A Phase II Study of Denileukin Diftitox (Ontak®) with CHOP Chemotherapy in Patients with Newly-Diagnosed Aggressive T-Cell Lymphomas, the CONCEPT Trial: Interim Analysis.

Denileukin diftitox, a genetically engineered fusion protein comprised of the enzymatically active domain of diphtheria toxin and the full length sequence of human interleukin-2 (IL-2) that targets malignancies expressing the IL-2 receptor, is approved for cutaneous T-cell lymphoma and has demonstrated a 48% objective response rate in relapsed/refractory PTCL. Because denileukin diftitox is not myelosuppressive and induces apoptosis by inhibition of protein synthesis, a mechanism of action non-cross-resistant with chemotherapy, we evaluated the efficacy and safety of the combination of denileukin diftitox plus CHOP in newly diagnosed aggressive T-cell lymphomas. In this multicenter Phase II study, patients (pts) with aggressive T-cell histologies according to REAL classification were eligible. Pts were required to have absolute neutrophil count ≥1000, platelets ≥50,000, adequate renal and hepatic function with serum albumin ≥3.0 g/dL, and LVEF ≥50%. Denileukin diftitox was given by IV infusion at 18 mcg/kg/day on Days 1 and 2 of each cycle, followed by CHOP chemotherapy on Day 3, and G-CSF support starting Day 4 of each cycle. Cycles were administered every 3 weeks for up to 6 cycles. Restaging evaluation of response is performed after every 2 cycles. The study objective for efficacy is to achieve an overall response rate (CR+PR) of 70%. Twenty-one patients (76% PTCLnos) have been enrolled to date, with a median age of 56 (range 40–80), 10 male, and 11 female. Six patients are not evaluable for response; one discontinued therapy during Cycle 1 due to a hypersensitivity reaction, and 5 are too early to evaluate (1 cycle of therapy given). For the 15 evaluable patients, the overall response rate is 87% with 9 CR or CRu (60%), 4 PR (27%) and 1 each for stable and progressive disease (see Table below). Four of 13 responders (31%) have progressed, with duration of response ranging from 1.5 to 5.9 months. Toxicities have generally been grade 1–2, were transient, and caused few treatment delays. The most common adverse events have been edema (27%), elevated transaminases (20%), and hypoalbuminemia (14%). Only two Grade 4 toxicities were noted (one each of neutropenia and deniluekin diftitox infusion-related allergic reaction). This is the first trial to report on the use of ONTAK in combination with chemotherapy. The novel combination of denileukin diftitox and CHOP appears to be clinically active, and is well tolerated with no unexpected, new, or overlapping toxicities. Pt accrual is ongoing.