Adult T-Cell Leukemia and Lymphoma (ATL), Adult Peripheral T-Cell Lymphoma (PTCL)
Conditions
Keywords
Adult T-Cell Leukemia, ATL, Adult Peripheral T-Cell Lymphoma, PTCL
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.
Interventions
DRUGKW-0761
IV administration at 4 escalating dose levels.
Sponsors
Kyowa Kirin Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 69 Years
Healthy volunteers
No
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
1. 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; 2. Active tuberculosis; 3. Prior stem cell transplantation; 4. Myocardial infarction (within 12 months prior to the study entry); 5. Concurrent acute or chronic hepatitis, or cirrhosis; 6. Anti-HCV: positive, Anti-HIV: positive 7. Concurrent active malignant disease; 8. Known allergic reaction to antibody therapy; 9. Concomitant treatment with systemic steroids; 10. Prior and Concurrent psychiatric disorder including dementia, epilepsy or any other CNS diseases; 11. Evidence of CNS metastasis at baseline; 12. Prior and Concurrent spinal cord disease; 13. Radiation therapy for bulky mass disease at the time of study entry or considered to require radiation therapy during the study; 14. Female patients who are pregnant or breast feeding; 15. Female patients of childbearing potential, unwilling to use an approved, effective means of contraception in accordance with the institution's standards; 16. Treatment with any other investigational agent within the 4 months prior to study entry; 17. For any reason is judged by the Investigator to be inappropriate for study participation, including an inability to communicate or cooperate with the Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | 28 days | 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. |
| Pharmacokinetics-Pharmacokinetic Parameters of KW-0761 (AUC0-7 Days) | 0-7 days post final dose | 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. |
| Pharmacokinetics-Pharmacokinetic Parameters of KW-0761 (t1/2) | 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). | 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. |
| Incidence of Dose-Limiting Toxicities (DLTs) | 28 days | Subjects who were properly monitored for DLTs were to be analyzed to determine the number of subjects with a DLT by dose level. |
| Pharmacokinetics-Plasma KW-0761 Concentrations | 0-7 days post final dose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression (TTP) | Baseline to response | 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. |
| Antitumor Effect | 50 days | 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). |
Countries
Japan
Participant flow
Recruitment details
Participants were enrolled from 6 February 2007 through 22 October 2008
Participants by arm
| Arm | Count |
|---|---|
| KW-0761 KW-0761 was administered 4 times at one-week intervals at a dose of 0.01, 0.1, 0.5 or 1.0 mg/kg in patients with CCR4 positive ATL or CCR4 positive PTCL | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | KW-0761 |
|---|---|
| Age Continuous | 62 years |
| Diagnosis ATL | 13 participants |
| Diagnosis PTCL | 3 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 1 / 3 | 1 / 4 | 0 / 3 | 1 / 6 |
Outcome results
Primary
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.
Time frame: 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| KW-0761 | Incidence of Dose-Limiting Toxicities (DLTs) | 1 participants |
Primary
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.
Time frame: 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| KW-0761 | Maximum Tolerated Dose (MTD) | 1.0 mg/kg |
Primary
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.
Time frame: 0-7 days post final dose
Population: AUC0-7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KW-0761 | Pharmacokinetics-Pharmacokinetic Parameters of KW-0761 (AUC0-7 Days) | 36586 ng·h/mL | Standard Deviation 2987 |
| KW-0761 0.1mg | Pharmacokinetics-Pharmacokinetic Parameters of KW-0761 (AUC0-7 Days) | 327609 ng·h/mL | Standard Deviation 322298 |
| KW-0761 0.5mg | Pharmacokinetics-Pharmacokinetic Parameters of KW-0761 (AUC0-7 Days) | 1625609 ng·h/mL | Standard Deviation 142277 |
| KW-0761 1.0mg | Pharmacokinetics-Pharmacokinetic Parameters of KW-0761 (AUC0-7 Days) | 4190238 ng·h/mL | Standard Deviation 544757 |
Primary
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.
Time frame: 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).
