E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of patients with relapsed or refractory ATL |
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E.1.1.1 | Medical condition in easily understood language |
Treatment of a rare type of cancer affecting white blood cells |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10001416 |
E.1.2 | Term | Adult T-cell lymphoma/leukaemia recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To estimate overall response rate of KW-0761 for subjects with relapsed or refractory ATL. |
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E.2.2 | Secondary objectives of the trial |
1. To estimate the median progression free survival and overall survival rates of the KW-0761 and investigator’s choice arms of the study; 2. To compare the overall response rates between the KW-0761 and investigator’s choice arms of the study; 3. To compare the median progression free survival and overall survival rates between the KW-0761 and investigator’s choice arms of the study; 4. To estimate the median duration of response of KW-0761 and investigator’s choice within both arms for those subjects with relapsed or refractory ATL responding to treatment; 5. To determine if subjects who relapse on investigator’s choice can achieve response upon cross over to treatment with KW-0761; 6. To evaluate quality of life for subjects receiving KW-0761 and investigator’s choice; 7. To further assess the safety of KW-0761; 8. To describe the immunogenicity of KW-0761; 9. To conduct exploratory evaluation of KW-0761 exposure-response relationships. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Voluntarily signed and dated IRB/EC approved informed consent form in accordance with regulatory and institutional guidelines. Written informed consent must be obtained prior to performing any study-related procedure; 2) Males and female subjects ≥ 18 years of age at the time of enrollment; 3) Confirmed diagnosis of ATL: a. Subjects must have been determined to be positive for HTLV-1 virus b. Subjects must have hematologically or pathohistologically diagnosed peripheral lymphoid tissue which surface antigen analysis has identified to be of T-cell origin 4) Subjects must currently have evidence of disease in at least one of the following: a. Lymph nodes b. Extranodal masses c. Spleen or liver d. Skin e. Peripheral blood f. Bone marrow 5) Relapsed or refractory after at least one prior systemic therapy regimen for ATL; 6) Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2 at study entry; 7) The subject has resolution of all clinically significant toxic effects of prior cancer therapy to grade ≤1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE, v.4.0) excluding the specifications required in 8, 9 and 10 below; 8) Adequate hematological function: a. absolute neutrophil count (ANC) ≥ 1,000/mm3; b. platelets ≥ 50,000 / mm3 c. If ANC and/or platelet count is less than the level specified above in the setting of documented bone marrow involvement, investigator may discuss individual case with the Medical Monitor, who will determine if subject may be enrolled Note: Retesting for values out of criteria will be permitted 9) Adequate hepatic function: a. bilirubin ≤ 2 times the specific institutional ULN; b. aspartate transaminase (AST) and alanine transaminase (ALT) each ≤ 2.5 x ULN or ≤ 5.0 x ULN in the presence of known hepatic ATL involvement. Note: Retesting for values out of criteria will be permitted 10) Adequate renal function: a. serum creatinine < 2 x ULN or b. calculated creatinine clearance > 60 mL/min ( or >30 mL/min with documented renal infiltration); Note: Retesting for values out of criteria will be permitted 11) Women of childbearing potential (WOCBP) must have a negative pregnancy test within 7 days of receiving study medication; 12) WOCBP must agree to use effective contraception, defined as oral contraceptives, double barrier method (condom plus spermicide or diaphragm plus spermicide) or practice true abstinence from sexual intercourse (periodic abstinence ,e.g., calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable methods of contraception) during the study and for 3 months after the last dose. WOCBP includes any female who has experienced menarche and who has not undergone successful surgical sterilization or is not postmenopausal (defined as amenorrhea ≥ 12 consecutive months); 13) Male subjects and their female partners of child bearing potential must be willing to use an appropriate method of contraception defined as oral contraceptives, double barrier method (condom plus spermicide or diaphragm plus spermicide) or practice true abstinence from sexual intercourse (periodic abstinence, e.g., calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable methods of contraception) during the study and for 3 months after the last dose. |
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E.4 | Principal exclusion criteria |
