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

• Sponsor: Celgene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01324323
• Collaborator: (none)
• Enrollment: 14
• Locations: 3
• Arm: 1
• Actual Duration (Months): 11
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 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 Rifampin on the Single Dose Pharmacokinetics of Romidepsin in Subjects With Advanced Cancer
• Actual Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Romidepsin and rifampin Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 1 and Day 8. Rifampin 600 mg oral once daily on Days 4-8	Drug: Romidepsin; 14 mg/m^2 intravenous infused over 4 hours on Day 1 and Day 8.; Other Names: Istodax®, Romi, ROMI ; Drug: Rifampin; 600 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.

2. Area Under the Plasma Concentration Time-curve From Time 0 to 24-hour (AUC0-24) for Romidepsin [Day 1 and Day 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.]

   Individual and mean romidepsin plasma concentrations by treatment and scheduled time data were collected. AUC0-24: 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.

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

   AUC0-∞: area under the plasma concentration time-curve from Time 0 extrapolated to infinity, calculated as [AUCt + Ct/λz]. λz is the apparent terminal rate constant. No AUC extrapolation was performed with unreliable λz. If the percentage of AUC extrapolated is ≥ 25%, AUC0-∞ will not be reported.

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

   Maximum observed plasma concentration (Cmax)was obtained directly from the observed concentration versus time data.

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

   Time to maximum observed plasma concentration (Tmax) was 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 (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.]

   The terminal elimination half-life (t1/2) in plasma, was calculated as [(ln 2)/λz]. This was only calculated when a reliable estimate for λz could be obtained.

7. Clearance (CL): Apparent Total Plasma Clearance. [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.]

   The apparent total plasma clearance (CL) was calculated as [Dose/AUC0-∞] for Romidepsin alone and co-administered with rifampin plasma concentrations.

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.]

   Apparent total volume of distribution (Vz) was calculated as [(CL)/λz] for Romidepsin and co-administered with Rifampin.

Secondary Outcome Measures

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

   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 Canon 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: NCT01324323
• Other Study ID Numbers: ROMI-ADVM-002; 2010-022149-75
• 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; Rifampin; Romidepsin

Study Results

Participant Flow

Recruitment Details	The study was conducted at 3 study centers (2 in the United States and 1 in the United Kingdom). The first subject was enrolled in April 2011 and the last subject completed the study in Feb 2012.

Arm/Group Title	Romidepsin and Rifampin
Arm/Group Description	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 1 and Day 8. Rifampin 600 mg oral once daily on Days 4-8
Period Title: Overall Study
STARTED	14
COMPLETED	13
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Romidepsin and Rifampin
Arm/Group Description	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 1 and Day 8. Rifampin 600 mg oral once daily on Days 4-8
Overall Participants	14
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.6 (12.57)
Sex: Female, Male (Count of Participants)
Female	9 64.3%
Male	5 35.7%
Race/Ethnicity, Customized (Number) [Number]
White	13 92.9%
Black or African American	1 7.1%
Other	0 0%
Race/Ethnicity, Customized (Number) [Number]
Hispanic or Latino	0 0%
Not Hispanic or Latino	14 100%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United Kingdom	5 35.7%
United States	9 64.3%
Height (Centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Centimeters]	167.6 (9.54)
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	78.2 (18.85)
Body Surface Area (BSA) (Metered Squares m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Metered Squares m^2]	1.9 (0.22)
Eastern Cooperative Oncology Group Performance Status (ECOG) (Number) [Number]
0 = Fully active	7 50%
1 = Restricted in physical strenuous activity	7 50%
2 = Ambulaotry 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.
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

The PK population included all participants who received at least 1 dose of study drug and had evaluable PK profiles. The primary reason for study discontinuation for the 1 participant was due to withdrawal of consent.

Arm/Group Title	Romidepsin Day 1	Romidepsin and Rifampin Day 8
Arm/Group Description	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 1 and Day 8.	Romidepsin 14mg/m^2 intravenous infused over 4 hours on Day 8. Rifampin 600mg oral once daily on Days 4-8.
Measure Participants	14	13
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	2225.1 (71.4)	3966.3 (76.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Romidepsin Day 1, Romidepsin and Rifampin 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	179.3
	Confidence Interval	(2-Sided) 90%; 160.3 to 200.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio ("Romidepsin + rifampin"/"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 (AUC0-24) for Romidepsin
Description	Individual and mean romidepsin plasma concentrations by treatment and scheduled time data were collected. AUC0-24: 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.
Time Frame	Day 1 and Day 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

The PK population included all participants who received at least 1 dose of study drug and had evaluable PK profiles. The primary reason for study discontinuation for the 1 participant was due to withdrawal of consent.

