Trial Outcomes & Findings for Influence of Rifampin on the Pharmacokinetics of Romidepsin in Patients With Advanced Cancer (NCT NCT01324323)
NCT ID: NCT01324323
Last Updated: 2019-11-25
Results Overview
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.
COMPLETED
PHASE1
14 participants
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.
2019-11-25
Participant Flow
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.
Participant milestones
| Measure |
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
|
|---|---|
|
Overall Study
STARTED
|
14
|
|
Overall Study
COMPLETED
|
13
|
|
Overall Study
NOT COMPLETED
|
1
|
Reasons for withdrawal
| Measure |
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
|
|---|---|
|
Overall Study
Withdrawal by Subject
|
1
|
Baseline Characteristics
Influence of Rifampin on the Pharmacokinetics of Romidepsin in Patients With Advanced Cancer
Baseline characteristics by cohort
| Measure |
Romidepsin and Rifampin
n=14 Participants
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
|
|---|---|
|
Age, Continuous
|
63.6 years
STANDARD_DEVIATION 12.57 • n=93 Participants
|
|
Sex: Female, Male
Female
|
9 Participants
n=93 Participants
|
|
Sex: Female, Male
Male
|
5 Participants
n=93 Participants
|
|
Race/Ethnicity, Customized
White
|
13 Participants
n=93 Participants
|
|
Race/Ethnicity, Customized
Black or African American
|
1 Participants
n=93 Participants
|
|
Race/Ethnicity, Customized
Other
|
0 Participants
n=93 Participants
|
|
Race/Ethnicity, Customized
Hispanic or Latino
|
0 Participants
n=93 Participants
|
|
Race/Ethnicity, Customized
Not Hispanic or Latino
|
14 Participants
n=93 Participants
|
|
Race/Ethnicity, Customized
Unknown or Not Reported
|
0 Participants
n=93 Participants
|
|
Region of Enrollment
United Kingdom
|
5 participants
n=93 Participants
|
|
Region of Enrollment
United States
|
9 participants
n=93 Participants
|
|
Height
|
167.6 Centimeters
STANDARD_DEVIATION 9.54 • n=93 Participants
|
|
Weight
|
78.2 kilograms
STANDARD_DEVIATION 18.85 • n=93 Participants
|
|
Body Surface Area (BSA)
|
1.9 Metered Squares m^2
STANDARD_DEVIATION 0.22 • n=93 Participants
|
|
Eastern Cooperative Oncology Group Performance Status (ECOG)
0 = Fully active
|
7 Participants
n=93 Participants
|
|
Eastern Cooperative Oncology Group Performance Status (ECOG)
1 = Restricted in physical strenuous activity
|
7 Participants
n=93 Participants
|
|
Eastern Cooperative Oncology Group Performance Status (ECOG)
2 = Ambulaotry but unable to work
|
0 Participants
n=93 Participants
|
|
Eastern Cooperative Oncology Group Performance Status (ECOG)
3 = Limited Self-Care
|
0 Participants
n=93 Participants
|
|
Eastern Cooperative Oncology Group Performance Status (ECOG)
4 = Completely Disabled
|
0 Participants
n=93 Participants
|
PRIMARY outcome
Timeframe: 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.Population: 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.
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.
Outcome measures
| Measure |
Romidepsin Day 1
n=14 Participants
Romidepsin 14 mg/m\^2 intravenous infused over 4 hours on Day 1 and Day 8.
|
Romidepsin and Rifampin Day 8
n=13 Participants
Romidepsin 14mg/m\^2 intravenous infused over 4 hours on Day 8. Rifampin 600mg oral once daily on Days 4-8.
|
|---|---|---|
|
Area Under the Plasma Concentration Time-curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-t)of Romidepsin
|
2225.1 ng*hr/mL
Geometric Coefficient of Variation 71.4
|
3966.3 ng*hr/mL
Geometric Coefficient of Variation 76.5
|
PRIMARY outcome
Timeframe: 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.Population: 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.
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.
Outcome measures
| Measure |
Romidepsin Day 1
n=14 Participants
Romidepsin 14 mg/m\^2 intravenous infused over 4 hours on Day 1 and Day 8.
|
Romidepsin and Rifampin Day 8
n=13 Participants
Romidepsin 14mg/m\^2 intravenous infused over 4 hours on Day 8. Rifampin 600mg oral once daily on Days 4-8.
|
|---|---|---|
|
Area Under the Plasma Concentration Time-curve From Time 0 to 24-hour (AUC0-24) for Romidepsin
|
2204.2 ng*hr/mL
Geometric Coefficient of Variation 72.0
|
3903.9 ng*hr/mL
Geometric Coefficient of Variation 78.0
|
PRIMARY outcome
Timeframe: 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.Population: 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.
