Lymphoma, T-cell, Peripheral
Conditions
Brief summary
The purpose of the study was to assess efficacy, tolerability, safety and pharmacokinetics of Romidepsin in subjects with progressive or relapsed peripheral T-cell lymphoma
Detailed description
This is a Phase 1/2, non-randomized, open-label, single-arm trial with two phases. The first phase is a 3 + 3 dose escalation phase to determine a recommended dose for treating patients with Peripheral T-Cell Lymphoma (PTCL) or Cutaneous T-Cell Lymphoma (CTCL) based on the assessment of Dose Limiting Toxicities (DLTs).The second phase will assess efficacy at the recommended dose by measuring objective response \[Complete Response (CR), Unconfirmed Complete Response (CR(u)) or Partial Response (PR)\] and determining best overall response of each patient. Phase 1 will enroll a maximum of 12 patients and Phase 2 will enroll up to approximately 40 patients
Interventions
DRUGRomidepsin
Intravenous dosing for 4 hours on Days 1, 8, and 15 of each 28-day cycle
Sponsors
Celgene
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients must fulfill all of the following criteria to be eligible for study participation and have: * Histologically confirmed Peripheral T cell Lymphoma (PTCL) Not Otherwise Specified (NOS), Angioimmunoblastic T-cell Lymphoma, enteropathy- type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, cutaneous T-cell lymphoma (excludes mycosis fungoides or Sezary syndrome) , hepatosplenic T-cell lymphoma, Anaplastic Large cell lymphoma (ALCL) \[anaplastic lymphoma kinase-1 (ALK-1) negative\], patients with ALK 1 expressing ALCL (ALK-1 positive) who have relapsed disease after Autologous Stem-Cell Transplantation, Transformed mycosis fungoides (MF), or Sézary syndrome (SS); * Age ≥20 years; * Written informed consent; * Progressive Disease following at least one systemic therapy or refractory to at least one prior systemic therapy; * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; * Sufficient functions of bone marrow or other organs as evidenced by * Hemoglobin ≥8.0 g/dL (The value after the 7th day of transfusion) * Absolute neutrophil count (ANC) ≥1.0×10\^9/L (The value after the 7th day of G-CSF) * Platelet counts ≥100 x 10\^9/L, or, if bone marrow infiltration is recognized, ≥75 ×10\^9/L * Total bilirubin (Total-Bil) ≤2 x upper limit of normal (ULN) (≤3.0 x ULN in the presence of demonstrable liver metastasis) * Aspartate Aminotransferase (AST)/Serum Glutamic-Oxaloacetic Transaminase (SGOT) ≤2 x Upper Limit Normal (ULN) (≤3.0 x ULN in the presence of demonstrable liver metastasis) * Alanine Aminotransferase (ALT)/Serum Glutamic-Oxaloacetic Transaminase (SGOT) ≤2 x ULN (≤3.0 x ULN in the presence of demonstrable liver metastasis) * Serum creatinine ≤ 2 x ULN * Serum potassium ≥ lower limit of normal (LLN) and magnesium * Patients for whom at least 1 measurable lesion is confirmed in the lesion assessment before enrollment; and * Negative urine or serum pregnancy test on females of childbearing potential.
Exclusion criteria
Confirmation should be made before enrollment, and the subjects corresponding to the criteria should not be enrolled. 1. Subjects in whom central nervous lymphoma is recognized during the screening period (If brain metastasis is suspected clinically, CT should be performed.) 2. Subjects undergoing chemotherapy or immunotherapy for the purpose of treatment of the target disease within 22 days before C1D1 (including C1D1) (using antibody drugs only within 3 months before C1D1) 3. Subjects receiving local application of steroids within 15 days before C1D1 (including C1D1) Use of steroids for the purpose other than that of treatment of the target disease should be allowed (Only CTCL subjects) 4. Subjects receiving systemic application of steroids within 22 days before C1D1 (including C1D1) (It is acceptable to continue the use of the steroid for the purpose of treatment of the target disease,which administered in doses ≤ 10mg/day prednisolone or equivalent dose of other glucocorticoid. However increase of steroid dose cannot be allowed during the study period) 5. Subjects undergoing radiation therapy, PUVA therapy or TSEB for the purpose of treatment of the target disease within 22 days before C1D1 (including C1D1) 6. Subjects using other investigational products within 22 days before C1D1 (including C1D1) (using antibody drugs only within 3 months before C1D1) 7. Subjects undergoing blood transfusion and using G-CSF within 8 days before C1D1 (including C1D1) 8. Subjects with the following abnormalities in the cardiac function 1. Congenital QT prolongation syndrome 2. QTc interval \>480 msec 3. Myocardial infarction within 6 months before C1D1. Subjects with a history of myocardial infarction between 6 and 12 months prior to C1D1 who are asymptomatic and have had a negative cardiac risk assessment (treadmill stress test, nuclear medicine stress test, or stress echocardiogram) since the event may occur 4. Significant ECG abnormalities including atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min) 5. Symptomatic coronary artery disease (CAD) (e.g., Angina Canadian Class II-IV). 6. An ECG recorded at screening showing significant ST depression (ST depression of ≥2 mm, measured from isoelectric line to the ST segment at a point 60 msec at the end of the QRS complex). If there is any doubt, the subject should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present. 7. Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or ejection fraction \<40% by MUGA scan or \<50% by echocardiogram and/or MRI 8. A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), torsade de pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD) 9. Hypertrophic cardiomyopathy or restrictive cardiomyopathy from prior treatment or other causes (if there is any doubt, see ejection fraction criteria above) 10. Uncontrolled hypertension, i.e., systolic blood pressure (BP) is greater than or equal to 160 mmHg or diastolic BP is greater than or equal to 95 mmHg; subjects who have a history of hypertension controlled by medication must be on a stable dose (for at least one month) 11. Subjects with cardiac arrhythmia requiring an anti-arrhythmic drug 9. Concomitant use of a drug which may induce significant QT prolongation (refer to 9.2. Prohibited Concomitant Medications and Procedures.) 10. Concomitant use of strong or moderate CYP3A4 inhibitors which include grapefruit juice 11. Concomitant use of CYP3A4 inducers which include St John's Wort (1st step only) 12. Concomitant use of therapeutic warfarin which has a potential drug interaction. Use of a small dose of warfarin or other anticoagulant agent to maintain patency of venous access port and cannulas is permitted. 