| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of patients with relapsed or refractory ATL |
|
| E.1.1.1 | Medical condition in easily understood language |
| Treatment of a rare type of cancer affecting white blood cells |
|
| 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 | 17.1 |
| 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) |
|
| 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. |
|
| 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. |
|
| 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, excluding smoldering subtype:
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. Subjects being recruited to this study will not necessarily meet the inclusion/exclusion criteria for baseline organ function, for the investigator's choice regimens due to the leukemic nature of their illness and bone marrow involvement by the neoplastic process; this should be taken into account by the
investigator and if necessary discussed with the medical monitor.
9) Adequate hepatic function:
a. bilirubin ≤ 2 times the specific institutional ULN; except for subjects with Gilbert’s Syndrome;
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 using the Cockroft-Gault formula (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 and prior to each treatment cycle;
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 6 months after the last dose of study drug.
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 without an alternative medical cause). * In Belgium, abstinence is not accepted as a method of contraception;
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 6 months after the last dose of study drug. * In Belgium, abstinence is not accepted as a method of
contraception. |
|
| E.4 | Principal exclusion criteria |
1) Smoldering subtype of ATL;
2) Lymphomatous or acute subtype subject with > 2 prior systemic
therapy regimens and who has not achieved a response (CR or PR) or
maintained stable disease for at least 12 weeks on last immediate prior
therapy;
3) History of allogeneic transplant;
4) Autologous hematopoietic stem cell transplant within 90 days of study entry;
5) 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;
6) Has known hepatitis C. Patients who are hepatitis C antibody positive but are hepatitis C quantitative PCR negative may be enrolled;
7) Has hepatitis B based on PCR testing for hepatitis B virus DNA. Patients who are hepatitis B core antibody positive but PCR negative may be enrolled if placed on appropriate anti-hepatitis B virus prophylaxis. Patients who are hepatitis B core antibody positive based on prior vaccination need not receive prophylaxis;
8) 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;
9) Clinical evidence of CNS involvement or metastasis.
10) Psychiatric illness, disability or social situation that would compromise the subject’s safety or ability to provide consent, or limit compliance with study requirements;
11) Significant uncontrolled intercurrent illness (as per protocol) 12) 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.
13) Experienced allergic reactions to monoclonal antibodies or other therapeutic proteins;
14) Subjects randomized to the investigator’s choice treatment group may not receive a treatment they
have had previously or any contra-indication to any of the comparators according to local SmPCs/Prescribing
Information would preclude treatment with that option;
15) Known active autoimmune disease will be excluded. (For example; Grave’s disease; systemic lupus erythematosus; rheumatoid arthritis; Crohn’s disease).
16) Is pregnant or lactating.
17) Prior treatment with KW-0761;
18) Initiation of treatment with systemic corticosteroids 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 corticosteroids 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 corticosteroid should be tapered to discontinuation as rapidly as possible. All tests to document extent of disease must be performed after completion of corticosteroid treatment and prior to first study treatment (subjects may receive intra-articular corticosteroid
injections, intraocular corticosteroid drops, inhalation or nasal corticosteroids and replacement doses of systemic corticosteroids as needed);
19) Subjects on a stable dose of medium or low potency topical corticosteroids for at least 4 weeks prior to study entry may continue use at the same dose, although the investigator should attempt to taper to the lowest dosage tolerable while on study. Initiation of treatment with topical corticosteroids while on study is not permitted except to treat an acute rash. Assessment of skin disease must be documented after completion of corticosteroid treatment and before study treatment is reinitiated;
20) Have had interferon-α, and/or zidovudine, within 1 week, or antineoplastic
chemotherapy, radiation, immunotherapy, or investigational medications within 2 weeks of first study treatment. However, subjects with rapidly progressive malignant disease may be enrolled prior to these periods after discussion of the case with the Medical Monitor;
21) Subjects treated with any immunomodulatory drug, for concomitant or intercurrent conditions other than T-cell lymphoma or who received any of these agents within 4 weeks of treatment including but not limited to low dose or oral methotrexate; azathioprine; intravenous (i.v.) immunoglobulin; low dose or oral cyclophosphamide; cyclosporine; mycophenolate; infliximab; etanercept; leflunomide; adalimumab; abatacept; rituximab; anakinra; interferon-β; IL-2, lenalidomide and natalizumab.
|
|
| 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. |
|
| 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. |
|
| 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. |
|
| 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. |
|
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
| Martinique |
| Peru |
| United Kingdom |
| United States |
|
| 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
|
|
| 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 |
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