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

• Sponsor: Celgene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01324310
• Collaborator: (none)
• Enrollment: 15
• Locations: 3
• Arm: 1
• Actual Duration (Months): 9
• Patients Per Site: 5
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hematologic Malignancy; Malignant Lymphoma	Drug: Romidepsin; Drug: Ketoconazole	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• 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
• Actual Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Romidepsin and ketoconazole 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; Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 1 and Day 8.; Other Names: Istodax®, Romi, ROMI ; Drug: Ketoconazole; Ketoconazole 400 mg oral once daily on Days 4-8

Outcome Measures

Primary Outcome Measures

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

   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.

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

   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

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

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

4. Maximum Observed Plasma Concentration (Cmax) [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.]

   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

5. Time to Maximum Observed Plasma Concentration (Tmax) [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.]

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

6. Estimate of the Terminal Elimination Half-life in Plasma (t1/2) [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.]

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

7. Apparent Total Plasma Clearance (CL) [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) calculated as [Dose/AUC 0-∞].

8. Apparent Total Volume of Distribution (Vz) [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.]

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

Secondary Outcome Measures

1. Summary of Participants With Treatment Emergent Adverse Events (TEAEs) [Day 1 up to Day 36 (28 days after last treatment)]

   All 15 subjects in the safety population received at least 1 dose of romidepsin. AEs were considered related if assessed by the Investigator as possibly, probably or definitely related to study drug. Serious AEs (SAEs) are those that resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in an important medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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;

1. 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.

2. 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.

3. Major surgery within 2 weeks of study entry (day 1).

4. Concomitant use of any other anti-cancer therapy.

5. Concomitant use of any investigational agent.

6. Prior exposure to romidepsin (other histone deacetylase[HDAC] inhibitors are allowed).

7. 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

1. Subjects who are pregnant or breast-feeding.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Florida Cancer Specialists	Sarasota	Florida	United States	34232
2	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
3	Sarah Cannon Research UK	London		United Kingdom	W1G6AD

Sponsors and Collaborators

• Celgene

Investigators

• Study Director: Ken Takeshita, MD, Celgene Corporation

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT01324310
• Other Study ID Numbers: ROMI-ADVM-001; 2010-022144-20
• First Posted: Mar 29, 2011
• Last Update Posted: Nov 25, 2019
• Last Verified: Nov 1, 2019

• Keywords provided by Celgene: ROMI-001; romi; Romidepsin; Istodax; advanced malignancy; PK; pharmacokinetics
• Additional relevant MeSH terms: Neoplasms; Hematologic Neoplasms; Lymphoma; Ketoconazole; Romidepsin

Study Results

Participant Flow

Recruitment Details	The recruitment period occured over 6 months; the first participant enrolled on 01 July 2011; the last participant completed was 04 Jan 2012; 3 participating sites were involved (2 sites from the US and 1 in the UK); Overall, 15 subjects with advanced cancer were enrolled to ensure there was a minimum of 12 evaluable subjects

Arm/Group Title	Romidepsin and Ketoconazole
Arm/Group 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
Period Title: Overall Study
STARTED	15
COMPLETED	13
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Romidepsin and Ketoconazole
Arm/Group 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
Overall Participants	15
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.8 (11.50)
Sex: Female, Male (Count of Participants)
Female	4 26.7%
Male	11 73.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	15 100%
Unknown or Not Reported	0 0%
Race/Ethnicity, Customized (Number) [Number]
White	12 80%
Asian	2 13.3%
Black or African American	0 0%
Other	1 6.7%
Region of Enrollment (Number) [Number]
United Kingdom	6 40%
United States	9 60%
Height (Centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Centimeters]	174.9 (9.59)
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	78.4 (18.77)
Body Surface Area (BSA) (m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m^2]	1.9 (0.24)
Eastern Cooperative Oncology Group Performance Status (ECOG) (Number) [Number]
0 = Fully Active	7 46.7%
1 = Restricted in physical strenuous activity	8 53.3%
2 = Ambulatory but unable to work	0 0%
3 = Limited Self Care	0 0%
4 = Completely Disabled	0 0%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Assessment on the influence of multiple doses of ketoconazole on the Pharmacokinetic (PK) of romidepsin; the PK population included participants who received at least 1 dose of study drug and had evaluable PK profiles. The reasons for study discontinuation: 1 subject withdrew due to an AE while another subject had disease progression.