13. Clinically important active infections 14. Known infection with human immunodeficiency virus (HIV) antibody positive, HBs antigen positive or HCV antibody positive. If negative for HBsAg but HBcAb and/or HBsAb positive status, a HBV DNA test will be performed and if positive the subject will be excluded. 15. Subjects undergoing a wide range of radiation therapy in ≥30% of the bone marrow (such as all parts of the pelvic area or a half of the spinal cord) in the past. The subjects undergoing systemic radiation (including systemic electron therapy) as previous treatment for ASCT will be excluded. 16. Subjects undergoing a surgery within 15 days before C1D1 (including C1D1); however, even if more than 15 days have passed since the surgery, subjects without evidence of wound healing will be excluded. 17. Subjects who are during recovery process from severe wound or fracture. 18. Subjects with a history of allogeneic stem cell transplantation 19. Patients who are breast-feed during period of the IP administration or within 28 days after the end of the IP administration. 20. Subjects with a history of any other malignant tumor or solid cancer within previous 3 years (excluding basal or squamous cell carcinoma of skin, and in situ carcinoma of the cervix (CIN3) that has been treated curatively) 21. Subject with a history of hematological malignant tumor (other than T-cell lymphoma) 22. Subjects for whom transfusion of red blood cells or platelets is impossible (such as clinical state and religious beliefs) 23. Significant medical or psychiatric situation by which all of the study procedures may not be observed 24. Subjects receiving romidepsin in the past (Other HDAC inhibitors are acceptable) 25. Subjects judged to be inappropriate for this study by the investigator or sub-investigator. 26. Concomitant use of rifampicin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicity (DLT) in Accordance With National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 as Determined by the Efficacy and Safety Evaluation Committee (ESEC) | Up to Day 28; Cycle 1 | DLT was defined as an adverse event (AE) occurring in Cycle 1 in Phase 1 and judged that the causal relationship to the investigational product could not be denied. The severity of all AEs was graded based upon the NCI CTCAE version 3.0. DLTs were defined as: • Grade 4 Hemoglobin \<6.5 g/dL • Grade 4 Neutrophil \<500/μL continuing for at least 5 days • Febrile neutropenia (Grade 4 neutropenia caused by fever and ≥ 38.5° C for more than 1 hour) • Grade 4 thrombocyte (\< 25,000/μL), or thrombocytopenia with hemorrhage requiring platelet transfusion • Nausea, vomiting, or diarrhea at \> grade 3 in spite of treatment • Grade 3 ALT (alanine aminotransferase) or AST (aspartate aminotransferase) values continued for 7 days. • Grade 4 ALT or AST • Grade 2 arrhythmia • Grade 4 non-hematological AEs • Other grade 3 non-hematological AEs except transient fatigue, anorexia, hyponatremia, and tumor lysis syndrome • Other AEs leading to discontinuation of administration |
| Percentage of PTCL Participants With an Overall Best Response in Accordance With a Modified International Workshop Response Criteria (IWC) 1999 in Phase 2 | Tumor assessments performed every 2 months; median follow-up time was 100 days; up to the data cut-off of 28 July 2015 | Objective disease response in PTCL was defined as patients with a complete response (CR), unconfirmed complete response (CRu) or a partial response (PR) according to modified IWC 1999 criteria and assessed by an independent efficacy reviewer. A CR is \>75% decrease in size of maximum 6 largest target within nodal and extranodal lesions, complete disappearance of other nodal and extranodal; total disappearance of clinical disease; disease-related signs and symptoms, normalization of biochemical abnormalities, disappearance of spleen, liver, or kidney enlargement; no bone marrow (BM) involvement, no new sites of disease. CRu: all above criteria fulfilled except for BM involvement is indeterminate. PR: a ≥50% decrease in size of 6 largest target lesions and no increase other nodal and extranodal; no progression of clinical disease; disease-related signs and symptoms, normalization or biochemical abnormalities, no progression in size of liver, spleen, or kidney; and no new sites of disease |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of Romidepsin in Phase 1 | Day 1 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration | Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC∞) of romidepsin on Day 1; if possible the area under the concentration-time curve from time zero to infinity, calculated by the linear trapezoidal rule and extrapolated to infinity was calculated according to the following equation: AUC∞ = AUCt + (Ct/ λz ), where Ct is the last quantifiable concentration. |
| Maximum Plasma Concentration (Cmax) of Romidepsin in Phase 1 | Day 1 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration | The maximum observed plasma concentration of romidepsin (Cmax) obtained directly from the observed concentration versus time data |
| Time to Maximum Plasma Concentration of Romidepsin (Tmax) in Phase 1 | Day 1 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration | The time to first maximum observed plasma concentration of romidepsin after a single dose on Day 1. |
| Terminal Phase Half-life of Romidepsin (t½) in Phase 1 | Day 1 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration. | The terminal phase half-life of romidepsin after a single dose on Day 1, calculated according to the following equation: t½ = 0.693/λz, where λz is the terminal phase rate constant. |
| Apparent Total Clearance of Romidepsin (CL/F) of Romidepsin in Phase 1 | Day 1 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration. | The apparent total clearance of romidepsin after a single dose on Day 1, calculated as dose/AUC0-infinity. |
| Apparent Volume of Distribution (Vz/F) of Romidepsin in Phase 1 | Day 1 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration | Apparent volume of distribution, was calculated according to the equation: Vd/F = (CL/F)/λz |
| AUC0-t, at Steady State (ss) of Romidepsin in Phase 1 at Cycle 1, Day 15 | Day 15 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration | Area under the plasma concentration-time curve from time zero to the last quantifiable time point at steady state, calculated by the linear trapezoidal rule when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing |
| Cmax, ss of Romidepsin in Phase 1 at Cycle 1, Day 15 | Day 15 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration | Maximum observed concentration in plasma at steady state |
| Tmax,ss of Romidepsin in Phase 1 at Cycle 1, Day 15 | Day 15 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration | Observed time to first maximum plasma concentration at steady state |
| Terminal Phase Half-life of Romidepsin (t½) in Phase 1 at Cycle 1, Day 15 | Day 15 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration. | The terminal phase half-life of romidepsin after a single dose on Day 15, calculated according to the following equation: t½ = 0.693/λz, where λz is the terminal phase rate constant. |
| Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Day 1 of study drug through 30 days after the last dose of study drug or discontinuation date; Up to data cut-off of 28 July 2015; maximum follow up time was 184.3 weeks | An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. An AE that resulted in any of the outcomes was defined as a serious (SAE): • Death • Life-threatening event • An inpatient hospitalization or prolongation of existing hospitalization • Persistent or significant disability or incapacity; • Congenital anomaly or birth defect • Other important medical event The investigator judged the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide an explanation for the event. The severity of an AE was evaluated by the investigator according to Common Terminology Criteria for Adverse Events (CTCAE Version 3.0), Japanese Clinical Oncology Group (JCOG) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death. |
| Cmax Accumulation Ratio of Romidepsin in Phase 1, Cycle 1 | Day 1 and Day 15 in Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at end of administration) hours after the start of administration, 0.25, 0.5, 1, 2, 4, 6, 20, and 44 hours after the end of administration. Day 8, Cycle 1, samples collected at 0 hour | Cmax of Romidepsin: accumulation ratio based on Cmax calculated as Cmax,ss/Cmax |
| The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | Median follow-up: 100 days; up to data cut-off of 28 July 2015 | The time from the start of the Q-wave to the end of the T-wave QTc intervals greater than 450 msec post-baseline performed by centralized reviewer. The Bazett's (QTcB) and Fridericia (QTcF) correction were used as the standard clinical correction for calculating the heart rate-corrected QTc interval |
| Percentage of PTCL Participants With the Best Response in Accordance With the Modified 2007 International Workshop Response Criteria as Assessed by IER | Tumor assessments performed every 2 months; median follow-up time was 100 days; up to the data cut-off of 28 July 2015 | Objective disease response in PTCL was defined as achieving a CR or PR based on the Modified 2007 IWC. A CR = a complete disappearance of all disease; lymph node mass regression to normal size on computerized tomography (CT) scan or negative on positron emission tomography (PET); non-palpable splenic and disappearance of liver nodules; infiltrate cleared on repeat bone marrow (BM), immunohistochemistry negative. PR = a reduction of measurable lesions; ≥ 50% decrease in sum of the products of the greatest diameters (SPD) of up to 6 largest dominant masses, no enlargement in size of other nodes; ≥ 50% decrease in SPD and no increase in liver or spleen. |
| Time to Response (TTR) for PTCL Participants With at Least a PR Based on the Modified 1999 IWC as Assessed by IER | Median follow-up time was 100 days; up to the data cut-off of 28 July 2015 | TTR for PTCL was defined as the time in days from first dose date to the first date of objective disease response. |
| Time to Response (TTR) for PTCL Participants With at Least a PR Based on the Modified 2007 IWC as Assessed by IER | Median follow-up time was 100 days; up to the data cut-off of 28 July 2015 | TTR for PTCL was defined as the time in days from first dose date to the first date of objective disease response. |
| Kaplan Meier Estimate of Duration of Response (DOR) for PTCL Responders Based on the Modified 1999 IWC as Assessed by the IER. | Median follow-up time was 100 days; up to the data cut-off of 28 July 2015 | DOR was defined as the number of days from the date of the first disease response (Complete, Unconfirmed Complete or Partial Response) until the date of progression, analyzed using Kaplan-Meier methods. |
| Kaplan Meier Estimate of Duration of Response (DOR) for PTCL Responders Based on the Modified 2007 IWC as Assessed by the IER. | Median follow-up time was 100 days; up to the data cut-off of 28 July 2015 | DOR was defined as the number of days from the date of the first disease response (Complete, Unconfirmed Complete or Partial Response) until the date of progression, analyzed using Kaplan-Meier methods. |
| Kaplan Meier Estimate of Time to Progression (TTP) in PTCL Participants Based on the 1999 IWC as Assessed by IER | Median follow-up time was 100 days; up to the data cut-off of 28 July 2015 | Time to progression (≥50% increase from the nadir in the individual sum of the products of the diameters of any index lesion; the reappearance of pathology, enlargement of liver/spleen, or unequivocal progression of non-measurable disease or appearance of any new lesions) was defined as the duration from the date of the first study drug dose to the date of relapse or progression |
| Kaplan Meier (K-M) Estimate of Time to Progression (TTP) in PTCL Participants Based on the Modified 2007 IWC as Assessed by IER | Median follow-up time was 100 days; up to the data cut-off of 28 July 2015 | Time to progression (≥50% increase from the nadir in the individual sum of the products of the diameters of any index lesion; the reappearance of pathology, enlargement of liver/spleen, or unequivocal progression of non-measurable disease or appearance of any new lesions) was defined as the duration from the date of the first study drug dose to the date of relapse or progression |
| AUC0-t, Accumulation Ratio of Romidepsin in Phase 1, Cycle 1 | Day 1 and Day 15 in Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration | Area under the plasma concentration-time curve from time zero to the last quantifiable time point; accumulation ratio calculated as AUC (0-t),ss/AUC (0-t) |
| Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Romidepsin in Phase 1 | Day 1 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration | Area under the plasma concentration-time curve from time zero to the last quantifiable time point, calculated by the linear trapezoidal rule when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing. |
Countries
Japan
Participant flow
Recruitment details
This was a Phase 1/2 open-label dose-escalation study. Phase 1 part composed of Cohort 1 (9mg/m\^2) and Cohort 2 (14mg/m\^2). Japanese participants were enrolled in order from Cohort 1. The dose used in the Phase 2 part was determined based on the frequency of dose limiting toxicities in Phase 1.