Population: t1/2
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KW-0761 | Pharmacokinetics-Pharmacokinetic Parameters of KW-0761 (t1/2) | 179 hours | Standard Deviation 40 |
| KW-0761 0.1mg | Pharmacokinetics-Pharmacokinetic Parameters of KW-0761 (t1/2) | 201 hours | Standard Deviation 196 |
| KW-0761 0.5mg | Pharmacokinetics-Pharmacokinetic Parameters of KW-0761 (t1/2) | 332 hours | Standard Deviation 122 |
| KW-0761 1.0mg | Pharmacokinetics-Pharmacokinetic Parameters of KW-0761 (t1/2) | 462 hours | Standard Deviation 51 |
Primary
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.
Time frame: 0-7 days post final dose
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| KW-0761 | Pharmacokinetics-Plasma KW-0761 Concentrations | Cmax | 350.0 ng/mL | Standard Deviation 47.8 |
| KW-0761 | Pharmacokinetics-Plasma KW-0761 Concentrations | Ctrough | 158.2 ng/mL | Standard Deviation 7.4 |
| KW-0761 0.1mg | Pharmacokinetics-Plasma KW-0761 Concentrations | Ctrough | 1515.2 ng/mL | Standard Deviation 1873.4 |
| KW-0761 0.1mg | Pharmacokinetics-Plasma KW-0761 Concentrations | Cmax | 2806.7 ng/mL | Standard Deviation 1664.5 |
| KW-0761 0.5mg | Pharmacokinetics-Plasma KW-0761 Concentrations | Cmax | 15181.2 ng/mL | Standard Deviation 872 |
| KW-0761 0.5mg | Pharmacokinetics-Plasma KW-0761 Concentrations | Ctrough | 6824.7 ng/mL | Standard Deviation 872.9 |
| KW-0761 1.0mg | Pharmacokinetics-Plasma KW-0761 Concentrations | Cmax | 40428.4 ng/mL | Standard Deviation 5350.8 |
| KW-0761 1.0mg | Pharmacokinetics-Plasma KW-0761 Concentrations | Ctrough | 19516.8 ng/mL | Standard Deviation 4264.7 |
Secondary
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).
Time frame: 50 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| KW-0761 | Antitumor Effect | Uncertain Complete Response (CRu) | 0 participants |
| KW-0761 | Antitumor Effect | Complete Response (CR) | 0 participants |
| KW-0761 | Antitumor Effect | Stable Disease (SD) | 1 participants |
| KW-0761 | Antitumor Effect | Progressive Disease (PD) | 1 participants |
| KW-0761 | Antitumor Effect | Partial Response (PR) | 1 participants |
| KW-0761 | Antitumor Effect | Not Evaluable (NE) | 0 participants |
| KW-0761 0.1mg | Antitumor Effect | Progressive Disease (PD) | 1 participants |
| KW-0761 0.1mg | Antitumor Effect | Not Evaluable (NE) | 0 participants |
| KW-0761 0.1mg | Antitumor Effect | Partial Response (PR) | 0 participants |
| KW-0761 0.1mg | Antitumor Effect | Uncertain Complete Response (CRu) | 0 participants |
| KW-0761 0.1mg | Antitumor Effect | Complete Response (CR) | 1 participants |
| KW-0761 0.1mg | Antitumor Effect | Stable Disease (SD) | 2 participants |
| KW-0761 0.5mg | Antitumor Effect | Complete Response (CR) | 0 participants |
| KW-0761 0.5mg | Antitumor Effect | Uncertain Complete Response (CRu) | 0 participants |
| KW-0761 0.5mg | Antitumor Effect | Progressive Disease (PD) | 3 participants |
| KW-0761 0.5mg | Antitumor Effect | Stable Disease (SD) | 0 participants |
| KW-0761 0.5mg | Antitumor Effect | Not Evaluable (NE) | 0 participants |
| KW-0761 0.5mg | Antitumor Effect | Partial Response (PR) | 0 participants |
| KW-0761 1.0mg | Antitumor Effect | Not Evaluable (NE) | 0 participants |
| KW-0761 1.0mg | Antitumor Effect | Stable Disease (SD) | 2 participants |
| KW-0761 1.0mg | Antitumor Effect | Complete Response (CR) | 1 participants |
| KW-0761 1.0mg | Antitumor Effect | Uncertain Complete Response (CRu) | 0 participants |
| KW-0761 1.0mg | Antitumor Effect | Partial Response (PR) | 2 participants |
| KW-0761 1.0mg | Antitumor Effect | Progressive Disease (PD) | 1 participants |
Secondary
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.
Time frame: Baseline to response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| KW-0761 | Time to Progression (TTP) | 46.5 days |