Trial Outcomes & Findings for Influence of Ketoconazole on the Pharmacokinetics of Romidepsin in Patients With Advanced Cancer (NCT NCT01324310)

NCT ID: NCT01324310

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. 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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

15 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.

Results posted on

2019-11-25

Participant Flow

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

Participant milestones

Participant milestones
Measure
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
Overall Study
STARTED
15
Overall Study
COMPLETED
13
Overall Study
NOT COMPLETED
2

Reasons for withdrawal

Reasons for withdrawal
Measure
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
Overall Study
Adverse Event
1
Overall Study
Disease Progression
1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure
Romidepsin and Ketoconazole
n=15 Participants
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
Age, Continuous
61.8 years
STANDARD_DEVIATION 11.50 • n=99 Participants
Sex: Female, Male
Female
4 Participants
n=99 Participants
Sex: Female, Male
Male
11 Participants
n=99 Participants
Ethnicity (NIH/OMB)
Hispanic or Latino
0 Participants
n=99 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
15 Participants
n=99 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
0 Participants
n=99 Participants
Race/Ethnicity, Customized
White
12 Participants
n=99 Participants
Race/Ethnicity, Customized
Asian
2 Participants
n=99 Participants
Race/Ethnicity, Customized
Black or African American
0 Participants
n=99 Participants
Race/Ethnicity, Customized
Other
1 Participants
n=99 Participants
Region of Enrollment
United Kingdom
6 Participants
n=99 Participants
Region of Enrollment
United States
9 Participants
n=99 Participants
Height
174.9 Centimeters
STANDARD_DEVIATION 9.59 • n=99 Participants
Weight
78.4 kilograms
STANDARD_DEVIATION 18.77 • n=99 Participants
Body Surface Area (BSA)
1.9 m^2
STANDARD_DEVIATION 0.24 • n=99 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG)
0 = Fully Active
7 Participants
n=99 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG)
1 = Restricted in physical strenuous activity
8 Participants
n=99 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG)
2 = Ambulatory but unable to work
0 Participants
n=99 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG)
3 = Limited Self Care
0 Participants
n=99 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG)
4 = Completely Disabled
0 Participants
n=99 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: 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.

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.

Outcome measures

Outcome measures
Measure
Romidepsin Day 1
n=15 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 1
Romidepsin and Ketoconazole Day 8
n=13 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg 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
911.0 ng*hr/mL
Geometric Coefficient of Variation 76.0
1020.7 ng*hr/mL
Geometric Coefficient of Variation 56.4

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: 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.

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

Outcome measures

Outcome measures
Measure
Romidepsin Day 1
n=15 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 1
Romidepsin and Ketoconazole Day 8
n=13 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg oral once daily on Days 4-8
Area Under the Plasma Concentration Time-curve From Time 0 to 24-hour (AUC 0-24)
900.1 ng*hr/mL
Geometric Coefficient of Variation 76.1
1002.2 ng*hr/mL
Geometric Coefficient of Variation 56.2

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: 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.

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

Outcome measures

Outcome measures
Measure
Romidepsin Day 1
n=15 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 1
Romidepsin and Ketoconazole Day 8
n=13 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg oral once daily on Days 4-8
Area Under the Plasma Concentration Time-curve From Time 0 Extrapolated to Infinity (AUC0-∞)
915.3 ng*hr/mL
Geometric Coefficient of Variation 75.9
1027.6 ng*hr/mL
Geometric Coefficient of Variation 59.3

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: 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.

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

Outcome measures

Outcome measures
Measure
Romidepsin Day 1
n=15 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 1
Romidepsin and Ketoconazole Day 8
n=13 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg oral once daily on Days 4-8
Maximum Observed Plasma Concentration (Cmax)
229.05 ng/mL
Geometric Coefficient of Variation 76.1
224.79 ng/mL
Geometric Coefficient of Variation 45.2

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: 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.

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

Outcome measures

Outcome measures
Measure
Romidepsin Day 1
n=15 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 1
Romidepsin and Ketoconazole Day 8
n=13 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg oral once daily on Days 4-8
Time to Maximum Observed Plasma Concentration (Tmax)
3.257 hours
90% Confidence Interval 1.98,4.62 • Interval 1.98 to 4.62
2.992 hours
90% Confidence Interval 0.92,4.50 • Interval 0.93 to 4.5

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: 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.

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

Outcome measures

Outcome measures
Measure
Romidepsin Day 1
n=15 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 1
Romidepsin and Ketoconazole Day 8
n=13 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg oral once daily on Days 4-8
Estimate of the Terminal Elimination Half-life in Plasma (t1/2)
9.69 hours
Geometric Coefficient of Variation 26.4
10.171 hours
Geometric Coefficient of Variation 15.5

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: 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.

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

Outcome measures

Outcome measures
Measure
Romidepsin Day 1
n=15 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 1
Romidepsin and Ketoconazole Day 8
n=13 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg oral once daily on Days 4-8
Apparent Total Plasma Clearance (CL)
16.922 L/hr
Geometric Coefficient of Variation 77.7
14.84 L/hr
Geometric Coefficient of Variation 63

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: 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.