1) History of allogeneic transplant; 2) Autologous hematopoietic stem cell transplant within 90 days of study entry; 3) Untreated human immunodeficiency virus (HIV). Patients on HIV therapy with undetectable viral loads as measured by HIV RNA quantitative real time PCR may be enrolled; 4) Has known or tests positive for hepatitis C; 5) Has known or tests positive for hepatitis B. Patients who are negative on qualitative HBV DNA assay may be enrolled; 6) Have had a malignancy in the past two years. However, subjects with non-melanoma skin cancers, melanoma in situ, localized cancer of the prostate with current PSA of < 0.1 μg/mL, treated thyroid cancer or cervical carcinoma in situ or ductal/lobular carcinoma in situ of the breast with in the past two years may enroll as long as there is no current evidence of disease; 7) Clinical evidence of CNS involvement or metastasis. In subjects suspected of having CNS disease, an MRI of the brain and/or lumbar puncture should be done to confirm; 8) Psychiatric illness, disability or social situation that would compromise the subject’s safety or ability to provide consent, or limit compliance with study requirements; 9) Significant uncontrolled intercurrent illness including, but not limited to: a. uncontrolled infection requiring antibiotics; b. clinically significant cardiac disease (class III or IV of the New York Heart Association [NYHA] classification); c. unstable angina pectoris; d. angioplasty, stenting, or myocardial infarction within 6 months; e. uncontrolled hypertension (systolic blood pressure (BP) >160 mm Hg or diastolic BP >100 mmHg, found on two consecutive measurements separated by a 1-week period) despite two anti-hypertensive medications; f. clinically significant cardiac arrhythmia; or g. uncontrolled diabetes. 10) Subjects with a history of moderate or severe psoriasis or with psoriasis associated with systemic symptoms e.g., arthropathy, or with a 1st degree relative with history of psoriasis that required systemic medical intervention. 11) Experienced allergic reactions to monoclonal antibodies or other therapeutic proteins; 12) Known active autoimmune disease will be excluded. (For example; Grave’s disease; systemic lupus erythematosus; rheumatoid arthritis; Crohn’s disease). 13) Is pregnant (confirmed by beta human chorionic gonadotrophin [β-HCG]) or lactating. 14) Prior treatment with KW-0761; 15) Initiation of treatment with systemic steroids while on study is only permitted for acute and brief complications of underlying disease (e.g., hypercalcemia) or for treatment related side effects (e.g., including pre-medication for infusion reaction, nausea and vomiting). Subjects on systemic steroids prior to enrollment must be off for 7 days before initiation of study treatment, unless specifically indicated for the treatment of hypercalcemia. However, once the calcium returns to normal and the subject is on protocol treatment, the steroid should be tapered to discontinuation as rapidly as possible. All tests to document extent of disease must be performed after completion of steroid treatment and prior to first study treatment (subjects may receive inhalation steroids and replacement doses of systemic steroids as needed); 16) Initiation of treatment with topical steroids while on study is not permitted except to treat an acute rash. Assessment of skin disease must be documented after completion of steroid treatment and before study treatment is reinitiated; 17) Have had interferon-α, zidovudine, anti-neoplastic chemotherapy, radiation, immunotherapy, or investigational medications within 2 weeks of first study treatment; 18) Subjects on any immunomodulatory drug, including but not limited to the following, will be excluded: methotrexate; azathioprine; intravenous immunoglobulin; cyclophosphamide; cyclosporine; mycophenolate; infliximab; etanercept; leflunomide; adalimumab; abatacept; rituximab; anakinra; interferon-β; IL-2, lenalidomide and natalizumab. Subjects on any of the foregoing agents within 4 weeks of their first dose of KW-0761 are also excluded. |
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E.5 End points |
E.5.1 | Primary end point(s) |
To estimate overall response rate of KW-0761 for subjects with relapsed or refractory ATL. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Response will be evaluated at Day 26-28 of the first treatment cycle and then every 8 weeks thereafter. |
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E.5.2 | Secondary end point(s) |
1. To estimate the median progression free survival and overall survival rates of the KW-0761 and investigator’s choice arms of the study; 2. To compare the overall response rates between the KW-0761 and investigator’s choice arms of the study; 3. To compare the median progression free survival and overall survival rates between the KW-0761 and investigator’s choice arms of the study; 4. To estimate the median duration of response of KW-0761 and investigator’s choice within both arms for those subjects with relapsed or refractory ATL responding to treatment ; 5. To determine if subjects who relapse on investigator’s choice can achieve response upon cross over to treatment with KW-0761; 6. To evaluate quality of life for subjects receiving KW-0761 and investigator’s choice; 7. To further assess the safety of KW-0761; 8. To describe the immunogenicity of KW-0761; 9. To conduct exploratory evaluation of KW-0761 exposure-response relationships. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Response will be evaluated at Day 26-28 of the first treatment cycle and then every 8 weeks thereafter. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Brazil |
France |
Germany |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |