A Japanese Phase 1/2 Study to Assess the Efficacy, Safety and Pharmacokinetics of Romidepsin in Patients With Peripheral T-cell Lymphoma (PTCL)

• Sponsor: Celgene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01456039
• Collaborator: (none)
• Enrollment: 51
• Locations: 17
• Arm: 1
• Actual Duration (Months): 84.4
• Patients Per Site: 3
• Patients Per Site Per Month: 0

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, T-cell, Peripheral	Drug: Romidepsin	Phase 1/Phase 2

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Japanese Phase 1/2, Multicenter, Open-label Study to Assess the Efficacy, Tolerability, Safety and Pharmacokinetics of Romidepsin in Subjects With the Progressive or Relapsed Peripheral T-cell Lymphoma
• Actual Study Start Date: Dec 1, 2011
• Actual Primary Completion Date: Jul 28, 2015
• Actual Study Completion Date: Dec 14, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Romidepsin Patients will receive romidepsin intravenously for 4 hours on Days 1, 8, and 15 of each 28-day cycle until when/if a discontinuation criterion, e.g., disease progression, severe adverse events, or consent withdrawal.	Drug: Romidepsin; Intravenous dosing for 4 hours on Days 1, 8, and 15 of each 28-day cycle

Outcome Measures

Primary Outcome Measures

1. 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

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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

5. 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.

6. 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.

7. 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.

8. 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

9. 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

10. 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

11. 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

12. 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.

13. 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)

14. 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

15. 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

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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

22. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

9. Congenital QT prolongation syndrome

10. QTc interval >480 msec

11. 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

12. Significant ECG abnormalities including atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min)

13. Symptomatic coronary artery disease (CAD) (e.g., Angina Canadian Class II-IV).

14. 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.

15. 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

16. 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)

17. Hypertrophic cardiomyopathy or restrictive cardiomyopathy from prior treatment or other causes (if there is any doubt, see ejection fraction criteria above)

18. 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)

19. Subjects with cardiac arrhythmia requiring an anti-arrhythmic drug

20. Concomitant use of a drug which may induce significant QT prolongation (refer to 9.2. Prohibited Concomitant Medications and Procedures.)

21. Concomitant use of strong or moderate CYP3A4 inhibitors which include grapefruit juice

22. Concomitant use of CYP3A4 inducers which include St John's Wort (1st step only)

23. 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.

24. Clinically important active infections

25. 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.

26. 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.

27. 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.

28. Subjects who are during recovery process from severe wound or fracture.

29. Subjects with a history of allogeneic stem cell transplantation

30. Patients who are breast-feed during period of the IP administration or within 28 days after the end of the IP administration.

31. 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)

32. Subject with a history of hematological malignant tumor (other than T-cell lymphoma)

33. Subjects for whom transfusion of red blood cells or platelets is impossible (such as clinical state and religious beliefs)

34. Significant medical or psychiatric situation by which all of the study procedures may not be observed

35. Subjects receiving romidepsin in the past (Other HDAC inhibitors are acceptable)

36. Subjects judged to be inappropriate for this study by the investigator or sub-investigator.

37. Concomitant use of rifampicin.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Nagoya Daini Red Cross Hospital	Nagoya	Aichi	Japan	466-8650
2	Nagoya City University Hospital	Nagoya	Aichi	Japan	467-8602
3	National Cancer Center Hospital East	Kashiwa	Chiba	Japan	277-8577:
4	Ehime University Hospital	To-on	Ehime	Japan	791-0295
5	Chugoku Central Hospital	Fukuyamashi	Hiroshima	Japan	720-0001
6	Sapporo Hokuyu Hospital	Sapporo	Hokkaido	Japan	003-0006
7	Sapporo Medical University Hospital	Sapporo	Hokkaido	Japan	060-8543
8	Tokai University School of Medicine	Isehara	Kanagawa	Japan	259-1193
9	Kochi Medical School Hospital	Nankoku	Kochi	Japan	783-8505
10	Kinki University Hospital	Sayama	Osaka	Japan	589-8511
11	National Cancer Center Hospital	Chuo	Tokyo	Japan	104-0045
12	Japanese Red Cross Medical Center	Shibuya	Tokyo	Japan	150-8935
13	Kyushu University Hospital	Fukuoka		Japan	812-8582
14	Kumamoto University Hospital	Kumamoto		Japan	860-8556
15	University hospital, Kyoto prefectural University of Medicine	Kyoto		Japan	602-8566
16	Tohoku University Hospital	Miyagi		Japan	980-8574
17	The Cancer Institute Hospital of JFCR	Tokyo		Japan	135-8550

