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

NCT01324310 | Completed Phase 1 Results

• 2 other identifiers: ROMI-ADVM-0012010-022144-20
• Study Type: interventional
• Target: 15
• Locations: 2 countries
• Sites: 3

Brief 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.

Conditions

Hematologic Malignancy; Malignant Lymphoma

Keywords

ROMI-001; romi; Romidepsin; Istodax; advanced malignancy; PK; pharmacokinetics

Outcome Measures

Primary Outcomes (8)

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

  AUC0-t: area under the plasma concentration time-curve from Time 0 to the time of the last quantifiable concentration (Ct), calculated by linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing. For AUC0-t, an analysis of variance (ANOVA) model was used to estimate the ratio of geometric means and its 90% CI between romidepsin alone and romidepsin in the presence to ketoconazole.

  Days 1 and 8; at 0 (pre-dose) 1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion.

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

  AUC 0-24: area under the plasma concentration time-curve from Time 0 to 24 hours, calculated by linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing; for AUC 0-24 an analysis of variance (ANOVA) model was used to estimate the ratio of geometric means and its 90% confidence interval (CI) between romidepsin alone and romidepsin in the presence of ketoconazole

  Days 1 and 8; at 0 (predose), 1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion

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

  AUC0-∞: area under the plasma concentration time-curve from Time 0 extrapolated to infinity, calculated as \[AUCt + Ct/λz\].

  Days 1 and 8; at 0 (pre-dose), 1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion.

• Maximum Observed Plasma Concentration (Cmax)

  Cmax: maximum observed plasma concentration, obtained directly from the observed concentration versus time data; for Cmax, an analysis of variance (ANOVA) model was used to estimate the ratio of geometric means and its 90% confidence interval (CI) between romidepsin alone and romidepsin in the presence of ketoconazole

  Days 1 and 8; at 0 (pre-dose), 1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion.

• Time to Maximum Observed Plasma Concentration (Tmax)

  Tmax: time to maximum observed Tmax, obtained directly from the observed concentration versus time data

  Days 1 and 8; at 0 (pre-dose), 1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion.

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

  Terminal elimination half-life (t1/2) in plasma, was calculated as \[(ln 2)/λz\]

  Days 1 and 8; at 0 (pre-dose),1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion.

• Apparent Total Plasma Clearance (CL)

  Apparent total plasma clearance, (CL) calculated as \[Dose/AUC 0-∞\].

  Days 1 and 8; at 0 (pre-dose), 1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion.

• Apparent Total Volume of Distribution (Vz)

  Vz: apparent total volume of distribution, calculated as \[(CL)/λz\].

  Days 1 and 8, At 0 (predose), 1, 2, 3, and 4 hours (end of infusion) and at 4.25, 4.5, 5, 6, 8, 10, 12, 24 and 48 hours after the initiation of IV infusion.

Secondary Outcomes (1)

• Summary of Participants With Treatment Emergent Adverse Events (TEAEs)

  Day 1 up to Day 36 (28 days after last treatment)

Study Arms (1)

Romidepsin and ketoconazole

EXPERIMENTAL

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

Drug: Romidepsin; Drug: Ketoconazole

Interventions

Romidepsin DRUG

Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 1 and Day 8.

Also known as: Istodax®, Romi, ROMI

Romidepsin and ketoconazole

Ketoconazole DRUG

Ketoconazole 400 mg oral once daily on Days 4-8

Romidepsin and ketoconazole

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• Celgene: lead

Study Sites (3)

Florida Cancer Specialists

Sarasota, Florida, 34232, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

Sarah Cannon Research UK

London, W1G6AD, United Kingdom

Location

MeSH Terms

Conditions

Hematologic Neoplasms; Lymphoma

Interventions

romidepsin; Ketoconazole

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Senior Manager
• Organization: Celgene Corporation

clinicaltrialdisclosure@celgene.com

1-888-260-1599

Study Officials

• Ken Takeshita, MD

  Celgene Corporation

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 25, 2011
• First Posted: March 29, 2011
• Study Start: April 1, 2011
• Primary Completion: January 1, 2012
• Study Completion: January 1, 2012
• Last Updated: November 25, 2019
• Results First Posted: May 15, 2013

Record last verified: 2019-11

Locations

US (2); GB (1)