Phase 2 Study of E7777, a Diphtheria Toxin Fragment-Interleukin-2 Fusion Protein, in Japanese Patients with Relapsed or Refractory Peripheral and Cutaneous T-Cell Lymphoma
Authors: Maruyama Dai , Ando Kiyoshi , Yamamoto Kazuhito , Kiyohara Eiji , Terui Yasuhito , Fukuhara Noriko , Miyagaki Tomomitsu , Kawai Hidetsugu , Tokura Yoshiki , Sakata-Yanagimoto Mamiko , Igarashi Tadahiko , Kuroda Junya , Fujita Jiro , Uchida Toshiki , Ishikawa Takayuki , Yonekura Kentaro , Kato Koji , Nakanishi Tadashi , Nakai Kenya , Matsunaga Risa , Tobinai Kensei 
Published: November 2019

Background: E7777 is a recombinant cytotoxic fusion protein composed of diphtheria toxin fragments A, B and human interleukin-2. The amino acid sequence of E7777 is the same as that of denileukin diftitox, approved in the USA for treatment of persistent or recurrent CD25-positive cutaneous T-cell lymphoma in 1999, but the purity of E7777 is improved and then it has 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 was conducted in Japanese patients (pts) with peripheral and cutaneous T-cell lymphoma (PTCL and CTCL). The maximum tolerated and recommended dose of E7777 was 9 μg/kg/day for 5 consecutive days per 21-day cycle. E7777 was well tolerated and preliminary, but clinically meaningful antitumor activity was observed (Ohmachi, et al.: Cancer Sci 2018). Therefore, a subsequent phase 2 study of E7777 was conducted.
Methods: This multicenter, single-arm phase 2 study assessed the efficacy, safety, pharmacokinetics (PK) and immunogenicity (IM) of E7777 in pts with relapsed or refractory PTCL and CTCL. E7777 was administered by IV infusion over 60 min for 5 consecutive days of every 21-day cycle (up to 8 cycles) at dose of 9 μg/kg/day with premedication including systemic steroid. Primary endpoint was objective response rate (ORR) by the independent review assessment. Thirty-five patients were required to detect the lower limit of 2-sided 95% confidence interval (CI) to exceed the 5% threshold in ORR, with the expected ORR of 25% with a statistical power of 90%. Efficacy was evaluated based on integrated criteria of IWG2007 (Cheson, et al,: JCO 2007) for nodal/ex-nodal disease by CT or PET/CT assessment and ISCL2011 (Olsen, et al.: JCO 2011) for cutaneous and blood disease assessment, in both PTCL and CTCL. Tumor CD25 expression level (%) in archival tumor samples from all pts was examined by immunohistochemistry.
Results: As of 26 Apr 2019, a total of 37 pts were enrolled. Based on the central pathological review, 17 pts had PTCL [PTCL-not otherwise specified (NOS), n=13; angioimmunoblastic T-cell lymphoma, n=3; anaplastic large cell lymphoma-ALK negative, n=1], 19 pts had CTCL [mycosis fungoides, n=12; Sézary syndrome, n=2; primary cutaneous CD30+ T-cell lymphoproliferative disorder, n=2; primary cutaneous γδ T-cell lymphoma, n=1; primary cutaneous aggresive epidermotropic CD8+ cytotoxic T-cell lymphoma, n=1; PTCL-NOS, n=1] and 1 pt had the other disease (extranodal NK/T cell lymphoma, nasal type). The median age was 65 years (range 27-82), and the median number of prior chemotherapy regimens (excluding PUVA, interferon, etretinate) was 2 (range 1-10). Among the 36 pts with PTCL and CTCL, the ORR as assessed by the independent review was 36% (13/36 pts: 95%CI, 21%-54%), including 1 pt with complete response. The ORR were 41% (7/17 pts: 95%CI, 18%-67%) in PTCL and 31% (6/19 pts: 95%CI, 13%-57%) in CTCL, respectively. Responses were observed regardless of the level of CD25 expression in lymphoma cells. With a median follow-up time of 26.3 months, the median progression-free survival (mPFS) of all 36 pts with PTCL and CTCL was 3.1 months (95% CI, 1.9-6.0). The mPFS were 2.1 months (95% CI, 1.1-4.5) in PTCL and 4.2 months (95% CI, 2.6-NE) in CTCL, respectively. Among all 37 treated pts, the common adverse events (AEs) in any grade were AST increased (89%), ALT increased (87%), hypoalbuminemia (70%), lymphopenia (70%), pyrexia (51%), γ-GTP increased (46%), constipation (38%), thrombocytopenia (35%) and malaise (32%). The common Grade 3 or higher AEs were ALT increased (57%), lymphopenia (57%) and AST increased (43%). The common serious AEs considered related to study drug were ALT increased (14%), AST increased (14%) and capillary leak syndrome (11%). One pt died from rhabdomyolysis, which was considered as treatment related. PK and IM data will be presented.
Conclusions: The primary endpoint of the study was met with greater lower limit of 2-sided 95% CI in ORR than the predefined 5% threshold. The study results indicated the promising efficacy and acceptable safety profile of E7777 at the dose of 9 μg/kg/day in Japanese pts with relapsed or refractory PTCL and CTCL, regardless of the level of tumor CD25 expression. The common AEs were manageable, but ALT/AST increased, hypoalbuminemia and capillary leak syndrome should be carefully managed during the treatment.

Disclosures
Maruyama: Eisai: Honoraria, Research Funding. Ando:Eisai: Research Funding. Yamamoto:Chugai: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria; Novartis: Honoraria, Research Funding; Kyowa Kirin: Honoraria; Gilead Sciences: Research Funding; Otsuka: Honoraria; SymBio: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Bayer: Research Funding; AbbVie: Consultancy, Research Funding; ARIAD: Research Funding; Solasia Pharma: Research Funding; Janssen: Honoraria; MSD: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Research Funding; Sumitomo Dainippon: Honoraria; Pfizer: Honoraria; Eisai: Consultancy, Honoraria, Research Funding; HUYA/IQVIA Services Japan: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Meiji Seika Pharma: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Kiyohara:Eisai: Research Funding. Terui:Bristol-Myers Squibb K.K.: Research Funding; Bristol-Myers Squibb, Celgene, Janssen, Takeda, MSD, Eisai, Ono, and Chugai-Roche Pharmaceuticals Co.,Ltd.: Honoraria. Fukuhara:Chugai Pharmaceutical Co., Ltd.: Honoraria; Celgene Corporation: Honoraria, Research Funding; Zenyaku: Honoraria; Janssen Pharma: Honoraria; Eisai: Honoraria, Research Funding; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Mundi: Honoraria; Nippon Shinkyaku: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; AbbVie: Research Funding; Bayer: Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Tokura:Eisai: Consultancy, Honoraria. Kuroda:Eisai: Research Funding. Uchida:Eisai: Honoraria. Nakanishi:Eisai: Employment. Nakai:Eisai: Employment. Matsunaga:Eisai: Employment. Tobinai:HUYA Bioscience: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Verastem: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; AbbVie: Research Funding; Yakult: Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Mundi Pharma: Consultancy, Honoraria, Research Funding; Solasia: Honoraria; Meiji Seika: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding.

OffLabel Disclosure:
E7777 is investigational drug