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.
Outcome measures
| Measure |
Romidepsin Day 1
n=14 Participants
Romidepsin 14 mg/m\^2 intravenous infused over 4 hours on Day 1 and Day 8.
|
Romidepsin and Rifampin Day 8
n=13 Participants
Romidepsin 14mg/m\^2 intravenous infused over 4 hours on Day 8. Rifampin 600mg oral once daily on Days 4-8.
|
|---|---|---|
|
Area Under the Plasma Concentration Time-curve From Time Zero Extrapolated to Infinity (AUC0-∞).
|
2229.8 ng*hr/mL
Geometric Coefficient of Variation 71.3
|
3980.7 ng*hr/mL
Geometric Coefficient of Variation 76.1
|
PRIMARY outcome
Timeframe: 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.Population: 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.
Maximum observed plasma concentration (Cmax)was obtained directly from the observed concentration versus time data.
Outcome measures
| Measure |
Romidepsin Day 1
n=14 Participants
Romidepsin 14 mg/m\^2 intravenous infused over 4 hours on Day 1 and Day 8.
|
Romidepsin and Rifampin Day 8
n=13 Participants
Romidepsin 14mg/m\^2 intravenous infused over 4 hours on Day 8. Rifampin 600mg oral once daily on Days 4-8.
|
|---|---|---|
|
Maximum Observed Plasma Concentration (Cmax)of Romidepsin
|
571.2 ng/mL
Geometric Coefficient of Variation 81.0
|
900.1 ng/mL
Geometric Coefficient of Variation 104.9
|
PRIMARY outcome
Timeframe: 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.Population: 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.
Time to maximum observed plasma concentration (Tmax) was obtained directly from the observed concentration versus time data.
Outcome measures
| Measure |
Romidepsin Day 1
n=14 Participants
Romidepsin 14 mg/m\^2 intravenous infused over 4 hours on Day 1 and Day 8.
|
Romidepsin and Rifampin Day 8
n=13 Participants
Romidepsin 14mg/m\^2 intravenous infused over 4 hours on Day 8. Rifampin 600mg oral once daily on Days 4-8.
|
|---|---|---|
|
Time to Maximum Observed Plasma Concentration (Tmax)
|
3.0 hours
Full Range 51.5 • Interval 1.0 to 5.0
|
3.00 hours
Full Range 50.7 • Interval 1.0 to 4.27
|
PRIMARY outcome
Timeframe: 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.Population: 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.
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.
Outcome measures
| Measure |
Romidepsin Day 1
n=14 Participants
Romidepsin 14 mg/m\^2 intravenous infused over 4 hours on Day 1 and Day 8.
|
Romidepsin and Rifampin Day 8
n=13 Participants
Romidepsin 14mg/m\^2 intravenous infused over 4 hours on Day 8. Rifampin 600mg oral once daily on Days 4-8.
|
|---|---|---|
|
Estimate of the Terminal Elimination Half-life in Plasma (t1/2)
|
9.666 hours
Geometric Coefficient of Variation 27.9
|
8.341 hours
Geometric Coefficient of Variation 24.0
|
PRIMARY outcome
Timeframe: 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.Population: 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.
The apparent total plasma clearance (CL) was calculated as \[Dose/AUC0-∞\] for Romidepsin alone and co-administered with rifampin plasma concentrations.
Outcome measures
| Measure |
Romidepsin Day 1
n=14 Participants
Romidepsin 14 mg/m\^2 intravenous infused over 4 hours on Day 1 and Day 8.
|
Romidepsin and Rifampin Day 8
n=13 Participants
Romidepsin 14mg/m\^2 intravenous infused over 4 hours on Day 8. Rifampin 600mg oral once daily on Days 4-8.
|
|---|---|---|
|
Clearance (CL): Apparent Total Plasma Clearance.
|
11.59 L/hr
Geometric Coefficient of Variation 78.1
|
6.45 L/hr
Geometric Coefficient of Variation 82.2
|
PRIMARY outcome
Timeframe: 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.Population: The PK population was to consist of all participants who received at least 1 dose of study drug and had evaluable PK profiles.
Apparent total volume of distribution (Vz) was calculated as \[(CL)/λz\] for Romidepsin and co-administered with Rifampin.
