant use of any other anti-cancer therapy.

         16. Concomitant use of any investigational agent.

         17. Prior exposure to romidepsin (other histone deacetylase[HDAC] inhibitors are allowed).

         18. 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

         19. Subjects who are pregnant or breast-feeding.