Arm/Group Title	Romidepsin Day 1	Romidepsin and Rifampin Day 8
Arm/Group Description	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 1. Rifampin 600 mg oral once daily on Days 4-8	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 8. Rifampin 600 mg oral once daily on Days 4-8
Measure Participants	14	13
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	2204.2 (72.0)	3903.9 (78.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Romidepsin Day 1, Romidepsin and Rifampin 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	178.3
	Confidence Interval	(2-Sided) 90%; 159.4 to 199.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio ("Romidepsin + rifampin"/"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.

3. Primary Outcome

Title	Area Under the Plasma Concentration Time-curve From Time Zero Extrapolated to Infinity (AUC0-∞).
Description	AUC0-∞: area under the plasma concentration time-curve from Time 0 extrapolated to infinity, calculated as [AUCt + Ct/λz]. λz is the apparent terminal rate constant. No AUC extrapolation was performed with unreliable λz. If the percentage of AUC extrapolated is ≥ 25%, AUC0-∞ will not be reported.
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

The primary objective was to assess the influence of multiple doses of rifampin on the PK of romidepsin. The PK population included all participants who received at least 1 dose of study drug and had evaluable PK profiles. The primary reason for study discontinuation for the 1 participant was due to withdrawal of consent.

Arm/Group Title	Romidepsin Day 1	Romidepsin and Rifampin Day 8
Arm/Group Description	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 1	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 8. Rifampin 600 mg oral once daily on Days 4-8.
Measure Participants	14	13
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	2229.8 (71.3)	3980.7 (76.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Romidepsin Day 1, Romidepsin and Rifampin 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	179.6
	Confidence Interval	(2-Sided) 90%; 160.5 to 201.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio ("Romidepsin + rifampin"/"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.

4. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax)of Romidepsin
Description	Maximum observed plasma concentration (Cmax)was obtained directly from the observed concentration versus time data.
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

The primary objective was to assess the influence of multiple doses of rifampin on the PK of romidepsin. The PK population included all participants who received at least 1 dose of study drug and had evaluable PK profiles. The primary reason for study discontinuation for the 1 participant was due to withdrawal of consent.

Arm/Group Title	Romidepsin Day 1	Romidepsin and Rifampin Day 8
Arm/Group Description	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 1.	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 8. Rifampin 600mg oral once daily on Days 4-8
Measure Participants	14	13
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	571.2 (81.0)	900.1 (104.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Romidepsin Day 1, Romidepsin and Rifampin 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	159.1
	Confidence Interval	(2-Sided) 90%; 135.8 to 186.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio ("Romidepsin + rifampin"/"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.

5. Primary Outcome

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

The primary objective was to assess the influence of multiple doses of rifampin on the PK of romidepsin. The PK population included all participants who received at least 1 dose of study drug and had evaluable PK profiles. The primary reason for study discontinuation for the 1 participant was due to withdrawal of consent.

Arm/Group Title	Romidepsin Day 1	Romidepsin and Rifampin Day 8
Arm/Group Description	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 1.	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 8. Rifampin 600 mg oral once daily on Days 4-8
Measure Participants	14	13
Median (Full Range) [hours]	3.0 (51.5)	3.00 (50.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Romidepsin Day 1, Romidepsin and Rifampin Day 8
	Comments	Note: The median, median difference ("romidepsin + rifampin" 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	0.7910
	Comments
	Method	Wilcoxon signed-rank
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 90%; -1.0 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Primary Outcome

Title	Estimate of the Terminal Elimination Half-life in Plasma (t1/2)
Description	The terminal elimination half-life (t1/2) in plasma, was calculated as [(ln 2)/λz]. This was only calculated when a reliable estimate for λz could be obtained.
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

The primary objective was to assess the influence of multiple doses of rifampin on the PK of romidepsin. The PK population included all participants who received at least 1 dose of study drug and had evaluable PK profiles. The primary reason for study discontinuation for the 1 participant was due to withdrawal of consent.

Arm/Group Title	Romidepsin Day 1	Romidepsin and Rifampin Day 8
Arm/Group Description	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 1.	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 8. Rifampin 600 mg oral once daily on Days 4-8
Measure Participants	14	13
Geometric Mean (Geometric Coefficient of Variation) [hours]	9.666 (27.9)	8.341 (24.0)

7. Primary Outcome

Title	Clearance (CL): Apparent Total Plasma Clearance.
Description	The apparent total plasma clearance (CL) was calculated as [Dose/AUC0-∞] for Romidepsin alone and co-administered with rifampin plasma concentrations.
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

The primary objective was to assess the influence of multiple doses of rifampin on the PK of romidepsin. The PK population included all participants who received at least 1 dose of study drug and had evaluable PK profiles. The primary reason for study discontinuation for the 1 participant was due to withdrawal of consent.