Outcome measures
| Measure |
Romidepsin Day 1
n=14 Participants
Romidepsin 14 mg/m\^2 intravenous infused over 4 hours on Day 1 and Day 8.
|
Romidepsin and Rifampin Day 8
n=13 Participants
Romidepsin 14mg/m\^2 intravenous infused over 4 hours on Day 8. Rifampin 600mg oral once daily on Days 4-8.
|
|---|---|---|
|
Apparent Total Volume of Distribution (Vz).
|
161.48 Liters
Geometric Coefficient of Variation 78.6
|
77.6 Liters
Geometric Coefficient of Variation 93.8
|
SECONDARY outcome
Timeframe: Day 1 up to Day 36 (28 days after the last treatment)Population: The safety population included all subjects who received at least 1 dose of study drug.
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.
Outcome measures
| Measure |
Romidepsin Day 1
n=14 Participants
Romidepsin 14 mg/m\^2 intravenous infused over 4 hours on Day 1 and Day 8.
|
Romidepsin and Rifampin Day 8
Romidepsin 14mg/m\^2 intravenous infused over 4 hours on Day 8. Rifampin 600mg oral once daily on Days 4-8.
|
|---|---|---|
|
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 TEAE related to any study drug
|
13 participants
|
—
|
|
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 TEAE leading to discontinuation
|
0 participants
|
—
|
|
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 TEAE related discontinuation to any drug
|
0 participants
|
—
|
|
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 Romidepsin related TEAE discontinuation
|
0 participants
|
—
|
|
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 TEAE related to Romidepsin
|
13 participants
|
—
|
|
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 Rifampin related TEAE discontinuation
|
0 participants
|
—
|
|
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 TEAE related to Rifampin
|
2 participants
|
—
|
|
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 Serious TEAE
|
2 participants
|
—
|
|
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 Serious TEAE related to any drug
|
1 participants
|
—
|
|
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 Serious TEAE related to Romidepsin
|
1 participants
|
—
|
|
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 Serious TEAE related to Rifampin
|
1 participants
|
—
|
|
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 TEAE
|
13 participants
|
—
|
|
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
Participants who died
|
0 participants
|
—
|
Adverse Events
Romidepsin Plus Rifampin
Serious adverse events
| Measure |
Romidepsin Plus Rifampin
n=14 participants at risk
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.
|
|---|---|
|
Blood and lymphatic system disorders
Anaemia
|
14.3%
2/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Gastrointestinal disorders
Vomiting
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
General disorders
Fatigue
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Gastrointestinal disorders
Nausea
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Blood and lymphatic system disorders
Thrombocytopenia
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Gastrointestinal disorders
Melaena
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
Other adverse events
| Measure |
Romidepsin Plus Rifampin
n=14 participants at risk
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.
|
|---|---|
|
Gastrointestinal disorders
Nausea
|
71.4%
10/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Gastrointestinal disorders
Vomiting
|
42.9%
6/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Gastrointestinal disorders
Diarrhoea
|
35.7%
5/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Gastrointestinal disorders
Constipation
|
14.3%
2/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Gastrointestinal disorders
Abdominal Pain
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Gastrointestinal disorders
Abdominal Pain Upper
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Gastrointestinal disorders
Flatulence
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Gastrointestinal disorders
Gastrooesophageal Reflux Disease
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
General disorders
Fatigue
|
42.9%
6/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
General disorders
Asthenia
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
General disorders
Malaise
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
General disorders
Non-Cardiac Chest Pain
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Blood and lymphatic system disorders
Thrombocytopenia
|
35.7%
5/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Blood and lymphatic system disorders
Anaemia
|
21.4%
3/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Metabolism and nutrition disorders
Decreased Appetite
|
42.9%
6/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Metabolism and nutrition disorders
Hypokalaemia
|
14.3%
2/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
14.3%
2/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Musculoskeletal and connective tissue disorders
Musculoskeletal Discomfort
|
14.3%
2/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain
|
14.3%
2/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Musculoskeletal and connective tissue disorders
Back Pain
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Musculoskeletal and connective tissue disorders
Musculoskeletal Chest Pain
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Nervous system disorders
Dysgeusia
|
14.3%
2/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Nervous system disorders
Dizziness
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Nervous system disorders
Lethargy
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Psychiatric disorders
Anxiety
|
21.4%
3/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Psychiatric disorders
Insomnia
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Respiratory, thoracic and mediastinal disorders
Oropharyngeal Pain
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Skin and subcutaneous tissue disorders
Decubitus Ulcer
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
|
Gastrointestinal disorders
Haemorrhoids
|
7.1%
1/14 • Day 1 up to Day 36 (28 days after last treatment)
|
Additional Information
Senior Manager, Clinical Trials Disclosure
Celgene Corporation
Results disclosure agreements
- Principal investigator is a sponsor employee 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
- Publication restrictions are in place
Restriction type: OTHER