Arm/Group Title	Romidepsin Day 1	Romidepsin and Ketoconazole Day 8
Arm/Group Description	Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 1	Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg oral once daily on Days 4-8
Measure Participants	15	13
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	911.0 (76.0)	1020.7 (56.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Romidepsin Day 1, Romidepsin and Ketoconazole Day 8
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric Mean
	Estimated Value	124.4
	Confidence Interval	(2-Sided) 90%; 110.2 to 140.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric means ratio ("Romidepsin + Ketoconazole"/"Romidepsin") and 90% CI of the ratio of geometric means are from an ANOVA model with treatment as fixed effect and subject as random effect on the natural log transformed PK values.

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Assess the influence of multiple doses of ketoconazole on the pharmacokinetic (PK) of romidepsin; the PK population included participants who received at least 1 dose of study drug and had evaluable PK profiles. The reasons for study discontinuation: 1 subject withdrew due to an AE while another subject had disease progression.

Arm/Group Title	Romidepsin Day 1	Romidepsin and Ketoconazole Day 8
Arm/Group Description	Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 1	Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg oral once daily on Days 4-8
Measure Participants	15	13
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	900.1 (76.1)	1002.2 (56.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Romidepsin Day 1, Romidepsin and Ketoconazole Day 8
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the Geometric Mean
	Estimated Value	123.7
	Confidence Interval	(2-Sided) 90%; 109.6 to 139.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Area Under the Plasma Concentration Time-curve From Time 0 Extrapolated to Infinity (AUC0-∞)
Description	AUC0-∞: area under the plasma concentration time-curve from Time 0 extrapolated to infinity, calculated as [AUCt + Ct/λz].
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Assess the influence of multiple doses of ketoconazole on the PK of romidepsin. The PK population included participants who received at least 1 dose of study drug and had evaluable PK profiles. The reasons for study discontinuation: 1 subject withdrew due to an AE while another subject had disease progression.

Arm/Group Title	Romidepsin Day 1	Romidepsin and Ketoconazole Day 8
Arm/Group Description	Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 1	Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg oral once daily on Days 4-8
Measure Participants	15	13
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	915.3 (75.9)	1027.6 (59.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Romidepsin Day 1, Romidepsin and Ketoconazole Day 8
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the Geometric Mean
	Estimated Value	124.6
	Confidence Interval	(2-Sided) 90%; 109.0 to 142.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax)
Description	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
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Assess the influence of multiple doses of ketoconazole on the PK of romidepsin. The PK population included participants who received at least 1 dose of study drug and had evaluable PK profiles. The reasons for study discontinuation: 1 subject withdrew due to an AE while another subject had disease progression.

Arm/Group Title	Romidepsin Day 1	Romidepsin and Ketoconazole Day 8
Arm/Group Description	Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 1	Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg oral once daily on Days 4-8
Measure Participants	15	13
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	229.05 (76.1)	224.79 (45.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Romidepsin Day 1, Romidepsin and Ketoconazole Day 8
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the Geometric Mean
	Estimated Value	109.5
	Confidence Interval	(2-Sided) 90%; 94.9 to 126.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Primary Outcome

Title	Time to Maximum Observed Plasma Concentration (Tmax)
Description	Tmax: time to maximum observed Tmax, obtained directly from the observed concentration versus time data
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Assess the influence of multiple doses of ketoconazole on the PK of romidepsin; the PK population included participants who received at least 1 dose of study drug and had evaluable PK profiles. The reasons for study discontinuation: 1 subject withdrew due to an AE while another subject had disease progression.