Arm/Group Title	Romidepsin Day 1	Romidepsin and Rifampin Day 8
Arm/Group Description	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 1.	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 8. Rifampin 600 mg oral once daily on Days 4-8
Measure Participants	14	13
Geometric Mean (Geometric Coefficient of Variation) [L/hr]	11.59 (78.1)	6.45 (82.2)

8. Primary Outcome

Title	Apparent Total Volume of Distribution (Vz).
Description	Apparent total volume of distribution (Vz) was calculated as [(CL)/λz] for Romidepsin and co-administered with Rifampin.
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

The PK population was to consist of all participants who received at least 1 dose of study drug and had evaluable PK profiles.

Arm/Group Title	Romidepsin Day 1	Romidepsin and Rifampin Day 8
Arm/Group Description	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 1.	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 8. Rifampin 600 mg oral once daily on Days 4-8
Measure Participants	14	13
Geometric Mean (Geometric Coefficient of Variation) [Liters]	161.48 (78.6)	77.6 (93.8)

9. Secondary Outcome

Title	Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
Description	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 the last treatment)

Outcome Measure Data

Analysis Population Description

The safety population included all subjects who received at least 1 dose of study drug.

Arm/Group Title	Romidepsin Plus Rifampin
Arm/Group Description	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Days 1 and 8. Rifampin 600 mg oral once daily on Days 4-8
Measure Participants	14
= > 1 TEAE	13 92.9%
= > 1 TEAE related to any study drug	13 92.9%
= > 1 TEAE related to Romidepsin	13 92.9%
= > 1 TEAE related to Rifampin	2 14.3%
= > 1 Serious TEAE	2 14.3%
= > 1 Serious TEAE related to any drug	1 7.1%
= > 1 Serious TEAE related to Romidepsin	1 7.1%
= > 1 Serious TEAE related to Rifampin	1 7.1%
= > 1 TEAE leading to discontinuation	0 0%
= > 1 TEAE related discontinuation to any drug	0 0%
= > 1 Romidepsin related TEAE discontinuation	0 0%
= > 1 Rifampin related TEAE discontinuation	0 0%
Participants who died	0 0%

Adverse Events

Time Frame	Day 1 up to Day 36 (28 days after last treatment)
Arm/Group Title	Romidepsin Plus Rifampin
Arm/Group Description	Romidepsin 14 mg/m^2 intravenous infused over 4 hours on Day 1 and Day 8 and Rifampin 600 mg oral once daily on Days 4-8.
All Cause Mortality
	Romidepsin Plus Rifampin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Romidepsin Plus Rifampin
	Affected / at Risk (%)	# Events
Total	2/14 (14.3%)
Blood and lymphatic system disorders
Anaemia	2/14 (14.3%)
Thrombocytopenia	1/14 (7.1%)
Gastrointestinal disorders
Vomiting	1/14 (7.1%)
Nausea	1/14 (7.1%)
Melaena	1/14 (7.1%)
General disorders
Fatigue	1/14 (7.1%)
Other (Not Including Serious) Adverse Events
	Romidepsin Plus Rifampin
	Affected / at Risk (%)	# Events
Total	13/14 (92.9%)
Blood and lymphatic system disorders
Thrombocytopenia	5/14 (35.7%)
Anaemia	3/14 (21.4%)
Gastrointestinal disorders
Nausea	10/14 (71.4%)
Vomiting	6/14 (42.9%)
Diarrhoea	5/14 (35.7%)
Constipation	2/14 (14.3%)
Abdominal Pain	1/14 (7.1%)
Abdominal Pain Upper	1/14 (7.1%)
Flatulence	1/14 (7.1%)
Gastrooesophageal Reflux Disease	1/14 (7.1%)
Haemorrhoids	1/14 (7.1%)
General disorders
Fatigue	6/14 (42.9%)
Asthenia	1/14 (7.1%)
Malaise	1/14 (7.1%)
Non-Cardiac Chest Pain	1/14 (7.1%)
Metabolism and nutrition disorders
Decreased Appetite	6/14 (42.9%)
Hypokalaemia	2/14 (14.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/14 (14.3%)
Musculoskeletal Discomfort	2/14 (14.3%)
Musculoskeletal Pain	2/14 (14.3%)
Back Pain	1/14 (7.1%)
Musculoskeletal Chest Pain	1/14 (7.1%)
Nervous system disorders
Dysgeusia	2/14 (14.3%)
Dizziness	1/14 (7.1%)
Lethargy	1/14 (7.1%)
Psychiatric disorders
Anxiety	3/14 (21.4%)
Insomnia	1/14 (7.1%)
Respiratory, thoracic and mediastinal disorders
Cough	1/14 (7.1%)
Dyspnoea	1/14 (7.1%)
Oropharyngeal Pain	1/14 (7.1%)
Skin and subcutaneous tissue disorders
Decubitus Ulcer	1/14 (7.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Upon investigator submission of a publication or presentation to Celgene, Celgene shall complete its review within 60 days after receipt of the proposed publication or presentation. Upon Celgene's request, proposed publication or presentation will be delayed up to 60 additional days to enable Celgene to secure adequate intellectual property protection of property of Celgene that would be affected by such proposed publication or presentation