Safety Study to Evaluate Monoclonal Antibody KW-0761 in Subjects With Peripheral T-cell Lymphoma

Open-Label, Multi-Center, Dose Escalation Phase 1/2 Study of Anti-CCR4 Monoclonal Antibody KW-0761 as Monotherapy in Subjects With Previously Treated Peripheral T-Cell Lymphoma

This study will determine the maximum dose of KW-0761 administered intravenously that can be given safely in subjects with previously treated peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma(CTCL)and will see if it is effective in treating the disease.

This Phase 1/2, multicenter, open-label, dose escalation clinical study will enroll up to 47 subjects with previously treated PTCL including CTCL. The study is comprised of a dose escalation phase (Phase 1) and a preliminary assessment of efficacy (Phase 2).

In the dose escalation phase, the starting dose will be 0.1 mg/kg administered i.v. once every week for four weeks, followed by a 2-week observation period in the first treatment course. Succeeding dose levels will include 0.3 and 1 mg/kg. During the first course of treatment if assessments performed at day 29 (end of week 4) indicate that a subject has demonstrated an overall CR, the subject may continue on study for up to an additional four infusions beyond CR on an every other week infusion schedule. Treatment will then be discontinued in order to determine duration of response. If a subject experiences a PR or SD, the subject may continue therapy after consultation between the investigator and the medical monitor on an every other week infusion schedule until disease progression occurs or other withdrawal criteria are met.

Inclusion Criteria:

1. histologically/cytologically confirmed diagnosis of PTCL including CTCL (including MF and SS) but excluding ATLL.
2. failed at least one prior systemic therapy for PTCL or CTCL.
3. ECOG PS of <=2 at study entry.
4. >=18 years of age.
5. completed any prior therapy at least four weeks prior to entry; however, patients with rapidly progressive malignant disease may be enrolled prior to this period after discussion with the medical monitor.
6. resolution of all clinically significant toxic effects of prior cancer therapy to grade ≤1 by the NCI-CTCAE, v.3.0 excluding the specifications required in 7 and 8 below.
7. adequate hematological function: absolute neutrophil count>=1,500 cells/uL and platelets >=100,000 cells/uL except in patients with known bone marrow involvement where absolute neutrophil count must be >=1,000 cells/uL and platelets >=75,000 cells/uL.
8. adequate hepatic function: bilirubin ≤ 1.5 times the specific institutional ULN; aspartate transaminase and alanine transaminase each ≤ 2.5 x ULN or ≤ 5.0 x ULN in the presence of known hepatic malignancy.
9. serum creatinine ≤1.5 x ULN or a calculated creatinine clearance >60 mL/min.
10. CTCL subjects previously treated with zanolimumab are eligible provided their CD4+ cell counts have recovered to pre-treatment levels.
11. Subjects with MF and a history of staphylococcus colonization are eligible provided they continue to receive stable doses of prophylactic antibiotics.
12. provided signed informed consent.
13. WOCBP must have a negative pregnancy test within 7 days of receiving study medication.
14. WOCBP must agree to use effective contraception
15. Male subjects must be willing to use an appropriate method of contraception (e.g., condoms) or abstain from sexual intercourse and inform any sexual partners that they must also use a reliable method of contraception during the study.

Exclusion Criteria:

1. has a significant uncontrolled intercurrent illness including, but not limited to: uncontrolled infection requiring antibiotics; clinically significant cardiac disease (class III or IV of the New York Heart Association [NYHA] classification); unstable angina pectoris; angioplasty, stenting, or myocardial infarction within 6 months; uncontrolled hypertension (systolic blood pressure >160 mm Hg, diastolic BP >100 mmHg, found on two consecutive measurements separated by a 1-week period) despite two anti-hypertensive medications; clinically significant cardiac arrhythmia; or uncontrolled diabetes.
2. has known or tests positive for human immunodeficiency virus (HIV), human T-cell leukemia virus (HTLV-1), hepatitis B or hepatitis C.
3. has evidence of central nervous system (CNS) metastasis.
4. has received monoclonal antibodies within 6 weeks of study entry.
5. is pregnant (confirmed by beta human chorionic gonadotrophin [β-HCG]) or lactating.
6. Subjects on any immunomodulatory drug, (other than low dose corticosteroids equivalent to a daily dose of 10 mg of prednisone). Subjects on any immunomodulatory drug within 4 weeks of their first dose of KW-0761 are also excluded.
7. has a psychiatric illness, disability or social situation that would compromise the subject's safety or ability to provide consent, or limit his or her compliance with study requirements.
8. has experienced allergic reactions to monoclonal antibodies or other therapeutic proteins.
9. Subjects with active herpes simplex or herpes zoster. Subjects with a history of herpes zoster who have had an outbreak within the last year will also be excluded. Subjects on prophylaxis for herpes who started taking medication at least 30 days prior to study entry, should continue to take the prescribed medication for the duration of the study.
10. Subjects with known autoimmune diseases. Subjects with Hashimoto's thyroiditis controlled with medication are eligible for enrollment.