Sponsors and Collaborators

• Celgene

Investigators

• Study Director: Toru Sasaki, Celgene K.K.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT01456039
• Other Study ID Numbers: ROMI-TCL-001
• First Posted: Oct 20, 2011
• Last Update Posted: Feb 11, 2019
• Last Verified: Jan 1, 2019

• Additional relevant MeSH terms: Lymphoma; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Romidepsin

Study Results

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 Detail	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.

Arm/Group Title	Phase 1: Romidepsin 9mg/m^2	Phase 1: Romidepsin 14mg/m^2	Phase 2: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Period Title: Phase 1 (First Step)
STARTED	3	8	0
COMPLETED	1	1	0
NOT COMPLETED	2	7	0
Period Title: Phase 1 (First Step)
STARTED	0	0	40
COMPLETED	0	0	7
NOT COMPLETED	0	0	33

Baseline Characteristics

Arm/Group Title	Phase 1: Romidepsin 9mg/m^2	Phase 1: Romidepsin 14mg/m^2	Phase 2: Romidepsin 14mg/m^2	Total
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Total of all reporting groups
Overall Participants	3	7	40	50
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.0 (9.54)	73.6 (4.20)	68.5 (8.43)	68.7 (8.47)
Age, Customized (participants) [Number]
<65 years	2 66.7%	0 0%	12 30%	14 28%
≥65 years	1 33.3%	7 100%	28 70%	36 72%
Sex: Female, Male (Count of Participants)
Female	2 66.7%	2 28.6%	17 42.5%	21 42%
Male	1 33.3%	5 71.4%	23 57.5%	29 58%
Disease Type by Investigator (participants) [Number]
PTCL	2 66.7%	6 85.7%	40 100%	48 96%
CTCL	1 33.3%	1 14.3%	0 0%	2 4%
Eastern Cooperative Oncology Group (ECOG) (participants) [Number]
0 = (Fully Active)	0 0%	4 57.1%	22 55%	26 52%
1 = (Restrictive but ambulatory)	1 33.3%	2 28.6%	14 35%	17 34%
2 = (Ambulatory but unable to work)	2 66.7%	1 14.3%	4 10%	7 14%
3 = (Limited self care)	0 0%	0 0%	0 0%	0 0%
4 = (Completely Disabled)	0 0%	0 0%	0 0%	0 0%
Body Surface Area (BSA) (m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m2]	1.640 (0.1114)	1.563 (0.2034)	1.554 (0.1768)	1.561 (0.1757)

Outcome Measures

1. Primary Outcome

Title	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)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	3	6
Number [participants]	0 0%	0 0%

2. Primary Outcome

Title	Percentage of PTCL Participants With an Overall Best Response in Accordance With a Modified International Workshop Response Criteria (IWC) 1999 in Phase 2
Description	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

Outcome Measure Data

Analysis Population Description

Intent to treat population for participants with PTCL who received at least one dose of Romidepsin

Arm/Group Title	Phase 1: Romidepsin 9mg/m^2	Phase 1: Romidepsin 14mg/m^2	Phase 2: Romidepsin 14mg/m^2	Total: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	2	6	40	46
Number (95% Confidence Interval) [percentage of participants]	0 0%	66.7 952.9%	42.5 106.3%	45.7 91.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Romidepsin 14mg/m^2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Based on one sample binomial test for dichotomized response proportion against the null hypothesis ( H0 p≤0.1)
	Method	Binomial test for dichotomized response
	Comments

3. Secondary Outcome

Title	Participants With Treatment-Emergent Adverse Events (TEAEs) Associated With Romidepsin
Description	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

Outcome Measure Data

Analysis Population Description

Safety population includes all participants who received at least one dose of romidepsin

Arm/Group Title	Phase 1: Romidepsin 9mg/m^2	Phase 1: Romidepsin 14mg/m^2	Phase 2: Romidepsin 14mg/m^2	Total: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	3	7	40	47
Any 1 TEAE	3 100%	7 100%	40 100%	47 94%
TEAE related to any study drug	3 100%	7 100%	40 100%	47 94%
TEAE with CTCAE Grade 3 or greater	3 100%	6 85.7%	37 92.5%	43 86%
TEAE with CTCAE ≥Grade 3 related to study drug	3 100%	6 85.7%	37 92.5%	43 86%
≥ 1 serious TEAE	1 33.3%	4 57.1%	10 25%	14 28%
Serious TEAE related to study drug	0 0%	4 57.1%	6 15%	10 20%
TEAE leading to discontinuation of study drug	0 0%	3 42.9%	10 25%	13 26%
TEAE related leading to discontinuation of drug	0 0%	3 42.9%	9 22.5%	12 24%
TEAE leading to dose held of study drug	1 33.3%	4 57.1%	24 60%	28 56%
Related TEAE leading to dose held of study drug	1 33.3%	3 42.9%	22 55%	25 50%
TEAE leading to dose reduction of study drug	0 0%	4 57.1%	17 42.5%	21 42%
Related TEAE leading to dose reduction of drug	0 0%	4 57.1%	17 42.5%	21 42%
TEAE leading to dose interruption of study drug	1 33.3%	4 57.1%	23 57.5%	27 54%
Related TEAE leading to dose interruption of drug	1 33.3%	3 42.9%	22 55%	25 50%
At least one TEAE with NCI CTCAE Grade 5	0 0%	0 0%	2 5%	2 4%

4. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Romidepsin in Phase 1
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	3	7
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	1023.76 (66.7)	2325.55 (35.3)

5. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of Romidepsin in Phase 1
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	3	7
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	1027.08 (66.6)	2330.91 (35.2)

6. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Romidepsin in Phase 1
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	3	7
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	269.75 (48.9)	593.47 (37.2)

7. Secondary Outcome

Title	Time to Maximum Plasma Concentration of Romidepsin (Tmax) in Phase 1
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	3	7
Median (Full Range) [hours]	4.02	2.00

8. Secondary Outcome

Title	Terminal Phase Half-life of Romidepsin (t½) in Phase 1
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	3	7
Geometric Mean (Geometric Coefficient of Variation) [hours]	9.52 (19.8)	9.12 (11.6)

9. Secondary Outcome

Title	Apparent Total Clearance of Romidepsin (CL/F) of Romidepsin in Phase 1
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	3	7
Geometric Mean (Geometric Coefficient of Variation) [L/h]	14.29 (60.8)	9.31 (35.4)

10. Secondary Outcome

Title	Apparent Volume of Distribution (Vz/F) of Romidepsin in Phase 1
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	3	7
Geometric Mean (Geometric Coefficient of Variation) [Liters]	196.24 (86.8)	122.47 (40.4)

11. Secondary Outcome

Title	AUC0-t, at Steady State (ss) of Romidepsin in Phase 1 at Cycle 1, Day 15
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	3	6
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	1024.66 (78.1)	1825.74 (25.8)

12. Secondary Outcome

Title	Cmax, ss of Romidepsin in Phase 1 at Cycle 1, Day 15
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	3	6
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	250.05 (63.3)	489.47 (31.2)

13. Secondary Outcome

Title	Tmax,ss of Romidepsin in Phase 1 at Cycle 1, Day 15
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	3	6
Median (Full Range) [hours]	1.95	2.94

14. Secondary Outcome

Title	Terminal Phase Half-life of Romidepsin (t½) in Phase 1 at Cycle 1, Day 15
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	3	6
Geometric Mean (Geometric Coefficient of Variation) [hours]	8.77 (18.6)	9.01 (15.8)

15. Secondary Outcome

Title	AUC0-t, Accumulation Ratio of Romidepsin in Phase 1, Cycle 1
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	3	6
Geometric Mean (Geometric Coefficient of Variation) [ratio]	1.00 (19.6)	0.83 (24.3)

16. Secondary Outcome

Title	Cmax Accumulation Ratio of Romidepsin in Phase 1, Cycle 1
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	3	6
Geometric Mean (Geometric Coefficient of Variation) [ratio]	0.93 (15.3)	0.86 (22.2)

17. Secondary Outcome

Title	The Percentage of Participants With Abnormal Q-wave and T Wave Intervals
Description	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

Outcome Measure Data

Analysis Population Description

The ECG population includes all participants who received romidepsin on Day 1 of Cycle 1 with at least one post-baseline QTc result

