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

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

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

Eligibility Criteria:
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.