Arm/Group Title	Romidepsin Day 1	Romidepsin and Ketoconazole Day 8
Arm/Group Description	Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 1	Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg oral once daily on Days 4-8
Measure Participants	15	13
Median (90% Confidence Interval) [hours]	3.257 (1.98,4.62)	2.992 (0.92,4.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Romidepsin Day 1, Romidepsin and Ketoconazole Day 8
	Comments	Note: The median, median difference ("romidepsin + ketoconazole" minus "romidepsin") and 90% CI of the median difference are from Hodges-Lehmann Estimate. The P-value is from Wilcoxon signed-rank test.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7422
	Comments
	Method	Wilcoxon signed- rank
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0
	Confidence Interval	(2-Sided) 90%; -0.485 to 0.095
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Primary Outcome

Title	Estimate of the Terminal Elimination Half-life in Plasma (t1/2)
Description	Terminal elimination half-life (t1/2) in plasma, was calculated as [(ln 2)/λz]
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Assess the influence of multiple doses of ketoconazole on the PK of romidepsin; the PK population included participants who received at least 1 dose of study drug and had evaluable PK profiles. The reasons for study discontinuation: 1 subject withdrew due to an AE while another subject had disease progression.

Arm/Group Title	Romidepsin Day 1	Romidepsin and Ketoconazole Day 8
Arm/Group Description	Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 1	Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg oral once daily on Days 4-8
Measure Participants	15	13
Geometric Mean (Geometric Coefficient of Variation) [hours]	9.69 (26.4)	10.171 (15.5)

7. Primary Outcome

Title	Apparent Total Plasma Clearance (CL)
Description	Apparent total plasma clearance, (CL) calculated as [Dose/AUC 0-∞].
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Assess the influence of multiple doses of ketoconazole on the PK of romidepsin; the PK population included participants who received at least 1 dose of study drug and had evaluable PK profiles. The reasons for study discontinuation: 1 subject withdrew due to an AE while another subject had disease progression.

Arm/Group Title	Romidepsin Day 1	Romidepsin and Ketoconazole Day 8
Arm/Group Description	Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 1	Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg oral once daily on Days 4-8
Measure Participants	15	13
Geometric Mean (Geometric Coefficient of Variation) [L/hr]	16.922 (77.7)	14.84 (63)

8. Primary Outcome

Title	Apparent Total Volume of Distribution (Vz)
Description	Vz: apparent total volume of distribution, calculated as [(CL)/λz].
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Assess the influence of multiple doses of ketoconazole on the PK of romidepsin; the PK population included participants who received at least 1 dose of study drug and had evaluable PK profiles. The reasons for study discontinuation: 1 subject withdrew due to an AE while another subject had disease progression.

Arm/Group Title	Romidepsin Day 1	Romidepsin and Ketoconazole Day 8
Arm/Group Description	Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 1	Romidepsin 8 mg/m^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg oral once daily on Days 4-8
Measure Participants	15	13
Geometric Mean (Geometric Coefficient of Variation) [Liter]	236.4 (88.7)	217.78 (80.5)

9. Secondary Outcome

Title	Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
Description	All 15 subjects in the safety population received at least 1 dose of romidepsin. AEs were considered related if assessed by the Investigator as possibly, probably or definitely related to study drug. Serious AEs (SAEs) are those that resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in an important medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above.
Time Frame	Day 1 up to Day 36 (28 days after last treatment)

Outcome Measure Data

Analysis Population Description

The safety population consisted of all participants who received at least 1 dose of study drug. The Day 8 analysis population included 13 participants because two participants discontinued from the study prior to Day 8 (one due to an AE, the other due to disease progression).

