A Trial of E7777 in Persistent and Recurrent Cutaneous T-Cell Lymphoma

Study Overview
=================
Brief Summary
-----------------
The purpose of this trial is to assess the efficacy of E7777 in participants with recurrent or persistent Cutaneous T-Cell Lymphoma (CTCL) in Stage I - III participants as assessed by objective response rate (ORR). A lead-in dose-finding part was used to determine dose level 9 microgram per kilogram (mcg/kg) E7777 that is being used to test efficacy and safety.

Detailed Description
-----------------
This is a multicenter, open-label study of E7777 in participants with recurrent or persistent CTCL. The study consists of an initial Lead-in part (to select recommended dose of E7777 for Main part), followed by the Main part (to test efficacy). Participants will move through three phases while on study: Pretreatment Phase, Treatment Phase, and Extension Phase and a Follow-up Period.

Official Title
-----------------
A Clinical Study to Demonstrate Safety and Efficacy of E7777 in Persistent or Recurrent Cutaneous T-Cell Lymphoma

Conditions
-----------------
Persistent or Recurrent Cutaneous T-Cell Lymphoma

Intervention / Treatment
-----------------
* Drug: E7777 9 mcg/kg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants must meet all of the following criteria to be included in the study: Age greater than or equal to 18 years. Histopathologic diagnosis of CTCL (mycosis fungoides [MF] or Sezary Syndrome [SS]), confirmed by skin biopsy, or lymph node, or blood assessment, of current disease. CD25 assay-positive tumor, defined as detectable CD25 on greater than or equal to 20% of total lymphoid infiltrate in biopsied lesions by immunohistochemistry. CTCL disease stage at study entry as follows, according to ISCL/EORTC (Olsen 2011). Lead-In Part: Stage IA - IV, except participants with CNS involvement. Main Study: Stage I - III History of prior therapies for CTCL: must have had prior therapy, any number of prior therapies allowed. Topical treatments (except topical chemotherapy) and steroids are not considered as prior therapies. A minimum washout period of 4 weeks after previous CTCL therapy is recommended before the first dose of E7777. Participants must have recovered from any adverse effects from any previous CTCL therapy to Common Terminology Criteria for Adverse Events (CTCAE) Grade <2 before starting study drug. A shorter washout may be allowed if participant is experiencing progressive disease despite ongoing treatment. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 in the Lead-In Part and performance status of 0 or 1 in the Main Study. Life expectancy greater than or equal to 3 months in the Lead-In Part and greater than or equal to 12 months in the Main Study. Adequate bone marrow reserves as evidenced by: platelets greater than or equal to 100,000/mm^3 (100 x 10^9/L) clinically stable hemoglobin greater than or equal to 9 gram per deciliter (g/dL) (90 g/L) and hematocrit greater than or equal to 27% without transfusion support Normal hepatic function as evidenced by: bilirubin <= 1.5* upper limit if normal (ULN) and alkaline phosphatase <=3.0*ULN aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 3.0*ULN albumin >= 3.0 g/dL (30 g/L) Adequate renal function as evidenced by serum creatinine less than or equal to 1.8 mg/dL (158 umol/L) or calculated creatinine clearance greater than or equal to 50 mL/min (per the Cockcroft-Gault formula) with less than 2+ protein or 24- hour urine creatinine clearance greater than or equal to 50 mL/minute with 24- hour urine protein less than 1gram. Provide written informed consent prior to any study-specific screening procedures. Females may not be lactating or pregnant at Screening or Baseline All females will be considered to be of childbearing potential unless they are postmenopausal or have been sterilized surgically Male participants must have had a successful vasectomy (confirmed azoospermia) or they and their female partner must meet the criteria above Exclusion Criteria Participants who meet any of the following criteria will be excluded from the study: Prior denileukin diftitox therapy Use of topical steroids within 14 days of Day 1 of initial therapy is not allowed.Topical steroids or systemic low dose steroids of less than or equal to 10 milligram per day (mg/day) prednisone are allowed in participants with erythroderma who have been on corticosteroids for a prolonged period of time and where discontinuation may lead to rebound flare in disease. The concomitant steroid medication