Abstract: 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

Abstract: Introduction Fludarabine and a myeloablative dose of intravenous busulfan with or without total body irradiation (Flu/Bu4) is a widely accepted myeloablative conditioning regimen with reduced toxicity for allogeneic hematopoietic stem cell transplantation (HSCT) that has been able to expand the indications for allogeneic HSCT while maintaining the intensity. However, relapse is a major concern especially in patients with high-risk hematological malignancies. Accordingly, a novel conditioning regimen that included Flu/Bu4 plus melphalan (Flu/Bu4/Mel) was used, with excellent outcomes, i.e., the 2-year overall survival (OS) was 54.9% in patients with non-remission acute myeloid leukemia. However, no study has compared Flu/Bu4/Mel and other conditioning regimens. Therefore, this multicenter retrospective observational study aimed to investigate the impact of adding melphalan to Flu/Bu4 by comparing patients who received Flu/Bu4/Mel and those who received Flu/Bu4. Methods The present study included 2394 adult patients who received Flu/Bu4/Mel (n=581) or Flu/Bu4 (n=1813) between January 2010 and December 2016 at the Japan Society of Hematopoietic Cell Transplantation. High-risk disease was defined as incomplete remission in patients with acute myeloid leukemia and acute lymphoblastic leukemia as well as refractory anemia with excess blast transformation in patients with myelodysplastic syndrome; standard risk disease was defined as stable disease or disease progression in patients with malignant lymphoma before HSCT. We set the primary endpoint as the 5-year OS, evaluated by using the log-rank test. To compare the impact of the conditioning regimen on the primary endpoint, we used a multivariable Cox proportional hazards model. The following adjusted covariates were selected clinically based on previous studies: age, sex, disease, disease status at HSCT, hematopoietic cell transplant comorbidity index (HCT-CI), donor source, acute graft versus host disease prophylaxis, and years of HSCT. In addition, we performed propensity score matched analysis to minimize the potential treatment selection bias because the baseline characteristics of patients and disease could have influenced the selection of the conditioning regimen. Propensity score matching with a 1:1 ratio was performed by using the nearest neighbor-matching method with a caliper width fixed at 0.01. In addition, detailed analysis was performed by dividing patients into the high-risk and standard risk groups because the initial single-center retrospective studies mainly enrolled patients with high-risk disease. Results A total of 2394 patients were enrolled and analyzed: 581 patients received Flu/Bu4/Mel and 1813 patients received Flu/Bu4. The median age was 60 years (interquartile range, 53-63 years) and 1489 patients (62.2%) were men. The clinical characteristics of patients treated with Flu/Bu4/Mel and those treated with Flu/Bu4 were different. The Flu/Bu4/Mel group included more patients who were young, had acute myeloid leukemia and malignant lymphoma, had high-risk disease, had higher HCT-CI, received cord blood transplantation, received tacrolimus-based acute graft versus host disease prophylaxis, and had undergone transplantation recently. Regarding the primary endpoint, the 5-year OS after allogeneic HSCT was 33.7% (95% confidence interval [CI]: 27.5-40.1%) in the Flu/Bu4/Mel group vs 35.4% (95% CI: 32.7-38.1%) in the Flu/Bu4 group (p=0.794). The adjusted hazard ratio was 0.73 (95% CI: 0.62-0.85) for the Flu/Bu4/Mel group compared to the Flu/Bu4 group (p & lt;0.001). After propensity score matching, the 5-year OS after allogeneic HSCT was 35.1% (95% CI: 28.0-42.2%) in the Flu/Bu4/Mel group vs 28.1% (95% CI: 22.4-34.0%) in the Flu/Bu4 group (p=0.008; Figure). On detailed subgroup analysis, among patients with high-risk disease, the 5-year OS was 29.5% (95% CI: 23.0-36.4%) in the Flu/Bu4/Mel group vs 20.8% (95% CI: 17.3-24.6%) in the Flu/Bu4 group (p & lt;0.001), while among standard-risk patients, it was 46.3% (95% CI: 35.6-56.2%) in the Flu/Bu4/Mel group vs 43.8% (95% CI: 40.3-47.4%) in the Flu/Bu4 group (p=0.745; P for interaction: 0.010). Conclusion The results showed that Flu/Bu4/Mel resulted in superior 5-year OS compared to Flu/Bu4, with an adjusted hazard ratio of 0.73. In addition, patients with high-risk disease showed better survival benefit with Flu/Bu4/Mel treatment. Figure Disclosures Ichinohe: Astellas Pharma: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria.