A Dose Finding Lead-in Study of E7777 (Diphtheria toxin fragment-Interleukin-2 Fusion Protein) in Persistent or Recurrent Cutaneous T-Cell Lymphoma (CTCL)

Introduction: E7777 is a recombinant cytotoxic fusion protein composed of diphtheria toxin fragments A and B and human interleukin-2. E7777 has the same amino acid sequence as denileukin diftitox (DD) (approved as ONTAK in the USA for treatment of persistent or recurrent CTCL) but with improved purity and an increased percentage of active protein monomer species. This study is a pivotal multicenter open-label single-arm study comprising a Lead-In part (approx. 20 pts) to select the E7777 dose for the Main Study (70 patients [pts]) in which primary efficacy and safety of E7777 is assessed. Dose finding is necessary since the specific bioactivity of E7777 is 1.5 – 2 times that of the prior less purified form (ONTAK). The Lead-In study is reported in this abstract.

Methods: A Continual Reassessment Method (CRM) is used for dose-finding with E7777 doses ranging from 3 – 18 µg/kg to be tested. The CRM is designed to target a DLT rate of approx. 20%. Inclusion criteria were patients ≥ 18 yr old, with a diagnosis of Mycosis Fungoides (MF) or Sézary Syndrome (SS) with stage I-IV disease at study entry, measurable CD25+ tumor, and who have received at least one prior therapy for CTCL. Prior commercial DD therapy was not allowed. E7777 was administered as monotherapy by iv infusion over 60 min on 5 consecutive days every cycle of 21 days. Pts were be dosed up to 8 cycles; additional dosing is allowed if deemed beneficial by the treating physician. Required premedication included an antihistamine, anti-pyretic, and anti-emetic; in case of infusion-related reaction low-dose systemic steroid premedication was allowed. The aim of the Lead–in study was to establish the maximum tolerated dose (MTD) and the recommended Main Study dose (based on the MTD and clinical judgment), and to assess safety and tumor response. Tumor responses were assessed according to the new ISCL/EORTC criteria (Olsen 2011).

Results: Seventeen pts have been treated in the Lead-In. There were 8 males and 9 females, with median age 64 (range 26-81). Thirteen pts had MF (3, 7, 1, and 2 pts with Stage I, II, III, and IV disease, respectively) and 4 had SS (Stage IV). Fourteen or more pts had at least 4 lines of prior therapy. Pts were treated for a median of 4 cycles (range 1-8 cycles) and 8 patients are ongoing. Of the 9 pts who have discontinued from the study, 5 were for disease progression, 2 for AEs, 1 completed treatment per protocol, and 1 was pt choice.

Pts were treated at doses ranging from 6 to 15 µg/kg; dose levels were assigned by the CRM based on the cumulative DLT information. The dose levels for each pt are shown in chronological order in the Table below, with the corresponding DLT assessments.

In the 17 patients treated, there were two DLTs; both occurred at the 15 µg/kg dose level and were capillary leak syndrome (CLS) (one Gr 2 with hospitalization, and one Gr 4). Based on preliminary results from these 17 pts, the highest dose with a DLT rate of ≤ 20% is 12 µg/kg. The most frequent AEs occurring in ≥ 3 pts were nausea (6 pts), ALT increased and AST increased (4 pts each), and vomiting, chills, fatigue, pyrexia, myalgia, rash, staph skin infection (3 pts each). Serious AEs considered related to study drug were CLS (2 pts) and pruritus, rash, diarrhea, vomiting, hypoxemia, and tumor flare (all in 1 pt each). AEs leading to drug discontinuation were CLS (2 pts). There were no deaths on study.

Five pts achieved an objective response (OR) as assessed by the investigator, including 1 pt with relapse after allogeneic stem cell transplantation who received 8 courses and achieved a complete remission with associated skin graft-vs-host disease. These responses occurred at dose levels of 6, 9, and 12 µg/kg, including in 3 pts with stage IV disease (2 MF, 1 SS).

Conclusion: Dose finding of E7777 in CTCL is proceeding with the CRM method. The toxicity profile is acceptable and so far no new safety signals compared to ONTAK has been identified. Initial signs of activity have been observed. Final data from this Lead-in study will be presented.