is allowed as long as the type of steroid, route of administration, and steroid dose remain the same as what the participant had been receiving for a prolonged period of time. Active malignancy (except for CTCL, definitively treated basal or squamous cell carcinoma of the skin, and carcinoma in-situ of the cervix) within the past 24 months. Serious intercurrent illness Significant cardiac disease requiring ongoing treatment, including congestive heart failure (CHF), severe coronary artery disease (CAD), cardiomyopathy, uncontrolled cardiac arrhythmia, unstable angina pectoris, or myocardial infarction (MI) Significant pulmonary symptoms or disease History of uncontrolled seizure disorder or active central nervous system disease Major surgery within 2 weeks of study enrollment Significant or uncontrolled infections requiring systemic anti-infective therapy Known human immunodeficiency virus (HIV) infection; known active hepatitis B or hepatitis C infection Females who are pregnant (positive urine test) or breastfeeding Any history of a medical condition or a concomitant medical condition that, in the opinion of the investigator, would compromise the participant's ability to safely complete the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: E7777<br> | Drug: E7777 9 mcg/kg<br>* administered by intravenous (i.v.) infusion over 60 minutes (+/-10 minutes) on 5 consecutive days during every cycle of 21 days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicities (DLTs) in the Lead-In Part |  | Cycle 1 (21 days) | 
| Maximum Tolerated Dose (MTD) in the Lead-In Part |  | Up to12 months | 
| ORR in the Main study |  | Day 1 until disease progression/recurrence, or up to 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) |  | Day 1 until disease progression/recurrence, or up to 12 months (Lead-in Part) and Day 1 until disease progression/recurrence, or up to 30 months (Main Study) | 
| Time to Response (TTR) |  | Up to 12 months (Lead-In Part) and up to 30 months (Main study) | 
| ORR |  | Day 1 until disease progression/recurrence, up to 12 months (Lead-in Part) and Day 1 until disease progression/recurrence, up to 30 months (by using Prince (2010) criteria in Main Study) | 
| Number of Participants with Any Adverse Event and Any Serious Adverse Event (SAE) |  | From first dose of the study drug until 30 days after the last dose, or up to 30 months | 
| Maximum Drug Concentration (Cmax) |  | Cycles 1, 3, 5 Day 1: pre-dose-300 minutes post infusion stop (Lead-in part and for first 12 participants in the Main study) (Cycle length is equal to [=] 21 days) | 
| Area Under the Curve from Time 0 to Time t (AUC[0-t]) |  | Cycles 1, 3, 5 Day 1: pre-dose-300 minutes post infusion stop (Lead-in part and for first 12 participants in the Main study) (Cycle length=21 days) | 
| Area Under the Curve from Time 0 to Time Infinity (AUC[0-inf]) |  | Cycles 1, 3, 5 Day 1: pre-dose-300 minutes post infusion stop (Lead-in part and for first 12 participants in the Main study) (Cycle length=21 days) | 
| Terminal Elimination Half-life (t1/2) |  | Cycles 1, 3, 5 Day 1: pre-dose-300 minutes post infusion stop (Lead-in part and for first 12 participants in the Main study) (Cycle length=21 days) | 
| Time to Reach Maximum (peak) Concentration After Drug Administration (Tmax) |  | Cycles 1, 3, 5 Day 1: pre-dose-300 minutes post infusion stop (Lead-in part and for first 12 participants in the Main study) (Cycle length=21 days) | 
| Total Body Clearance (CL) |  | Cycles 1, 3, 5 Day 1: pre-dose-300 minutes post infusion stop (Lead-in part and for first 12 participants in the Main study) (Cycle length=21 days) | 
| Volume of Distribution at Steady State (Vdss) |  | Cycles 1, 3, 5 Day 1: pre-dose-300 minutes post infusion stop (Lead-in part and for first 12 participants in the Main study) (Cycle length=21 days) | 
| Percentage of Participants Testing Positive for Anti-E7777 and Anti-IL-2 Antibodies |  | Da y 1 of Cycles 1, 2, 3, 5, and 8 (for Anti-E7777 and Anti-IL-2); Anti-IL-2 is to be tested at 6 month, 1 year, and thereafter every year until antibody levels decrease to baseline levels | 
| Number of Participants with Skin Response in the Main Study |  | Day 1 until disease progression/recurrence, or up to 30 months | 
| Duration of Skin Response in the Main Study |  | Day 1 until disease progression/recurrence, or up to 30 months | 
| Time to Skin Response in the Main Study |  | Up to 30 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Persistent or Recurrent Cutaneous T-Cell Lymphoma, E7777