Pre-assignment details
Those with relapsed, recurring or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) were enrolled in the Phase 1 part of this study. In Phase 2, the target disease was relapsed, recurring or refractory PTCL only. Results are reported up to the data cut-off of 28 July 2015.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Romidepsin 9mg/m^2 Romidepsin 9mg/m\^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle | 3 |
| Phase 1: Romidepsin 14mg/m^2 Romidepsin 14mg/m\^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle. | 7 |
| Phase 2: Romidepsin 14mg/m^2 Romidepsin 14mg/m\^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle. | 40 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Phase 1 (First Step) | Adverse Event | 0 | 3 | 0 |
| Phase 1 (First Step) | Disease Progression | 1 | 1 | 0 |
| Phase 1 (First Step) | Other | 0 | 1 | 0 |
| Phase 1 (First Step) | Withdrawal by Subject | 1 | 2 | 0 |
| Phase 2 (Second Step) | Adverse Event | 0 | 0 | 10 |
| Phase 2 (Second Step) | Disease Progression | 0 | 0 | 17 |
| Phase 2 (Second Step) | Other | 0 | 0 | 1 |
| Phase 2 (Second Step) | Protocol Violation | 0 | 0 | 1 |
| Phase 2 (Second Step) | Withdrawal by Subject | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | Phase 1: Romidepsin 9mg/m^2 | Phase 1: Romidepsin 14mg/m^2 | Phase 2: Romidepsin 14mg/m^2 | Total |
|---|---|---|---|---|
| Age, Continuous | 59.0 years STANDARD_DEVIATION 9.54 | 73.6 years STANDARD_DEVIATION 4.2 | 68.5 years STANDARD_DEVIATION 8.43 | 68.7 years STANDARD_DEVIATION 8.47 |
| Age, Customized <65 years | 2 participants | 0 participants | 12 participants | 14 participants |
| Age, Customized ≥65 years | 1 participants | 7 participants | 28 participants | 36 participants |
| Body Surface Area (BSA) | 1.640 m2 STANDARD_DEVIATION 0.1114 | 1.563 m2 STANDARD_DEVIATION 0.2034 | 1.554 m2 STANDARD_DEVIATION 0.1768 | 1.561 m2 STANDARD_DEVIATION 0.1757 |
| Disease Type by Investigator CTCL | 1 participants | 1 participants | 0 participants | 2 participants |
| Disease Type by Investigator PTCL | 2 participants | 6 participants | 40 participants | 48 participants |
| Eastern Cooperative Oncology Group (ECOG) 0 = (Fully Active) | 0 participants | 4 participants | 22 participants | 26 participants |
| Eastern Cooperative Oncology Group (ECOG) 1 = (Restrictive but ambulatory) | 1 participants | 2 participants | 14 participants | 17 participants |
| Eastern Cooperative Oncology Group (ECOG) 2 = (Ambulatory but unable to work) | 2 participants | 1 participants | 4 participants | 7 participants |
| Eastern Cooperative Oncology Group (ECOG) 3 = (Limited self care) | 0 participants | 0 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group (ECOG) 4 = (Completely Disabled) | 0 participants | 0 participants | 0 participants | 0 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 17 Participants | 21 Participants |
| Sex: Female, Male Male | 1 Participants | 5 Participants | 23 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 7 / 7 | 40 / 40 | 47 / 47 |
| serious Total, serious adverse events | 1 / 3 | 4 / 7 | 10 / 40 | 14 / 47 |
Outcome results
Primary
Number of Participants With Dose-limiting Toxicity (DLT) in Accordance With National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 as Determined by the Efficacy and Safety Evaluation Committee (ESEC)
DLT was defined as an adverse event (AE) occurring in Cycle 1 in Phase 1 and judged that the causal relationship to the investigational product could not be denied. The severity of all AEs was graded based upon the NCI CTCAE version 3.0. DLTs were defined as: • Grade 4 Hemoglobin \<6.5 g/dL • Grade 4 Neutrophil \<500/μL continuing for at least 5 days • Febrile neutropenia (Grade 4 neutropenia caused by fever and ≥ 38.5° C for more than 1 hour) • Grade 4 thrombocyte (\< 25,000/μL), or thrombocytopenia with hemorrhage requiring platelet transfusion • Nausea, vomiting, or diarrhea at \> grade 3 in spite of treatment • Grade 3 ALT (alanine aminotransferase) or AST (aspartate aminotransferase) values continued for 7 days. • Grade 4 ALT or AST • Grade 2 arrhythmia • Grade 4 non-hematological AEs • Other grade 3 non-hematological AEs except transient fatigue, anorexia, hyponatremia, and tumor lysis syndrome • Other AEs leading to discontinuation of administration
Time frame: Up to Day 28; Cycle 1
Population: DLT population included all participants in the Phase 1 portion who received at least one dose of romidepsin. Of 8 participants enrolled in the 14mg/m\^2 cohort, 2 participants, one with a critical Good Clinical Practice (GCP)violation and the other who did not complete Cycle 1 due to consent withdrawal, were excluded from the DLT assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Number of Participants With Dose-limiting Toxicity (DLT) in Accordance With National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 as Determined by the Efficacy and Safety Evaluation Committee (ESEC) | 0 participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Number of Participants With Dose-limiting Toxicity (DLT) in Accordance With National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 as Determined by the Efficacy and Safety Evaluation Committee (ESEC) | 0 participants |
Primary
Percentage of PTCL Participants With an Overall Best Response in Accordance With a Modified International Workshop Response Criteria (IWC) 1999 in Phase 2
Objective disease response in PTCL was defined as patients with a complete response (CR), unconfirmed complete response (CRu) or a partial response (PR) according to modified IWC 1999 criteria and assessed by an independent efficacy reviewer. A CR is \>75% decrease in size of maximum 6 largest target within nodal and extranodal lesions, complete disappearance of other nodal and extranodal; total disappearance of clinical disease; disease-related signs and symptoms, normalization of biochemical abnormalities, disappearance of spleen, liver, or kidney enlargement; no bone marrow (BM) involvement, no new sites of disease. CRu: all above criteria fulfilled except for BM involvement is indeterminate. PR: a ≥50% decrease in size of 6 largest target lesions and no increase other nodal and extranodal; no progression of clinical disease; disease-related signs and symptoms, normalization or biochemical abnormalities, no progression in size of liver, spleen, or kidney; and no new sites of disease
Time frame: Tumor assessments performed every 2 months; median follow-up time was 100 days; up to the data cut-off of 28 July 2015
Population: Intent to treat population for participants with PTCL who received at least one dose of Romidepsin
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Percentage of PTCL Participants With an Overall Best Response in Accordance With a Modified International Workshop Response Criteria (IWC) 1999 in Phase 2 | 0 percentage of participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Percentage of PTCL Participants With an Overall Best Response in Accordance With a Modified International Workshop Response Criteria (IWC) 1999 in Phase 2 | 66.7 percentage of participants |
| Phase 2: Romidepsin 14mg/m^2 | Percentage of PTCL Participants With an Overall Best Response in Accordance With a Modified International Workshop Response Criteria (IWC) 1999 in Phase 2 | 42.5 percentage of participants |
| Total: Romidepsin 14mg/m^2 | Percentage of PTCL Participants With an Overall Best Response in Accordance With a Modified International Workshop Response Criteria (IWC) 1999 in Phase 2 | 45.7 percentage of participants |
p-value: <0.0001Binomial test for dichotomized response
Secondary
Apparent Total Clearance of Romidepsin (CL/F) of Romidepsin in Phase 1
The apparent total clearance of romidepsin after a single dose on Day 1, calculated as dose/AUC0-infinity.
Time frame: Day 1 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration.
Population: PK population includes of all participants who had sufficient concentration-time data to enable the calculation of PK parameters for at least one PK day. For those who were determined to be noncompliant to receiving romidepsin, or for those with incomplete data, a decision to include the analysis was made on a case-by-case basis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Apparent Total Clearance of Romidepsin (CL/F) of Romidepsin in Phase 1 | 14.29 L/h | Geometric Coefficient of Variation 60.8 |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Apparent Total Clearance of Romidepsin (CL/F) of Romidepsin in Phase 1 | 9.31 L/h | Geometric Coefficient of Variation 35.4 |
Secondary
Apparent Volume of Distribution (Vz/F) of Romidepsin in Phase 1
Apparent volume of distribution, was calculated according to the equation: Vd/F = (CL/F)/λz
Time frame: Day 1 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration
Population: PK Population includes of all participants who had sufficient concentration-time data to enable the calculation of PK parameters for at least one PK day. For those who were determined to be noncompliant to receiving romidepsin, or for those with incomplete data, a decision to include the analysis was made on a case-by-case basis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Apparent Volume of Distribution (Vz/F) of Romidepsin in Phase 1 | 196.24 Liters | Geometric Coefficient of Variation 86.8 |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Apparent Volume of Distribution (Vz/F) of Romidepsin in Phase 1 | 122.47 Liters | Geometric Coefficient of Variation 40.4 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of Romidepsin in Phase 1
Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC∞) of romidepsin on Day 1; if possible the area under the concentration-time curve from time zero to infinity, calculated by the linear trapezoidal rule and extrapolated to infinity was calculated according to the following equation: AUC∞ = AUCt + (Ct/ λz ), where Ct is the last quantifiable concentration.
Time frame: Day 1 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration
Population: PK Population consisted of all participants who had sufficient concentration-time data to enable the calculation of PK parameters for romidepsin for at least one PK day. For those who were determined to be noncompliant to receiving romidepsin, or for those with incomplete data, a decision to include the analysis was made on a case-by-case basis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of Romidepsin in Phase 1 | 1027.08 ng*h/mL | Geometric Coefficient of Variation 66.6 |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of Romidepsin in Phase 1 | 2330.91 ng*h/mL | Geometric Coefficient of Variation 35.2 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Romidepsin in Phase 1
Area under the plasma concentration-time curve from time zero to the last quantifiable time point, calculated by the linear trapezoidal rule when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing.
Time frame: Day 1 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration
Population: PK Population includes of all participants who had sufficient concentration-time data to enable the calculation of PK parameters for at least one PK day. For those who were determined to be noncompliant to receiving romidepsin, or for those with incomplete data, a decision to include the analysis was made on a case-by-case basis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Romidepsin in Phase 1 | 1023.76 ng*h/mL | Geometric Coefficient of Variation 66.7 |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Romidepsin in Phase 1 | 2325.55 ng*h/mL | Geometric Coefficient of Variation 35.3 |
Secondary
AUC0-t, Accumulation Ratio of Romidepsin in Phase 1, Cycle 1
Area under the plasma concentration-time curve from time zero to the last quantifiable time point; accumulation ratio calculated as AUC (0-t),ss/AUC (0-t)
Time frame: Day 1 and Day 15 in Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration
Population: PK Population includes of all participants who had sufficient concentration-time data to enable the calculation of PK parameters for at least one PK day. For those who were determined to be noncompliant to receiving romidepsin, or for those with incomplete data, a decision to include the analysis was made on a case-by-case basis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | AUC0-t, Accumulation Ratio of Romidepsin in Phase 1, Cycle 1 | 1.00 ratio | Geometric Coefficient of Variation 19.6 |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | AUC0-t, Accumulation Ratio of Romidepsin in Phase 1, Cycle 1 | 0.83 ratio | Geometric Coefficient of Variation 24.3 |
Secondary
AUC0-t, at Steady State (ss) of Romidepsin in Phase 1 at Cycle 1, Day 15
Area under the plasma concentration-time curve from time zero to the last quantifiable time point at steady state, calculated by the linear trapezoidal rule when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing
Time frame: Day 15 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration
Population: PK Population includes of all participants who had sufficient concentration-time data to enable the calculation of PK parameters for at least one PK day. For those who were determined to be noncompliant to receiving romidepsin, or for those with incomplete data, a decision to include the analysis was made on a case-by-case basis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | AUC0-t, at Steady State (ss) of Romidepsin in Phase 1 at Cycle 1, Day 15 | 1024.66 ng*h/mL | Geometric Coefficient of Variation 78.1 |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | AUC0-t, at Steady State (ss) of Romidepsin in Phase 1 at Cycle 1, Day 15 | 1825.74 ng*h/mL | Geometric Coefficient of Variation 25.8 |
Secondary
Cmax Accumulation Ratio of Romidepsin in Phase 1, Cycle 1
Cmax of Romidepsin: accumulation ratio based on Cmax calculated as Cmax,ss/Cmax
Time frame: Day 1 and Day 15 in Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at end of administration) hours after the start of administration, 0.25, 0.5, 1, 2, 4, 6, 20, and 44 hours after the end of administration. Day 8, Cycle 1, samples collected at 0 hour
Population: PK Population includes of all participants who had sufficient concentration-time data to enable the calculation of PK parameters for at least one PK day. For those who were determined to be noncompliant to receiving romidepsin, or for those with incomplete data, a decision to include the analysis was made on a case-by-case basis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Cmax Accumulation Ratio of Romidepsin in Phase 1, Cycle 1 | 0.93 ratio | Geometric Coefficient of Variation 15.3 |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Cmax Accumulation Ratio of Romidepsin in Phase 1, Cycle 1 | 0.86 ratio | Geometric Coefficient of Variation 22.2 |
Secondary
Cmax, ss of Romidepsin in Phase 1 at Cycle 1, Day 15
Maximum observed concentration in plasma at steady state
Time frame: Day 15 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration
Population: PK Population includes of all participants who had sufficient concentration-time data to enable the calculation of PK parameters for at least one PK day. For those who were determined to be noncompliant to receiving romidepsin, or for those with incomplete data, a decision to include the analysis was made on a case-by-case basis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Cmax, ss of Romidepsin in Phase 1 at Cycle 1, Day 15 | 250.05 ng/mL | Geometric Coefficient of Variation 63.3 |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Cmax, ss of Romidepsin in Phase 1 at Cycle 1, Day 15 | 489.47 ng/mL | Geometric Coefficient of Variation 31.2 |
Secondary
Kaplan Meier Estimate of Duration of Response (DOR) for PTCL Responders Based on the Modified 1999 IWC as Assessed by the IER.
DOR was defined as the number of days from the date of the first disease response (Complete, Unconfirmed Complete or Partial Response) until the date of progression, analyzed using Kaplan-Meier methods.
Time frame: Median follow-up time was 100 days; up to the data cut-off of 28 July 2015
Population: Intent to treat population for participants with PTCL who received at least one dose of romidepsin and achieved a PR or better (CR, CRu or PR)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Kaplan Meier Estimate of Duration of Response (DOR) for PTCL Responders Based on the Modified 1999 IWC as Assessed by the IER. | 106.00 days |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Kaplan Meier Estimate of Duration of Response (DOR) for PTCL Responders Based on the Modified 1999 IWC as Assessed by the IER. | 337.00 days |
| Phase 2: Romidepsin 14mg/m^2 | Kaplan Meier Estimate of Duration of Response (DOR) for PTCL Responders Based on the Modified 1999 IWC as Assessed by the IER. | 337.00 days |
Secondary
Kaplan Meier Estimate of Duration of Response (DOR) for PTCL Responders Based on the Modified 2007 IWC as Assessed by the IER.
DOR was defined as the number of days from the date of the first disease response (Complete, Unconfirmed Complete or Partial Response) until the date of progression, analyzed using Kaplan-Meier methods.
Time frame: Median follow-up time was 100 days; up to the data cut-off of 28 July 2015
Population: Intent to treat population for participants with PTCL who received at least one dose of romidepsin and achieved a PR or better (CR, CRu or PR)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Kaplan Meier Estimate of Duration of Response (DOR) for PTCL Responders Based on the Modified 2007 IWC as Assessed by the IER. | 163.00 days |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Kaplan Meier Estimate of Duration of Response (DOR) for PTCL Responders Based on the Modified 2007 IWC as Assessed by the IER. | 337.00 days |
| Phase 2: Romidepsin 14mg/m^2 | Kaplan Meier Estimate of Duration of Response (DOR) for PTCL Responders Based on the Modified 2007 IWC as Assessed by the IER. | 163.00 days |
Secondary
Kaplan Meier Estimate of Time to Progression (TTP) in PTCL Participants Based on the 1999 IWC as Assessed by IER
Time to progression (≥50% increase from the nadir in the individual sum of the products of the diameters of any index lesion; the reappearance of pathology, enlargement of liver/spleen, or unequivocal progression of non-measurable disease or appearance of any new lesions) was defined as the duration from the date of the first study drug dose to the date of relapse or progression
Time frame: Median follow-up time was 100 days; up to the data cut-off of 28 July 2015
Population: ITT includes all participants who received at least one dose of romidepsin
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Kaplan Meier Estimate of Time to Progression (TTP) in PTCL Participants Based on the 1999 IWC as Assessed by IER | 114.00 days |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Kaplan Meier Estimate of Time to Progression (TTP) in PTCL Participants Based on the 1999 IWC as Assessed by IER | 899.00 days |
| Phase 2: Romidepsin 14mg/m^2 | Kaplan Meier Estimate of Time to Progression (TTP) in PTCL Participants Based on the 1999 IWC as Assessed by IER | 170.00 days |
| Total: Romidepsin 14mg/m^2 | Kaplan Meier Estimate of Time to Progression (TTP) in PTCL Participants Based on the 1999 IWC as Assessed by IER | 179.00 days |
Secondary
Kaplan Meier (K-M) Estimate of Time to Progression (TTP) in PTCL Participants Based on the Modified 2007 IWC as Assessed by IER
Time to progression (≥50% increase from the nadir in the individual sum of the products of the diameters of any index lesion; the reappearance of pathology, enlargement of liver/spleen, or unequivocal progression of non-measurable disease or appearance of any new lesions) was defined as the duration from the date of the first study drug dose to the date of relapse or progression
Time frame: Median follow-up time was 100 days; up to the data cut-off of 28 July 2015
Population: ITT includes all participants who received at least one dose of romidepsin
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Kaplan Meier (K-M) Estimate of Time to Progression (TTP) in PTCL Participants Based on the Modified 2007 IWC as Assessed by IER | NA days |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Kaplan Meier (K-M) Estimate of Time to Progression (TTP) in PTCL Participants Based on the Modified 2007 IWC as Assessed by IER | 899.00 days |
| Phase 2: Romidepsin 14mg/m^2 | Kaplan Meier (K-M) Estimate of Time to Progression (TTP) in PTCL Participants Based on the Modified 2007 IWC as Assessed by IER | 179.00 days |
| Total: Romidepsin 14mg/m^2 | Kaplan Meier (K-M) Estimate of Time to Progression (TTP) in PTCL Participants Based on the Modified 2007 IWC as Assessed by IER | 179.00 days |
Secondary
Maximum Plasma Concentration (Cmax) of Romidepsin in Phase 1
The maximum observed plasma concentration of romidepsin (Cmax) obtained directly from the observed concentration versus time data
Time frame: Day 1 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration
Population: Pharmacokinetic (PK) Population includes of all participants who had sufficient concentration-time data to enable the calculation of PK parameters for at least one PK day. For those who were determined to be noncompliant to receiving romidepsin, or for those with incomplete data, a decision to include the analysis was made on a case-by-case basis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Maximum Plasma Concentration (Cmax) of Romidepsin in Phase 1 | 269.75 ng/mL | Geometric Coefficient of Variation 48.9 |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Maximum Plasma Concentration (Cmax) of Romidepsin in Phase 1 | 593.47 ng/mL | Geometric Coefficient of Variation 37.2 |
Secondary
Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. An AE that resulted in any of the outcomes was defined as a serious (SAE): • Death • Life-threatening event • An inpatient hospitalization or prolongation of existing hospitalization • Persistent or significant disability or incapacity; • Congenital anomaly or birth defect • Other important medical event The investigator judged the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide an explanation for the event. The severity of an AE was evaluated by the investigator according to Common Terminology Criteria for Adverse Events (CTCAE Version 3.0), Japanese Clinical Oncology Group (JCOG) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death.
Time frame: Day 1 of study drug through 30 days after the last dose of study drug or discontinuation date; Up to data cut-off of 28 July 2015; maximum follow up time was 184.3 weeks
Population: Safety population includes all participants who received at least one dose of romidepsin
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Any 1 TEAE | 3 participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Related TEAE leading to dose reduction of drug | 0 participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE leading to dose held of study drug | 1 participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE with CTCAE Grade 3 or greater | 3 participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Related TEAE leading to dose held of study drug | 1 participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE leading to dose reduction of study drug | 0 participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE with CTCAE ≥Grade 3 related to study drug | 3 participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE related to any study drug | 3 participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Related TEAE leading to dose interruption of drug | 1 participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | ≥ 1 serious TEAE | 1 participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Serious TEAE related to study drug | 0 participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE leading to dose interruption of study drug | 1 participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE leading to discontinuation of study drug | 0 participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | At least one TEAE with NCI CTCAE Grade 5 | 0 participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE related leading to discontinuation of drug | 0 participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE related leading to discontinuation of drug | 3 participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Related TEAE leading to dose reduction of drug | 4 participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | ≥ 1 serious TEAE | 4 participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE leading to dose held of study drug | 4 participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE related to any study drug | 7 participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE leading to dose reduction of study drug | 4 participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE leading to dose interruption of study drug | 4 participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Related TEAE leading to dose held of study drug | 3 participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE with CTCAE Grade 3 or greater | 6 participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE leading to discontinuation of study drug | 3 participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | At least one TEAE with NCI CTCAE Grade 5 | 0 participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Related TEAE leading to dose interruption of drug | 3 participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Serious TEAE related to study drug | 4 participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE with CTCAE ≥Grade 3 related to study drug | 6 participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Any 1 TEAE | 7 participants |
| Phase 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE related leading to discontinuation of drug | 9 participants |
| Phase 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Any 1 TEAE | 40 participants |
| Phase 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE related to any study drug | 40 participants |
| Phase 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE with CTCAE Grade 3 or greater | 37 participants |
| Phase 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE with CTCAE ≥Grade 3 related to study drug | 37 participants |
| Phase 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | ≥ 1 serious TEAE | 10 participants |
| Phase 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Serious TEAE related to study drug | 6 participants |
| Phase 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE leading to discontinuation of study drug | 10 participants |
| Phase 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE leading to dose held of study drug | 24 participants |
| Phase 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Related TEAE leading to dose held of study drug | 22 participants |
| Phase 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE leading to dose reduction of study drug | 17 participants |
| Phase 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Related TEAE leading to dose reduction of drug | 17 participants |
| Phase 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE leading to dose interruption of study drug | 23 participants |
| Phase 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Related TEAE leading to dose interruption of drug | 22 participants |
| Phase 2: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | At least one TEAE with NCI CTCAE Grade 5 | 2 participants |
| Total: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE leading to discontinuation of study drug | 13 participants |
| Total: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE related to any study drug | 47 participants |
| Total: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Related TEAE leading to dose reduction of drug | 21 participants |
| Total: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Serious TEAE related to study drug | 10 participants |
| Total: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | ≥ 1 serious TEAE | 14 participants |
| Total: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Any 1 TEAE | 47 participants |
| Total: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE leading to dose interruption of study drug | 27 participants |
| Total: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE with CTCAE ≥Grade 3 related to study drug | 43 participants |
| Total: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE with CTCAE Grade 3 or greater | 43 participants |
| Total: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | At least one TEAE with NCI CTCAE Grade 5 | 2 participants |
| Total: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Related TEAE leading to dose held of study drug | 25 participants |
| Total: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE leading to dose held of study drug | 28 participants |
| Total: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | Related TEAE leading to dose interruption of drug | 25 participants |
| Total: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE leading to dose reduction of study drug | 21 participants |
| Total: Romidepsin 14mg/m^2 | Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin | TEAE related leading to discontinuation of drug | 12 participants |
Secondary
Percentage of PTCL Participants With the Best Response in Accordance With the Modified 2007 International Workshop Response Criteria as Assessed by IER
Objective disease response in PTCL was defined as achieving a CR or PR based on the Modified 2007 IWC. A CR = a complete disappearance of all disease; lymph node mass regression to normal size on computerized tomography (CT) scan or negative on positron emission tomography (PET); non-palpable splenic and disappearance of liver nodules; infiltrate cleared on repeat bone marrow (BM), immunohistochemistry negative. PR = a reduction of measurable lesions; ≥ 50% decrease in sum of the products of the greatest diameters (SPD) of up to 6 largest dominant masses, no enlargement in size of other nodes; ≥ 50% decrease in SPD and no increase in liver or spleen.
Time frame: Tumor assessments performed every 2 months; median follow-up time was 100 days; up to the data cut-off of 28 July 2015
Population: Intent to treat population for participants with PTCL who received at least one dose of romidepsin
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Percentage of PTCL Participants With the Best Response in Accordance With the Modified 2007 International Workshop Response Criteria as Assessed by IER | 0 percentage of participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Percentage of PTCL Participants With the Best Response in Accordance With the Modified 2007 International Workshop Response Criteria as Assessed by IER | 16.7 percentage of participants |
| Phase 2: Romidepsin 14mg/m^2 | Percentage of PTCL Participants With the Best Response in Accordance With the Modified 2007 International Workshop Response Criteria as Assessed by IER | 42.5 percentage of participants |
| Total: Romidepsin 14mg/m^2 | Percentage of PTCL Participants With the Best Response in Accordance With the Modified 2007 International Workshop Response Criteria as Assessed by IER | 39.1 percentage of participants |
Secondary
Terminal Phase Half-life of Romidepsin (t½) in Phase 1
The terminal phase half-life of romidepsin after a single dose on Day 1, calculated according to the following equation: t½ = 0.693/λz, where λz is the terminal phase rate constant.
Time frame: Day 1 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration.
Population: PK Population includes of all participants who had sufficient concentration-time data to enable the calculation of PK parameters for at least one PK day. For those who were determined to be noncompliant to receiving romidepsin, or for those with incomplete data, a decision to include the analysis was made on a case-by-case basis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Terminal Phase Half-life of Romidepsin (t½) in Phase 1 | 9.52 hours | Geometric Coefficient of Variation 19.8 |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Terminal Phase Half-life of Romidepsin (t½) in Phase 1 | 9.12 hours | Geometric Coefficient of Variation 11.6 |
Secondary
Terminal Phase Half-life of Romidepsin (t½) in Phase 1 at Cycle 1, Day 15
The terminal phase half-life of romidepsin after a single dose on Day 15, calculated according to the following equation: t½ = 0.693/λz, where λz is the terminal phase rate constant.
Time frame: Day 15 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration.