Arm/Group Title	Phase 1: Romidepsin 9mg/m^2	Phase 1: Romidepsin 14mg/m^2	Phase 2: Romidepsin 14mg/m^2	Total: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	3	7	40	47
QTcB >450 msec	100 3333.3%	57.1 815.7%	55.0 137.5%	55.3 110.6%
QTcB >480 msec	66.7 2223.3%	28.6 408.6%	0.0 0%	4.3 8.6%
QTcB >500 msec	33.3 1110%	14.3 204.3%	0.0 0%	2.1 4.2%
QTcB increase from predose >30 msec	66.7 2223.3%	57.1 815.7%	10.0 25%	17.0 34%
QTcB increase from predose >60 msec	33.3 1110%	28.6 408.6%	0.0 0%	4.3 8.6%
QTcF >450 msec	33.3 1110%	14.3 204.3%	10.0 25%	10.6 21.2%
QTcF >480 msec	33.3 1110%	14.3 204.3%	0.0 0%	2.1 4.2%
QTcF >500 msec	33.3 1110%	14.3 204.3%	0.0 0%	2.1 4.2%
QTcF increase from predose >30 msec	66.7 2223.3%	57.1 815.7%	10.0 25%	17.0 34%
QTcF increase from predose >60 msec	33.3 1110%	14.3 204.3%	0.0 0%	2.1 4.2%

18. Secondary Outcome

Title	Percentage of PTCL Participants With the Best Response in Accordance With the Modified 2007 International Workshop Response Criteria as Assessed by IER
Description	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

Outcome Measure Data

Analysis Population Description

Intent to treat population for participants with PTCL who received at least one dose of romidepsin

Arm/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2	Phase 2: Romidepsin 14mg/m^2	Total: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	2	6	40	46
Number (95% Confidence Interval) [percentage of participants]	0 0%	16.7 238.6%	42.5 106.3%	39.1 78.2%

19. Secondary Outcome

Title	Time to Response (TTR) for PTCL Participants With at Least a PR Based on the Modified 1999 IWC as Assessed by IER
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Romidepsin 14mg/m^2	Phase 2: Romidepsin 14mg/m^2	Total: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	4	17	21
Median (Full Range) [days]	109.0	56.0	56.0

20. Secondary Outcome

Title	Time to Response (TTR) for PTCL Participants With at Least a PR Based on the Modified 2007 IWC as Assessed by IER
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Romidepsin 14mg/m^2	Phase 2: Romidepsin 14mg/m^2	Total: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	1	17	18
Median (Full Range) [days]	737.0	56.0	56.0

21. Secondary Outcome

Title	Kaplan Meier Estimate of Duration of Response (DOR) for PTCL Responders Based on the Modified 1999 IWC as Assessed by the IER.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Cohort 2: Romidepsin 14mg/m^2	Phase 2: Romidepsin 14mg/m^2	Total: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	4	17	21
Median (95% Confidence Interval) [days]	106.00	337.00	337.00

22. Secondary Outcome

Title	Kaplan Meier Estimate of Duration of Response (DOR) for PTCL Responders Based on the Modified 2007 IWC as Assessed by the IER.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Phase 1: Cohort 2: Romidepsin 14mg/m^2	Phase 2: Romidepsin 14mg/m^2	Total: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	1	17	18
Median (95% Confidence Interval) [days]	163.00	337.00	163.00

23. Secondary Outcome

Title	Kaplan Meier Estimate of Time to Progression (TTP) in PTCL Participants Based on the 1999 IWC as Assessed by IER
Description	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

Outcome Measure Data

Analysis Population Description

ITT includes all participants who received at least one dose of romidepsin

Arm/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2	Phase 2: Romidepsin 14mg/m^2	Total: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	2	6	40	46
Median (95% Confidence Interval) [days]	114.00	899.00	170.00	179.00

24. Secondary Outcome

Title	Kaplan Meier (K-M) Estimate of Time to Progression (TTP) in PTCL Participants Based on the Modified 2007 IWC as Assessed by IER
Description	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

Outcome Measure Data

Analysis Population Description

ITT includes all participants who received at least one dose of romidepsin

Arm/Group Title	Phase 1: Cohort 1: Romidepsin 9mg/m^2	Phase 1: Cohort 2: Romidepsin 14mg/m^2	Phase 2: Romidepsin 14mg/m^2	Total: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.	Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
Measure Participants	2	6	40	46
Median (95% Confidence Interval) [days]	NA	899.00	179.00	179.00

Adverse Events

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 time exposed to study was 1290 days; maximum time on study treatment was 184.3 weeks
Arm/Group Title	Phase 1: Romidepsin 9mg/m^2		Phase 1: Romidepsin 14mg/m^2		Phase 2: Romidepsin 14mg/m^2		Total: Romidepsin 14mg/m^2
Arm/Group Description	Romidepsin 9mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle		Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.		Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.		Romidepsin 14mg/m^2 by intravenous (IV) infusion on Days 1, 8, 15 of each 28-day cycle.
All Cause Mortality
	Phase 1: Romidepsin 9mg/m^2		Phase 1: Romidepsin 14mg/m^2		Phase 2: Romidepsin 14mg/m^2		Total: Romidepsin 14mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase 1: Romidepsin 9mg/m^2		Phase 1: Romidepsin 14mg/m^2		Phase 2: Romidepsin 14mg/m^2		Total: Romidepsin 14mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		4/7 (57.1%)		10/40 (25%)		14/47 (29.8%)
Cardiac disorders
Angina pectoris	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Cardiac failure acute	0/3 (0%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Cardio-respiratory arrest	0/3 (0%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Eye disorders
Retinal detachment	0/3 (0%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
General disorders
Pyrexia	0/3 (0%)		0/7 (0%)		2/40 (5%)		2/47 (4.3%)
Multi-organ failure	0/3 (0%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Hepatobiliary disorders
Hepatic function abnormal	0/3 (0%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Infections and infestations
Cytomegalovirus infection	0/3 (0%)		1/7 (14.3%)		1/40 (2.5%)		2/47 (4.3%)
Bacterial infection	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Hepatitis B	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Pneumocystis jiroveci pneumonia	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Pneumonia	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Pneumonia bacterial	0/3 (0%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Sepsis	0/3 (0%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Urinary tract infection	0/3 (0%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Metabolism and nutrition disorders
Dehydration	0/3 (0%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Hyperkalemia	0/3 (0%)		0/7 (0%)		1/40 (2.5%)		0/47 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	0/3 (0%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Diffuse large B-cell lymphoma	0/3 (0%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Tumour associated fever	0/3 (0%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Nervous system disorders
Akathisia	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Altered state of consciousness	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Depressed level of consciousness	0/3 (0%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/3 (0%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Other (Not Including Serious) Adverse Events
	Phase 1: Romidepsin 9mg/m^2		Phase 1: Romidepsin 14mg/m^2		Phase 2: Romidepsin 14mg/m^2		Total: Romidepsin 14mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		7/7 (100%)		40/40 (100%)		47/47 (100%)
Blood and lymphatic system disorders
Thrombocytopenia	3/3 (100%)		7/7 (100%)		39/40 (97.5%)		46/47 (97.9%)
Lymphopenia	3/3 (100%)		7/7 (100%)		34/40 (85%)		41/47 (87.2%)
Leukopenia	3/3 (100%)		6/7 (85.7%)		33/40 (82.5%)		39/47 (83%)
Neutropenia	3/3 (100%)		5/7 (71.4%)		32/40 (80%)		37/47 (78.7%)
Anaemia	2/3 (66.7%)		3/7 (42.9%)		12/40 (30%)		15/47 (31.9%)
Cardiac disorders
Atrial fibrillation	0/3 (0%)		1/7 (14.3%)		3/40 (7.5%)		4/47 (8.5%)
Supraventriclar extrasystoles	0/3 (0%)		1/7 (14.3%)		1/40 (2.5%)		2/47 (4.3%)
Angina pectoris	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Long QT syndrome	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Pericardial effusion	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Eye disorders
Iritis	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Vitreous Floaters	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Gastrointestinal disorders
Nausea	3/3 (100%)		4/7 (57.1%)		20/40 (50%)		24/47 (51.1%)
Vomiting	3/3 (100%)		3/7 (42.9%)		15/40 (37.5%)		18/47 (38.3%)
Diarrhoea	2/3 (66.7%)		2/7 (28.6%)		14/40 (35%)		16/47 (34%)
Constipation	0/3 (0%)		1/7 (14.3%)		15/40 (37.5%)		16/47 (34%)
Stomatitis	0/3 (0%)		2/7 (28.6%)		6/40 (15%)		8/47 (17%)
Abdominal discomfort	0/3 (0%)		1/7 (14.3%)		1/40 (2.5%)		2/47 (4.3%)
Abdominal pain upper	1/3 (33.3%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Lip dry	2/3 (66.7%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Periodontal disease	0/3 (0%)		0/7 (0%)		2/40 (5%)		2/47 (4.3%)
Dental caries	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Gastritis	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Haemorrhoids	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Sensitivity of teeth	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
General disorders
Pyrexia	3/3 (100%)		5/7 (71.4%)		23/40 (57.5%)		28/47 (59.6%)
Fatigue	3/3 (100%)		1/7 (14.3%)		12/40 (30%)		13/47 (27.7%)
Malaise	0/3 (0%)		3/7 (42.9%)		10/40 (25%)		13/47 (27.7%)
Injection site reaction	0/3 (0%)		2/7 (28.6%)		4/40 (10%)		6/47 (12.8%)
Oedema peripheral	1/3 (33.3%)		0/7 (0%)		3/40 (7.5%)		3/47 (6.4%)
Chills	0/3 (0%)		0/7 (0%)		2/40 (5%)		2/47 (4.3%)
Face oedema	0/3 (0%)		0/7 (0%)		2/40 (5%)		2/47 (4.3%)
Hypothermia	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Influenza like illness	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Non-cardiac chest pain	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Hepatobiliary disorders
Hepatic function abnormal	0/3 (0%)		0/7 (0%)		3/40 (7.5%)		3/47 (6.4%)
Biliary colic	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Hyperbilirubinaemia	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Infections and infestations
Nasopharyngitis	1/3 (33.3%)		1/7 (14.3%)		2/40 (5%)		3/47 (6.4%)
Influenza	1/3 (33.3%)		1/7 (14.3%)		1/40 (2.5%)		2/47 (4.3%)
Cytomegalovirus infection	0/3 (0%)		1/7 (14.3%)		1/40 (2.5%)		2/47 (4.3%)
Upper respiratory tract infection	1/3 (33.3%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Urinary Tract Infection	0/3 (0%)		1/7 (14.3%)		1/40 (2.5%)		2/47 (4.3%)
Bacterial Infection	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Infected epidermal cyst	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Infection	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Pneumocystis jiroveci pneumonia	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Injury, poisoning and procedural complications
Contusion	1/3 (33.3%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Excoriation	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Fall	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Procedural Pain	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Investigations
Haemoglobin decreased	2/3 (66.7%)		2/7 (28.6%)		9/40 (22.5%)		11/47 (23.4%)
Alanine aminotransferase increased	1/3 (33.3%)		2/7 (28.6%)		7/40 (17.5%)		9/47 (19.1%)
Weight decreased	2/3 (66.7%)		2/7 (28.6%)		6/40 (15%)		8/47 (17%)
Aspartate aminotransferase increased	0/3 (0%)		1/7 (14.3%)		8/40 (20%)		9/47 (19.1%)
Blood alkaline phosphatase increased	1/3 (33.3%)		0/7 (0%)		3/40 (7.5%)		3/47 (6.4%)
Blood lactate dehydrogenase increased	0/3 (0%)		0/7 (0%)		4/40 (10%)		4/47 (8.5%)
Electrocardiogram QT prolonged	0/3 (0%)		2/7 (28.6%)		1/40 (2.5%)		3/47 (6.4%)
Blood phosphorus increased	2/3 (66.7%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Blood urea increased	1/3 (33.3%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Blood bilirubin increased	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Electrocardiogram ST-T change	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Electrocardiogram ST-T segment elevation	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Electrocardiogram T wave inversion	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Renal Function Test abnormal	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Gamma-glutamyltransferase increased	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Metabolism and nutrition disorders
Decreased appetite	3/3 (100%)		4/7 (57.1%)		21/40 (52.5%)		25/47 (53.2%)
Hypokalaemia	1/3 (33.3%)		2/7 (28.6%)		7/40 (17.5%)		9/47 (19.1%)
Hypophosphataemia	0/3 (0%)		1/7 (14.3%)		9/40 (22.5%)		10/47 (21.3%)
Hyponatraemia	0/3 (0%)		2/7 (28.6%)		6/40 (15%)		8/47 (17%)
Hypermagnesaemia	1/3 (33.3%)		1/7 (14.3%)		4/40 (10%)		5/47 (10.6%)
Hypoalbuminaemia	0/3 (0%)		1/7 (14.3%)		5/40 (12.5%)		6/47 (12.8%)
Hypocalcaemia	1/3 (33.3%)		1/7 (14.3%)		4/40 (10%)		5/47 (10.6%)
Hyperkalaemia	0/3 (0%)		1/7 (14.3%)		4/40 (10%)		5/47 (10.6%)
Hypomagnesaemia	0/3 (0%)		0/7 (0%)		4/40 (10%)		4/47 (8.5%)
Dehydration	0/3 (0%)		0/7 (0%)		3/40 (7.5%)		3/47 (6.4%)
Hyperuricaemia	1/3 (33.3%)		0/7 (0%)		2/40 (5%)		2/47 (4.3%)
Tumour lysis syndrome	0/3 (0%)		0/7 (0%)		3/40 (7.5%)		3/47 (6.4%)
Hypercalcaemia	0/3 (0%)		0/7 (0%)		2/40 (5%)		2/47 (4.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/3 (33.3%)		1/7 (14.3%)		3/40 (7.5%)		4/47 (8.5%)
Back Pain	1/3 (33.3%)		2/7 (28.6%)		2/40 (5%)		4/47 (8.5%)
Musculoskeletal stiffness	1/3 (33.3%)		0/7 (0%)		2/40 (5%)		2/47 (4.3%)
Osteoarthritis	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Pain in extremity	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Periarthritis	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Muscle Spasms	0/3 (0%)		0/7 (0%)		2/40 (5%)		2/47 (4.3%)
Musculoskeletal pain	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer Pain	1/3 (33.3%)		0/7 (0%)		2/40 (5%)		2/47 (4.3%)
Tumour associated fever	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Nervous system disorders
Dysgeusia	3/3 (100%)		4/7 (57.1%)		24/40 (60%)		28/47 (59.6%)
Headache	1/3 (33.3%)		0/7 (0%)		6/40 (15%)		6/47 (12.8%)
Peripheral Sensory neuropathy	3/3 (100%)		0/7 (0%)		2/40 (5%)		2/47 (4.3%)
Akathisia	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Carotid arteriosclerosis	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Somnolence	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Psychiatric disorders
Insomnia	2/3 (66.7%)		0/7 (0%)		3/40 (7.5%)		3/47 (6.4%)
Renal and urinary disorders
Proteinuria	0/3 (0%)		1/7 (14.3%)		1/40 (2.5%)		2/47 (4.3%)
Pollakiuria	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/3 (33.3%)		3/7 (42.9%)		2/40 (5%)		5/47 (10.6%)
Upper respiratory tract inflammation	0/3 (0%)		0/7 (0%)		4/40 (10%)		4/47 (8.5%)
Cough	0/3 (0%)		1/7 (14.3%)		1/40 (2.5%)		2/47 (4.3%)
Oropharyngeal pain	0/3 (0%)		1/7 (14.3%)		1/40 (2.5%)		2/47 (4.3%)
Pleural effusion	0/3 (0%)		1/7 (14.3%)		1/40 (2.5%)		2/47 (4.3%)
Hiccups	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Pneumonitis	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Skin and subcutaneous tissue disorders
Rash	0/3 (0%)		1/7 (14.3%)		4/40 (10%)		5/47 (10.6%)
Dry Skin	0/3 (0%)		0/7 (0%)		2/40 (5%)		2/47 (4.3%)
Hyperhidrosis	1/3 (33.3%)		0/7 (0%)		1/40 (2.5%)		1/47 (2.1%)
Erythema	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Haemorrhage subcutaneous	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Henoch-Schonlein purpura	0/3 (0%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)
Rash macular	1/3 (33.3%)		0/7 (0%)		0/40 (0%)		0/47 (0%)
Vascular disorders
Phlebitis	1/3 (33.3%)		2/7 (28.6%)		1/40 (2.5%)		3/47 (6.4%)
Hypotension	2/3 (66.7%)		1/7 (14.3%)		0/40 (0%)		1/47 (2.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Disclosure agreements vary; the Investigators shall not disclose any material/information disclosed by the Sponsor (Celgene KK) with the clinical trial or information obtained by conducting the clinical trial to third parties without Sponsor's prior written approval.