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

Outcome measures

Outcome measures
Measure
Romidepsin Day 1
n=15 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 1
Romidepsin and Ketoconazole Day 8
n=13 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg oral once daily on Days 4-8
Apparent Total Volume of Distribution (Vz)
236.4 Liter
Geometric Coefficient of Variation 88.7
217.78 Liter
Geometric Coefficient of Variation 80.5

SECONDARY outcome

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

Population: 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).

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.

Outcome measures

Outcome measures
Measure
Romidepsin Day 1
n=15 Participants
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 1
Romidepsin and Ketoconazole Day 8
Romidepsin 8 mg/m\^2 intravenous infused over 4 hours on Day 8; Ketoconazole 400 mg oral once daily on Days 4-8
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 TEAE related discontinuation due to any drug
0 participants
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 TEAE
15 participants
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 TEAE related to any study drug
14 participants
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 TEAE related to Romidepsin
14 participants
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 TEAE related to Ketoconazole
4 participants
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 Serious TEAE
4 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 Ketoconazole
0 participants
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
= > 1 TEAE leading to discontinuation
1 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 Ketoconazole related TEAE discontinuation
0 participants
Summary of Participants With Treatment Emergent Adverse Events (TEAEs)
Participants who died
3 participants

Adverse Events

Romidepsin Plus Ketoconazole

Serious events: 4 serious events
Other events: 15 other events
Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure
Romidepsin Plus Ketoconazole
n=15 participants at risk
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
General disorders
General Physical Health Deterioration
13.3%
2/15 • Day 1 up to Day 36 (28 days after last treatment)
Infections and infestations
Pneumonia
13.3%
2/15 • Day 1 up to Day 36 (28 days after last treatment)
Cardiac disorders
Atrial Fibrillation
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bile Duct Cancer
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)

Other adverse events

Other adverse events
Measure
Romidepsin Plus Ketoconazole
n=15 participants at risk
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
Gastrointestinal disorders
Nausea
73.3%
11/15 • Day 1 up to Day 36 (28 days after last treatment)
Gastrointestinal disorders
Vomiting
53.3%
8/15 • Day 1 up to Day 36 (28 days after last treatment)
Gastrointestinal disorders
Constipation
20.0%
3/15 • Day 1 up to Day 36 (28 days after last treatment)
Gastrointestinal disorders
Abdominal Pain Upper
13.3%
2/15 • Day 1 up to Day 36 (28 days after last treatment)
Gastrointestinal disorders
Diarrhoea
13.3%
2/15 • Day 1 up to Day 36 (28 days after last treatment)
Gastrointestinal disorders
Dyspepsia
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Gastrointestinal disorders
Intestinal Obstruction
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Gastrointestinal disorders
Retching
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
General disorders
Fatigue
46.7%
7/15 • Day 1 up to Day 36 (28 days after last treatment)
General disorders
Asthenia
13.3%
2/15 • Day 1 up to Day 36 (28 days after last treatment)
General disorders
Chest Discomfort
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
General disorders
Chills
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
General disorders
Oedema Peripheral
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
General disorders
Pyrexia
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Metabolism and nutrition disorders
Decreased Appetite
53.3%
8/15 • Day 1 up to Day 36 (28 days after last treatment)
Metabolism and nutrition disorders
Hyperkalaemia
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Nervous system disorders
Headache
33.3%
5/15 • Day 1 up to Day 36 (28 days after last treatment)
Nervous system disorders
Dysgeusia
13.3%
2/15 • Day 1 up to Day 36 (28 days after last treatment)
Nervous system disorders
Dizziness
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Nervous system disorders
Neuropathy Peripheral
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Nervous system disorders
Somnolence
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Musculoskeletal and connective tissue disorders
Arthralgia
13.3%
2/15 • Day 1 up to Day 36 (28 days after last treatment)
Musculoskeletal and connective tissue disorders
Back Pain
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Musculoskeletal and connective tissue disorders
Musculoskeletal Chest Pain
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Musculoskeletal and connective tissue disorders
Neck Pain
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Musculoskeletal and connective tissue disorders
Polyarthritis
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Psychiatric disorders
Confusional State
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Psychiatric disorders
Depression
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Psychiatric disorders
Mental Status Changes
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Infections and infestations
Urinary Tract Infection
13.3%
2/15 • Day 1 up to Day 36 (28 days after last treatment)
Respiratory, thoracic and mediastinal disorders
Cough
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal Pain
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Respiratory, thoracic and mediastinal disorders
Productive Cough
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Vascular disorders
Hypotension
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Vascular disorders
Phlebitis
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Blood and lymphatic system disorders
Neutropenia
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Hepatobiliary disorders
Hyperbilirubinaemia
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Injury, poisoning and procedural complications
Fall
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm Malignant
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Renal and urinary disorders
Renal Failure Acute
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)
Skin and subcutaneous tissue disorders
Hyperhidrosis
6.7%
1/15 • Day 1 up to Day 36 (28 days after last treatment)

Additional Information

Senior Manager

Celgene Corporation

Phone: 1-888-260-1599

Results disclosure agreements

  • Principal investigator is a sponsor employee 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.
  • Publication restrictions are in place

Restriction type: OTHER