Open label, multicenter phase I study of IPH4102, a humanized anti-KIR3DL2 monoclonal antibody, in patients with relapsed/refractory cutaneous T-cell lymphomas (CTCL)

Note: In the dose escalation portion, all subtypes of relapsed/refractory CTCL will be
allowed, in the cohort expansion portion inclusion of specific CTCL subtypes is planned
according to findings of the dose escalation portion (e.g. tMF and SS).
1) Patients with relapsed/refractory, biopsy-proven primary cutaneous T-cell lymphoma who have
received at least two previous standard systemic therapies and, if MF/SS, is stage IBIVB
at study entry. Total skin electron beam irradiation is not regarded as systemic
therapy.
2) Centrally assessed KIR3DL2 expression on tumor cells. A blood sample and skin
biopsies will be obtained within 4 weeks of beginning study medication, for
assessment of KIR3DL2 by flow cytometry or immunohistochemistry (IHC). KIR3DL2
expression on *5% malignant cells in skin or on *5% malignant cells in blood
(Immunophenotype: CD3+CD4+CD8-) is regarded as KIR3DL2 positive. If a patient has
different lesion morphology (patch, plaque, tumor), a biopsy will be obtained from each
morphologic lesion and KIR3DL2-positivity in at least one lesion will be sufficient for
enrolment of a patient.
3) Patients must have the following minimum wash-out from previous treatments:
- *12 weeks for total skin electron beam irradiation,
- *4 weeks for monoclonal antibodies (* 8 weeks for alemtuzumab),
- *3 weeks for local radiation therapy, systemic cytotoxic anticancer therapy,
treatment with other anti-neoplastic investigational agents,
- *3 weeks for systemic retinoids, interferons, vorinostat, romidepsin, fusion proteins,
- *3 weeks for phototherapy,
- *2 weeks for topical therapy (including steroids, retinoids, nitrogen mustard or
imiquimod). Topical steroids (maximum strength: Class III according to World Health Organization Classification of Topical Corticosteroids) and/or oral
steroids (* 10 mg prednisone equivalent/day) are allowed, if the patient has been
on a stable dose with stable disease for at least 1 month prior to study entry.
4) At least 18 years of age.
5) ECOG performance status of * 2.
6) Adequate baseline laboratory data: hemoglobin >9 g/dL, absolute neutrophil count
(ANC) *1,000/*L, CD4+ T-cells *200/*l, platelets *50,000/*L, bilirubin *1.5 X upper
limit of normal (ULN) or *3 X ULN for patients with Gilbert's disease, serum creatinine
*1.5 X ULN, alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
*3 X ULN.
7) Women of childbearing potential (WOCBP) must have a negative serum beta-HCG
pregnancy test result within seven days of treatment and must practice an effective
method of contraception during treatment and for at least 9 months (270 days) following the last dose of study drug.
8) Female patients who are post-menopausal or surgically sterile.
9) Male patients who agree to practice effective barrier contraception.
10) Ability to understand and the willingness to sign a written informed consent document.
11) No psychological, familial, sociological, or geographical condition potentially
hampering compliance with the study protocol and follow-up schedule.

1) Patients with limited disease (if MF/SS: stages IA), or central nervous system (CNS)
disease.
2) Clinical relevant AEs or laboratory results related to previous anti-neoplastic therapy
have not resolved to a NCI-CTCAE grade *1.
3) Concomitant corticosteroid use, systemic or topical, for treatment of skin disease.
However, topical steroids (maximum strength: Class III according to World Health Organization Classification of Topical Corticosteroids) and/or oral steroids
(*10 mg prednisone equivalent/day) are allowed, if patient has been on a stable dose
with stable disease for at least 4 weeks prior to study entry.
4) Patients who have undergone major surgery < 4 weeks prior to starting study drug
5) Patients who have undergone a stem cell transplantation
6) Patients with known NCI CTCAE Grade 3 or higher (requiring IV antibiotics) active
systemic or cutaneous viral, bacterial, or fungal infection.
7) Patients who are Hepatitis B or Hepatitis C antibody positive.
8) Patients who are known to be HIV-positive.
9) Prior hypersensitivity reaction to monoclonal antibodies, other therapeutic proteins, or
immunotherapy.
10) Patients with a history of other malignancies during the past three years. (The
following are exempt from the three-year limit: non-melanoma skin cancer,
Lymphomatoid papulosis, curatively treated localized prostate cancer, curatively
treated localized breast cancer, resected thyroid cancer, cervical intraepithelial
neoplasia or cervical carcinoma in situ on biopsy).
11) Patients who are currently pregnant or breastfeeding.
12) Patients with congestive heart failure, Class III or IV, by New York Heart Association
(NYHA) criteria.
13) Patients with any serious underlying medical condition that would impair their ability to
receive or tolerate the planned treatment.
14) Patients with dementia or altered mental status that would preclude understanding
and rendering of informed consent document.