Phase I Trial of Siplizumab in CD2-Positive Lymphoproliferative Disease.

Siplizumab is a humanized IgG1κ class monoclonal antibody that binds to the CD2 receptor on human T- and NK-cells. In an animal model of adult T-cell leukemia/lymphoma (ATL), fifty percent of animals survived tumor challenge with 4 weeks of siplizumab treatment and the life-span of tumor bearing animals treated for six months was equivalent to that of animals not challenged with tumors. A single-center phase I dose escalation trial to assess maximum tolerated dose (MTD) and safety in patients (pts) with CD2-positive adult T-cell leukemia (ATL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), and large granular lymphocyte leukemia (LGL) is ongoing. Eligibility includes Karnofsky performance status ≥70%; life expectancy >2 months; appropriate hematological status and normal organ function; prior treatment with chemotherapy and monoclonal antibodies is allowed. Cohorts of 3 pts each receive escalating i.v. doses of siplizumab ranging from 0.4 to 4.8 mg/kg administered over 2–3 days per treatment week every other week for 16 weeks or until unacceptable toxicity or disease progression (PD). 16 pts have been enrolled into 5 cohorts: 0.4 (3 pts), 0.6 (3 pts), 0.8 (3 pts), 1.2 (4 pts) and 2.4 (3 pts) mg/kg per week with planned dose escalation to 3.4 and 4.8 mg/kg. Median number of courses received is 4 (range 1–8). Diagnoses include ATL (9), LGL (4), PTCL (1) and CTCL (2). Grade 1/2 infusional reactions primarily manifested as fever and chills were confined to the first dose of treatment in the majority of patients. Meperidine pretreatment significantly ameliorated infusional reactions. The median (range) percentage decrease in CD4, CD8, NK and malignant cell numbers in peripheral blood from baseline are 98(71–100%), 93(50–100%), 89(55–96%) and 88 (0–100%), respectively. No DLTs have occurred at this time. To date, 3 confirmed PRs have been observed (2 ATL, 1 LGL), 6 pts had stable disease, and 7 pts had PD. 1 pt discontinued therapy due to a siplizumab-related adverse event of polymyalgia rheumatica and 3 pts (2 ATL, 1 LGL) were removed due to CMV antigenemia (which was an off-treatment criterion at the time of study drug discontinuation). 4 patients have died during the one-year follow up period due to PD and 4 patients have completed all 8 courses of treatment. In conclusion-siplizumab has been well tolerated in this trial and the maximum tolerated dose has not been reached. The protocol has been amended to allow for treatment of CMV antigen positive patients provided oral antivirals are effective in preventing CMV disease and rising CMV levels. Anti-tumor activity has been observed in some patients. Enrollment in this study continues.