Population: PK Population includes of all participants who had sufficient concentration-time data to enable the calculation of PK parameters for at least one PK day. For those who were determined to be noncompliant to receiving romidepsin, or for those with incomplete data, a decision to include the analysis was made on a case-by-case basis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Terminal Phase Half-life of Romidepsin (t½) in Phase 1 at Cycle 1, Day 15 | 8.77 hours | Geometric Coefficient of Variation 18.6 |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Terminal Phase Half-life of Romidepsin (t½) in Phase 1 at Cycle 1, Day 15 | 9.01 hours | Geometric Coefficient of Variation 15.8 |
Secondary
The Percentage of Participants With Abnormal Q-wave and T Wave Intervals
The time from the start of the Q-wave to the end of the T-wave QTc intervals greater than 450 msec post-baseline performed by centralized reviewer. The Bazett's (QTcB) and Fridericia (QTcF) correction were used as the standard clinical correction for calculating the heart rate-corrected QTc interval
Time frame: Median follow-up: 100 days; up to data cut-off of 28 July 2015
Population: The ECG population includes all participants who received romidepsin on Day 1 of Cycle 1 with at least one post-baseline QTc result
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB >450 msec | 100 percentage of participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB >480 msec | 66.7 percentage of participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB >500 msec | 33.3 percentage of participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB increase from predose >30 msec | 66.7 percentage of participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB increase from predose >60 msec | 33.3 percentage of participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF >450 msec | 33.3 percentage of participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF >480 msec | 33.3 percentage of participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF >500 msec | 33.3 percentage of participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF increase from predose >30 msec | 66.7 percentage of participants |
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF increase from predose >60 msec | 33.3 percentage of participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB >500 msec | 14.3 percentage of participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF increase from predose >30 msec | 57.1 percentage of participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB increase from predose >30 msec | 57.1 percentage of participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB increase from predose >60 msec | 28.6 percentage of participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF >450 msec | 14.3 percentage of participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF >480 msec | 14.3 percentage of participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF increase from predose >60 msec | 14.3 percentage of participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF >500 msec | 14.3 percentage of participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB >450 msec | 57.1 percentage of participants |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB >480 msec | 28.6 percentage of participants |
| Phase 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF >500 msec | 0.0 percentage of participants |
| Phase 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF >480 msec | 0.0 percentage of participants |
| Phase 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF increase from predose >60 msec | 0.0 percentage of participants |
| Phase 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB >450 msec | 55.0 percentage of participants |
| Phase 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB increase from predose >30 msec | 10.0 percentage of participants |
| Phase 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF >450 msec | 10.0 percentage of participants |
| Phase 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF increase from predose >30 msec | 10.0 percentage of participants |
| Phase 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB >480 msec | 0.0 percentage of participants |
| Phase 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB increase from predose >60 msec | 0.0 percentage of participants |
| Phase 2: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB >500 msec | 0.0 percentage of participants |
| Total: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB increase from predose >60 msec | 4.3 percentage of participants |
| Total: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF >500 msec | 2.1 percentage of participants |
| Total: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF >450 msec | 10.6 percentage of participants |
| Total: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF increase from predose >60 msec | 2.1 percentage of participants |
| Total: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF >480 msec | 2.1 percentage of participants |
| Total: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB >480 msec | 4.3 percentage of participants |
| Total: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB >500 msec | 2.1 percentage of participants |
| Total: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB increase from predose >30 msec | 17.0 percentage of participants |
| Total: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcB >450 msec | 55.3 percentage of participants |
| Total: Romidepsin 14mg/m^2 | The Percentage of Participants With Abnormal Q-wave and T Wave Intervals | QTcF increase from predose >30 msec | 17.0 percentage of participants |
Secondary
Time to Maximum Plasma Concentration of Romidepsin (Tmax) in Phase 1
The time to first maximum observed plasma concentration of romidepsin after a single dose on Day 1.
Time frame: Day 1 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration
Population: PK Population includes of all participants who had sufficient concentration-time data to enable the calculation of PK parameters for at least one PK day. For those who were determined to be noncompliant to receiving romidepsin, or for those with incomplete data, a decision to include the analysis was made on a case-by-case basis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Time to Maximum Plasma Concentration of Romidepsin (Tmax) in Phase 1 | 4.02 hours |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Time to Maximum Plasma Concentration of Romidepsin (Tmax) in Phase 1 | 2.00 hours |
Secondary
Time to Response (TTR) for PTCL Participants With at Least a PR Based on the Modified 1999 IWC as Assessed by IER
TTR for PTCL was defined as the time in days from first dose date to the first date of objective disease response.
Time frame: Median follow-up time was 100 days; up to the data cut-off of 28 July 2015
Population: Intent to treat population for participants with PTCL who received at least one dose of romidepsin and achieved a PR or better (CR, CRu or PR)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Time to Response (TTR) for PTCL Participants With at Least a PR Based on the Modified 1999 IWC as Assessed by IER | 109.0 days |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Time to Response (TTR) for PTCL Participants With at Least a PR Based on the Modified 1999 IWC as Assessed by IER | 56.0 days |
| Phase 2: Romidepsin 14mg/m^2 | Time to Response (TTR) for PTCL Participants With at Least a PR Based on the Modified 1999 IWC as Assessed by IER | 56.0 days |
Secondary
Time to Response (TTR) for PTCL Participants With at Least a PR Based on the Modified 2007 IWC as Assessed by IER
TTR for PTCL was defined as the time in days from first dose date to the first date of objective disease response.
Time frame: Median follow-up time was 100 days; up to the data cut-off of 28 July 2015
Population: Intent to treat population for participants with PTCL who received at least one dose of romidepsin and achieved a PR or better (CR, CRu or PR)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Time to Response (TTR) for PTCL Participants With at Least a PR Based on the Modified 2007 IWC as Assessed by IER | 737.0 days |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Time to Response (TTR) for PTCL Participants With at Least a PR Based on the Modified 2007 IWC as Assessed by IER | 56.0 days |
| Phase 2: Romidepsin 14mg/m^2 | Time to Response (TTR) for PTCL Participants With at Least a PR Based on the Modified 2007 IWC as Assessed by IER | 56.0 days |
Secondary
Tmax,ss of Romidepsin in Phase 1 at Cycle 1, Day 15
Observed time to first maximum plasma concentration at steady state
Time frame: Day 15 at Cycle 1; collected at 0 (pre-dose), 1, 2, 3, and 4 (at the end of administration) hours after the start of administration, 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 20, and 44 hours after the end of administration
Population: PK Population includes of all participants who had sufficient concentration-time data to enable the calculation of PK parameters for at least one PK day. For those who were determined to be noncompliant to receiving romidepsin, or for those with incomplete data, a decision to include the analysis was made on a case-by-case basis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Cohort 1: Romidepsin 9mg/m^2 | Tmax,ss of Romidepsin in Phase 1 at Cycle 1, Day 15 | 1.95 hours |
| Phase 1: Cohort 2: Romidepsin 14mg/m^2 | Tmax,ss of Romidepsin in Phase 1 at Cycle 1, Day 15 | 2.94 hours |