Phase I Study of E7777, a Diphtheria Toxin Fragment-Interleukin-2 Fusion Protein, in Japanese Patients with Relapsed or Refractory Peripheral and Cutaneous T-Cell Lymphoma

Background: E7777 is a recombinant cytotoxic fusion protein composed of diphtheria toxin fragments A, B and human interleukin-2. E7777 has the same amino acid sequence as denileukin diftitox, approved in the USA for treatment of persistent or recurrent CD25 positive cutaneous T-cell lymphoma on 1999, but with improved purity and an increased percentage of active protein monomer species. Since the specific bioactivity of E7777 is 1.5-2 times higher than that of the prior less purified form, a phase 1 study of E7777 in Japanese patients (pts) with peripheral and cutaneous T-cell lymphoma (PTCL and CTCL) was conducted.

Methods: This multicenter, phase 1, dose-escalation (3+3 design) study assessed the safety, maximum tolerated dose (MTD), recommended dose (RD), pharmacokinetics (PK), immunogenicity (IM) and anti-tumor activity in pts with relapsed or refractory PTCL and CTCL. E7777 was administered by IV infusion over 60 min on 5 consecutive days of every 21 day cycle (up to 8 cycles) at planned dose-levels of 6, 12, 15 and 18 μg/kg/day (with evaluation of intermediate dose levels if necessary). Premedication including systemic steroid was required. Dose-limiting toxicity (DLT) was evaluated during the first cycle and MTD was determined as the highest dose at which less than 2 of a total 6 pts experienced a DLT. In the event that 2 of 6 pts experienced DLTs in a dose level, an Independent Safety Committee (ISC) will be consulted on whether that dose can be considered the MTD. Anti-tumor activity was evaluated by IWG-2007 criteria (only CT assessment) for PTCL and mSWAT for CTCL. Tumor CD25 expression was examined by immunohistochemistry in pts with available archival samples.

Results: A total of 13 pts were enrolled at E7777 dose-levels of 6, 9 and 12 μg/kg/day. 10 pts had PTCL [PTCL-not otherwise specified (NOS), n=4; angioimmunoblastic T-cell lymphoma (AITL), n=3; anaplastic large cell lymphoma (ALCL)-ALK positive, n=1; ALCL-ALK negative, n=1; enteropathy-associated T-cell lymphoma, n=1] and 3 had CTCL [mycosis fungoides (MF), n=3]. The median age was 64 years (range 23-75), and the median number of prior chemotherapy regimens (excluding PUVA, interferon, retinoid) was 1 (range 0-8). DLTs were observed in 3 of 3 pts in the 12 μg/kg/day cohort; ALT increased, hyponatremia, hypokalemia and lymphopenia in one pt, ALT increased, fatigue, hypoalbminemia, hyponatremia and rash in another, and lipase increased in the third. This dose-level was considered to exceed the MTD and the 9 μg/kg/day dose level was expanded. Per recommendation of the ISC, the DLT definition was modified to not include lymphopenia, Grade 3 abnormality of hepatic enzyme recovered to Grade 2 or lower within cycle 1, and any other Grade 3 clinical abnormal laboratory result without clinical symptoms recovered within 7 days. Two of 6 pts in 9 μg/kg/day cohort experienced DLT of decreased appetite and fatigue, respectively. These events were recovered from within 2-3 weeks while interrupting the treatment. Per protocol, the ISC evaluated the toxicity profile of all the pts, and recommended the MTD and RD to be 9 μg/kg/day.

As of 10 May 2015, the common adverse events (AEs) were ALT increased (85%), AST increased (77%), decreased appetite (77%), fatigue (77%), lymphopenia (77%), hypoalbuminemia (69%) and nausea (62%). Serious AEs considered related to study drug were reported in 3 pts; ALT increased, AST increased and fatigue in one pt, decreased appetite and hypoxia in another, and delirium in the third. AEs leading to study discontinuation were reported in 3 pts; AEs were hypersensitivity, respiratory failure (not related) and delirium. Objective response rate as assessed by investigator was 38% (5/13 pts), including response in 4 of 10 pts with PTCL and 1 of 3 pts with CTCL. All responses were PRs including 2 pts (AITL) at 6 μg/kg/day, 1 pt (MF) at 12 μg/kg/day followed by 6 μg/kg/day from 2nd cycle, and 2 pts (PTCL-NOS) at 9 μg/kg/day. Tumor responses were observed regardless of the level of CD25 expression in tumors. PK and IM data will be presented.

Conclusions: The MTD and RD of E7777 was 9 μg/kg/day. The common AEs observed were considered manageable. Tumor responses were observed in PTCL, which firstly demonstrated with E7777, and also for CTCL pts regardless of level of tumor CD25 expression. Subsequent phase 2 study to evaluate the efficacy and safety of E7777 in pts with PTCL and CTCL, including evaluation of the relationship with CD25 expression, is warranted.