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

Information source: Celgene Corporation
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Hematologic Malignancy; Malignant Lymphoma

Intervention: Romidepsin (Drug); Ketoconazole (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: Celgene Corporation

Official(s) and/or principal investigator(s):
Ken Takeshita, MD, Study Director, Affiliation: Celgene Corporation

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.

Clinical Details

Official title: A Phase I Open-label, 2-period Study to Evaluate the Influence of Multiple Oral Doses of Ketoconazole on the Single Dose Pharmacokinetics of Romidepsin in Subjects With Advanced Cancer

Study design: Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label

Primary outcome:

Area Under the Plasma Concentration Time-curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-t)of Romidepsin

Area Under the Plasma Concentration Time-curve From Time 0 to 24-hour (AUC 0-24)

Area Under the Plasma Concentration Time-curve From Time 0 Extrapolated to Infinity (AUC0-∞)

Maximum Observed Plasma Concentration (Cmax)

Time to Maximum Observed Plasma Concentration (Tmax)

Estimate of the Terminal Elimination Half-life in Plasma (t1/2)

Apparent Total Plasma Clearance (CL)

Apparent Total Volume of Distribution (Vz)

Secondary outcome: Summary of Participants With Treatment Emergent Adverse Events (TEAEs)

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

Locations and Contacts

Sarah Cannon Research UK, London W1G6AD, United Kingdom

Florida Cancer Specialists, Sarasota, Florida 34232, United States

Sarah Cannon Research Institute, Nashville, Tennessee 37203, United States

Additional Information

Starting date: April 2011
Last updated: September 5, 2013

Page last updated: August 23, 2015

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