Phase I Study of KW-0761 in Relapsed Patients With CCR4-Positive ATL and PTCL

Study Overview
=================
Brief Summary
-----------------
This is a Phase I label dose escalation study of KW-0761 in relapsed patients with CCR4 positive Adult T-Cell Leukemia-Lymphoma (ATL) and Peripheral T-Cell lymphoma (PTCL).

Detailed Description
-----------------
This is a Phase I open-label dose escalation study of KW-0761 in relapsed patients with CCR4 positive Adult T-Cell Leukemia-Lymphoma (ATL) and Peripheral T-Cell Lymphoma (PTCL). This study is designed to evaluate safety, pharmacokinetics, immunogenicity and preliminary efficacy. Enrollment will proceed until a maximum tolerated dose (MTD) and a recommended Phase II dose (RPIID) have been established.

Official Title
-----------------
Phase I Dose Escalation Study of KW-0761 in Patients With Relapsed Adult T-Cell Lymphoma (ATL) and Peripheral T-Cell Lymphoma (PTCL)

Conditions
-----------------
Adult T-Cell Leukemia and Lymphoma (ATL), Adult Peripheral T-Cell Lymphoma (PTCL)

Intervention / Treatment
-----------------
* Drug: KW-0761


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 1. Histologically confirmed diagnosis of a CCR4-positive ATL and PTCL that is any of the following: A. ATL (Adult T-Cell Leukemia-Lymphoma) Seropositive for anti-Human T-lymphotrophic Virus type-I (HTLV-I) antibody; Acute, Lymphoma, or Chronic phase with high-risk factors (within 14 days before the study entry); B. PTCL (Peripheral T-Cell Lymphoma) Includes Mycosis Fungoides and Sezary Syndrome; 2: Relapsed to the latest standard chemotherapy; 3: Received at least one prior chemotherapy; 4: After 4 weeks from a prior therapy; 5: Have measurable disease; 6:Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1; 7: Male or female, at least 20 years and not older than 70 years of age; 8: Signed written informed consent; 9: Stay in hospital for 4 weeks; 10: HBs antigen: negative, HBV-DNA: below the limit of quantification (within 14 days before the study entry); 11: Adequate bone marrow, hepatic and cardiac function including the followings: Neutrophil count ≥ 1,500 /mm3, Platelets ≥ 75,000 /mm3, Hemoglobin ≥ 8.0 g/dL Serum creatinine ≤ 1.5 x ULN; Serum SGOT (AST) and SGPT (ALT) ≤ 2.5 x ULN (≤ 5.0 x ULN if considered due to disease involvement in liver); Serum bilirubin ≤ 1.5 x ULN (≤ 3.0 x ULN if considered due to disease involvement in liver) Serum calcium ≤ 11.0 mg/dL PaO2 ≥ 65 mmHg or SaO2 ≥ 90% No clinically significant Electrocardiogram abnormality Left Ventricular Ejection Fraction ≥ 50% [by ECHO or MUGA] Exclusion Criteria: Co-existing active infection or any co-existing medical condition that may compromise the safety of patients during the study, affect the patient's ability to complete the study, or interfere with interpretation of study results; Active tuberculosis; Prior stem cell transplantation; Myocardial infarction (within 12 months prior to the study entry); Concurrent acute or chronic hepatitis, or cirrhosis; Anti-HCV: positive, Anti-HIV: positive Concurrent active malignant disease; Known allergic reaction to antibody therapy; Concomitant treatment with systemic steroids; Prior and Concurrent psychiatric disorder including dementia, epilepsy or any other CNS diseases; Evidence of CNS metastasis at baseline; Prior and Concurrent spinal cord disease; Radiation therapy for bulky mass disease at the time of study entry or considered to require radiation therapy during the study; Female patients who are pregnant or breast feeding; Female patients of childbearing potential, unwilling to use an approved, effective means of contraception in accordance with the institution's standards; Treatment with any other investigational agent within the 4 months prior to study entry; For any reason is judged by the Investigator to be inappropriate for study participation, including an inability to communicate or cooperate with the Investigator.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 69 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: 1<br>KW-0761 | Drug: KW-0761<br>* IV administration at 4 escalating dose levels.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose-Limiting Toxicities (DLTs) | Subjects who were properly monitored for DLTs were to be analyzed to determine the number of subjects with a DLT by dose level. | 28 days | 
| Maximum Tolerated Dose (MTD) | The dose level at which Dose-Limiting Toxicity (DLT) was recognized was to be regarded as Maximum Tolerated Dose (MTD), and the dose level below MTD by one level was to be regarded as the recommended dose level (when MTD was not reached, 1.0 mg/kg was to be regarded as the recommended dose level) and 3 more subjects were to be newly added to the recommended dose level. | 28 days | 
| Pharmacokinetics-Plasma KW-0761 Concentrations | Plasma KW-0761 concentrations were to be summarized in tabular form with the descriptive statistics on a dose-by-dose basis. Individual and mean (+ standard deviation) plasma KW-0761 concentrations on an actual or logarithmic scale were to be plotted against the time of blood sampling. | 0-7 days post final dose | 
| Pharmacokinetics-Pharmacokinetic Parameters of KW-0761 (AUC0-7 Days) | The pharmacokinetic parameters of the subjects were to be individually calculated, and their descriptive statistics were to be calculated on a dose-by-dose basis. | 0-7 days post final dose | 
| Pharmacokinetics-Pharmacokinetic Parameters of KW-0761 (t1/2) | The pharmacokinetic parameters of the subjects were to be individually calculated, and their descriptive statistics were to be calculated on a dose-by-dose basis. | 0 to 28 days post final dose and follow-up examinations (1 month and 2 months after the end of the post-dosing observation period). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antitumor Effect | The antitumor response criteria (Complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD)) were created based on the criteria for non-Hodgkin's lymphoma and chronic lymphocytic leukemia provided in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology as well as the criteria for non-Hodgkin's lymphoma by the Lymphoma Study Group of the Japan Clinical Oncology Group (JCOG-LSG). | 50 days | 
| Time to Progression (TTP) | TTP was defined as the period from the day starting the first KW-0761 dosing to the day of PD identification (or the day of death if the subject died before PD was documented). Subjects were to be censored at the time of starting post-treatment, if it was started before PD identification. | Baseline to response | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Adult T-Cell Leukemia, ATL, Adult Peripheral T-Cell Lymphoma, PTCL