Arm/Group Title	Romidepsin Plus Ketoconazole
Arm/Group Description	Romidepsin 8 mg/m2 intravenous infused over 4 hours on Day 1 and Day 8. Ketoconazole 400 mg oral once daily on Days 4-8
Measure Participants	15
= > 1 TEAE	15 100%
= > 1 TEAE related to any study drug	14 93.3%
= > 1 TEAE related to Romidepsin	14 93.3%
= > 1 TEAE related to Ketoconazole	4 26.7%
= > 1 Serious TEAE	4 26.7%
= > 1 Serious TEAE related to any drug	1 6.7%
= > 1 Serious TEAE related to Romidepsin	1 6.7%
= > 1 Serious TEAE related to Ketoconazole	0 0%
= > 1 TEAE leading to discontinuation	1 6.7%
= > 1 TEAE related discontinuation due to any drug	0 0%
= > 1 Romidepsin related TEAE discontinuation	0 0%
= > 1 Ketoconazole related TEAE discontinuation	0 0%
Participants who died	3 20%

Adverse Events

Time Frame	Day 1 up to Day 36 (28 days after last treatment)
Arm/Group Title	Romidepsin Plus Ketoconazole
Arm/Group 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
All Cause Mortality
	Romidepsin Plus Ketoconazole
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Romidepsin Plus Ketoconazole
	Affected / at Risk (%)	# Events
Total	4/15 (26.7%)
Cardiac disorders
Atrial Fibrillation	1/15 (6.7%)
General disorders
General Physical Health Deterioration	2/15 (13.3%)
Infections and infestations
Pneumonia	2/15 (13.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bile Duct Cancer	1/15 (6.7%)
Other (Not Including Serious) Adverse Events
	Romidepsin Plus Ketoconazole
	Affected / at Risk (%)	# Events
Total	15/15 (100%)
Blood and lymphatic system disorders
Neutropenia	1/15 (6.7%)
Gastrointestinal disorders
Nausea	11/15 (73.3%)
Vomiting	8/15 (53.3%)
Constipation	3/15 (20%)
Abdominal Pain Upper	2/15 (13.3%)
Diarrhoea	2/15 (13.3%)
Dyspepsia	1/15 (6.7%)
Intestinal Obstruction	1/15 (6.7%)
Retching	1/15 (6.7%)
General disorders
Fatigue	7/15 (46.7%)
Asthenia	2/15 (13.3%)
Chest Discomfort	1/15 (6.7%)
Chills	1/15 (6.7%)
Oedema Peripheral	1/15 (6.7%)
Pyrexia	1/15 (6.7%)
Hepatobiliary disorders
Hyperbilirubinaemia	1/15 (6.7%)
Infections and infestations
Urinary Tract Infection	2/15 (13.3%)
Injury, poisoning and procedural complications
Fall	1/15 (6.7%)
Metabolism and nutrition disorders
Decreased Appetite	8/15 (53.3%)
Hyperkalaemia	1/15 (6.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/15 (13.3%)
Back Pain	1/15 (6.7%)
Musculoskeletal Chest Pain	1/15 (6.7%)
Neck Pain	1/15 (6.7%)
Polyarthritis	1/15 (6.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm Malignant	1/15 (6.7%)
Nervous system disorders
Headache	5/15 (33.3%)
Dysgeusia	2/15 (13.3%)
Dizziness	1/15 (6.7%)
Neuropathy Peripheral	1/15 (6.7%)
Somnolence	1/15 (6.7%)
Psychiatric disorders
Confusional State	1/15 (6.7%)
Depression	1/15 (6.7%)
Mental Status Changes	1/15 (6.7%)
Renal and urinary disorders
Renal Failure Acute	1/15 (6.7%)
Respiratory, thoracic and mediastinal disorders
Cough	1/15 (6.7%)
Oropharyngeal Pain	1/15 (6.7%)
Productive Cough	1/15 (6.7%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/15 (6.7%)
Vascular disorders
Hypotension	1/15 (6.7%)
Phlebitis	1/15 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between the Principal Investigator and the Sponsor that restricts the PIs rights to publish trial results after the trial is completed. Upon investigator submission of a publication to Celgene, Celgene will complete its review within 60 days after receipt of the publication. Upon Celgene's request, the publication shall be delayed up to 90 additional days to enable Celgene to secure intellectual property protection that would be affected by such proposed publication.