| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of subjects with previously treated cutaneous T-cell lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Treatment of a type of cancer affecting the skin and/or other parts of the body, that has failed to respond to other treatments |
|
| 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 | 22.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011679 |
| E.1.2 | Term | Cutaneous T-cell lymphoma refractory |
| 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 compare the progression free survival of KW-0761 versus vorinostat for subjects with relapsed or refractory Cutaneous T-Cell Lymphoma (CTCL). |
|
| E.2.2 | Secondary objectives of the trial |
• To compare the overall response rate of KW-0761 versus vorinostat in subjects with relapsed or refractory CTCL;
• To evaluate and compare improvements in Quality of Life (QoL) measurements, Skindex-29, FACT-G, and EQ-5D-3L for subjects receiving KW-0761 versus vorinostat;
• To evaluate and compare improvements in the Pruritus Evaluation (Likert scale & Itchy QoL) for subjects receiving KW-0761 versus vorinostat;
• To estimate the duration of response for both the KW-0761 and vorinostat arms for those subjects with relapsed or refractory CTCL responding to treatment;
• To determine if subjects who relapse on vorinostat can achieve response upon cross over to treatment with KW-0761;
• To further assess the safety of KW-0761;
• To describe the immunogenicity of KW-0761. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Voluntarily signed and dated Institutional Review Board / Ethics Committee 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 Pre-treatment Visit, i.e., at the time that written informed consent is obtained, except in Japan where subjects must be ≥ 20 years of age;
3) Histologically confirmed diagnosis of MF or SS;
a. For SS (defined as meeting T4 plus B2 criteria), where the biopsy of erythrodermic skin may only reveal suggestive but not diagnostic histopathologic features, the diagnosis may be based on either a node biopsy or fulfillment of B2 criteria including a clone in the blood that matches that of the skin.
4) Stage IB, II-A, II-B, III and IV;
5) Subjects who have failed at least one prior course of systemic therapy (e.g., interferon, denileukin diftitox, bexarotene, photopheresis, anti-neoplastic chemotherapy, etc.). Psoralen plus ultraviolet light therapy (PUVA) is not considered to be a systemic therapy;
6) Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 1 ;
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) ≥ 1,500 cells/μL (≥ 1,500/mm3)
b. platelets ≥ 100,000 cells/μL; (≥ 100,000/mm3)
c. in subjects with known bone marrow involvement, ANC must be ≥ 1,000 cells/μL (≥ 1,000/mm3) and platelets ≥ 75,000 cells/μL. (≥ 75,000/mm3)
9) Adequate hepatic function:
a. bilirubin ≤ 1.5 times the specific institutional upper limit of normal (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 involvement
by CTCL.
10) Adequate renal function:
a. serum creatinine ≤ 1.5 x ULN;
or
b. calculated creatinine clearance > 50 mL/min using the Cockcroft-Gault formula.
11) Subjects previously treated with anti-CD4 antibody or alemtuzumab are eligible provided their CD4+ cell counts are ≥ 200/mm3.
12) Subjects with MF and a known history of non-complicated staphylococcus infection/colonization are eligible provided they continue to receive stable doses of prophylactic antibiotics.
13) Women of childbearing potential (WOCBP) must have a negative pregnancy test within 7 days of receiving study medication.
14) 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 without an alternative medical cause);
15) 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.
NOTE: For subjects continuing to receive study treatment as of protocol Amendment 8, the period of contraceptive use should be extended to 6 months after the last dose of KW-0761. |
|
| E.4 | Principal exclusion criteria |
1) Current evidence of large cell transformation (LCT). Subjects with clinical features suggestive of LCT must have a biopsy performed within 4 months prior to Cycle 1 Day 1 to rule out transformed disease. Subjects with a history of LCT but without current aggressive disease and no current evidence of LCT on pathology in skin or lymph nodes would be eligible;
2) Diagnosed with a malignancy in the past two years. However, subjects with non-melanoma skin cancers, melanoma in situ, localized cancer of the prostate with current prostate-specific antigen of < 0.1 ng/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.
3) Clinical evidence of central nervous system (CNS) metastasis.
4) Psychiatric illness, disability or social situation that would compromise the subject’s safety or ability to provide consent, or limit compliance with study requirements.
5) 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 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 mm Hg, 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.
6) Known or tests positive for human immunodeficiency virus, human T-cell leukemia virus, hepatitis B or hepatitis C disease.
7) Active herpes simplex or herpes zoster. Subjects on prophylaxis for herpes who started taking medication at least 30 days prior to the Pre-treatment Visit, and have no active signs of active infection, and whose last active infection was more than 6 months ago, may enter the study, and should continue to take the prescribed medication for the duration of the study.
8) Experienced allergic reactions to monoclonal antibodies or other therapeutic proteins.
9) Known active autoimmune disease will be excluded. (For example; Graves’ disease; systemic lupus erythematosus; rheumatoid arthritis; Crohn’s disease; psoriasis).
10) Is pregnant (confirmed by beta human chorionic gonadotrophin [β-HCG]) or lactating.
11) Prior treatment with KW-0761.
12) Prior treatment with vorinostat. Patients who were exposed to vorinostat for a short time, did not progress while on treatment, and did not have intolerable toxicity but were discontinued for another reason (e.g., comorbidity) may be
permitted to enter the study after discussion with the Medical Monitor.
13) Have had any therapy directed against the subject’s underlying cancer or any investigational medications within four weeks of randomization (skin directed treatments, including topicals and radiation within two weeks of randomization). However, subjects with rapidly progressive malignant disease may be enrolled prior to this period after discussion with the Medical Monitor.
14) Subjects on a stable dose of a low dose systemic corticosteroid (≤ 20 mg prednisone equivalent) for at least 4 weeks prior to Pre-treatment Visit may continue use although the investigator should attempt to taper the use to the lowest dosage tolerable while on study. Initiation of treatment with systemic corticosteroids or increase in dose while on study is not permitted except to treat an infusion reaction. Subjects may receive intra-articular corticosteroid injections, intraocular corticosteriod drops, inhalation or nasal corticosteroids and replacement doses of systemic corticosteroids as needed.
15) Subjects on a stable dose of medium or low potency topical corticosteroids for at least 4 weeks prior to Pre-treatment Visit may continue use at the same dose, although the investigator should attempt to taper the use 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.
16) History of allogeneic transplant.
17) Autologous hematopoietic stem cell transplant within 90 days of Pretreatment Visit.
18) Subjects on any immunomodulatory drug for concomitant or intercurrent conditions other than T-cell lymphoma or who have received any of these agents within 4 weeks of treatment, including but not limited to the following, will be excluded: low dose or oral methotrexate; azathioprine; intravenous
(iv) immunoglobulin; low dose or oral cyclophosphamide; cyclosporine; mycophenolate; infliximab;etanercept; leflunomide; adalimumab; lenalidomide; abatacept; rituximab; anakinra; interferon-β; IL-2 and natalizumab. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Progression will be evaluated at days 26-28. |
|
| E.5.2 | Secondary end point(s) |
Overall response rate;
Skindex-29;
FACT-G;
EQ-5D-3L. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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
| No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Australia |
| Denmark |
| France |
| Germany |
| Italy |
| Japan |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 8 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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