Trial Outcomes & Findings for A Japanese Phase 1/2 Study to Assess the Efficacy, Safety and Pharmacokinetics of Romidepsin in Patients With Peripheral T-cell Lymphoma (PTCL) (NCT NCT01456039)

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.

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.

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

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

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

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.

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.

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.

The maximum observed plasma concentration of romidepsin (Cmax) obtained directly from the observed concentration versus time data

The time to first maximum observed plasma concentration of romidepsin after a single dose on Day 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.

The apparent total clearance of romidepsin after a single dose on Day 1, calculated as dose/AUC0-infinity.

Apparent volume of distribution, was calculated according to the equation: Vd/F = (CL/F)/λz

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

Maximum observed concentration in plasma at steady state

Observed time to first maximum plasma concentration at steady state

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.

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)

Cmax of Romidepsin: accumulation ratio based on Cmax calculated as Cmax,ss/Cmax

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

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.

TTR for PTCL was defined as the time in days from first dose date to the first date of objective disease response.

TTR for PTCL was defined as the time in days from first dose date to the first date of objective disease response.

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.

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 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 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