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2966 Preliminary Clinical Results of a Phase 1 Study Evaluating the Safety and Anti-Tumor Activity of ACTR707 in Combination with Rituximab in Subjects with Relapsed or Refractory CD20+ B-Cell Lymphoma

Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Poster II
Hematology Disease Topics & Pathways:
Diseases, Biological, Adult, Therapies, bioengineering, CAR-Ts, Non-Hodgkin Lymphoma, B-Cell Lymphoma, Technology and Procedures, Study Population, Lymphoid Malignancies
Sunday, December 2, 2018, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Ian W. Flinn, MD, PhD1, Jonathon B. Cohen, MD, MS2, Luke P. Akard, MD3, Samantha Jaglowski, MD, MPH4, Michael Vasconcelles, MD5, Ann Ranger, PhD5*, Patricia Harris, MPH5*, Francis Payumo, BSc, MSc5*, Greg Motz, PhD5* and Veronika Bachanova, MD, PhD6

1Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN
2Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University, Atlanta, GA
3Indiana Bone and Marrow Transplantation, Franciscan Health, Indianapolis, IN
4Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
5Unum Therapeutics Inc., Cambridge, MA
6Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN

Background: Recent regulatory approvals of two CD19-targeted chimeric antigen receptor (CAR)-expressing autologous T lymphocyte therapies provide compelling evidence of the clinical potential of re-engineering T cells to specifically attack tumor cells, but the broader applicability of these therapies is constrained by safety considerations and target specificity. A universal approach to T cell therapy that enables flexibility in tumor target selection has been demonstrated by engineering autologous T cells to express an antibody-coupled T cell receptor (ACTR) composed of the ectodomain of the CD16 Fc receptor fused to costimulatory and CD3ζ signaling domains. Thus, the ACTR platform couples T cell anti-tumor effector functions, including cytotoxicity, cytokine production, and T cell proliferation, to target-specific therapeutic antibodies.

Here we present the preliminary clinical findings of the ongoing, multicenter Phase 1 study, ATTCK‑20-03 (NCT03189836), of ACTR707, a CD28-containing ACTR chimeric receptor, in combination with rituximab in subjects with relapsed or refractory CD20+ B cell lymphoma.

Methods: The primary objectives of this first-in-human, dose escalation study are to evaluate the safety of the combination of ACTR707 and rituximab and to determine a maximum tolerated dose (MTD) and a proposed recommended phase 2 dose (RP2D). Other objectives include evaluation of antitumor activity, and assessment of ACTR T cell persistence, cytokine levels, and rituximab pharmacokinetics. Eligible subjects must have histologically confirmed relapsed or refractory CD20+ non-Hodgkin lymphoma and have received prior anti-CD20 mAb in combination with chemotherapy. Subjects received lymphodepleting chemotherapy (cyclophosphamide 400 mg/m2 and fludarabine 30 mg/m2) for 3 days, followed by rituximab (375 mg/m2) and ACTR707. Additional doses of rituximab were administered, one dose every 3 weeks in the absence of disease progression. The study is separated into 2 sequential phases, a dose escalation and a safety expansion phase. During the dose escalation phase, ACTR707 is being tested at increasing doses in combination with rituximab.

Results: Six subjects were enrolled and received ACTR707 at the first dose level in combination with rituximab: 5 diagnosed with diffuse large B cell lymphoma (83%) and one with follicular lymphoma, Grade 3b (17%). Median age was 61 years (range: 57-76), 83% were male, 50% were treated with ≥3 lines of prior therapy, and 67% had no response to or relapse within 6 months from immediate prior therapy. ACTR707 was successfully manufactured for all subjects and demonstrated post-infusion expansion in the peripheral blood. ACTR+ T cells were detectable at Day 28 post-infusion for all subjects tested. No dose-limiting toxicities (DLTs) were observed at the first dose level in 4 DLT-evaluable subjects (2 subjects experienced disease progression during the DLT evaluation period). There were no cytokine release syndrome (CRS) or autoimmune adverse events (AEs), serious or severe (≥Gr3) neurotoxicity AEs, or deaths on treatment. AEs (all grades) reported in >1 subject included neutropenia (n=3), anemia, decreased appetite, febrile neutropenia, and thrombocytopenia (each in 2 subjects); the 2 events of febrile neutropenia were considered serious. Investigator-reported complete responses were observed in 3 of 6 subjects. These complete responses (duration of response range: 47+ to 81+ days) are ongoing as of the data cut-off. Enrollment into the second dose level is ongoing.

Conclusions: ACTR707 in combination with rituximab induced complete responses in 3 of 6 subjects with relapsed or refractory aggressive CD20+ B cell lymphoma treated at the first dose level with ACTR707 in combination with rituximab, with no CRS, serious or severe (≥Gr3) neurotoxicity, or AEs leading to treatment discontinuation. ACTR+ T cells were detectable in all subjects and persisted. These results support the continued dose escalation of ACTR707 in combination with rituximab. Updated data, inclusive of preliminary dose level 2 and correlative biomarkers, will be presented.

Disclosures: Flinn: Seattle Genetics: Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Portola: Research Funding; TG Therapeutics: Research Funding; BeiGene: Research Funding; ArQule: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Verastem: Consultancy, Research Funding; Incyte: Research Funding; Takeda: Research Funding; Genentech: Research Funding; Calithera: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Merck: Research Funding; Infinity: Research Funding; Forma: Research Funding; Agios: Research Funding; Trillium: Research Funding; Curis: Research Funding; Verastem: Research Funding. Cohen: BioInvent: Consultancy; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Akard: Gilead: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Jaglowski: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Consultancy. Vasconcelles: Unum Therapeutics: Employment. Ranger: Unum Therapeutics: Employment. Harris: Unum Therapeutics: Employment. Payumo: Unum Therapeutics: Employment. Motz: Unum Therapeutics: Employment. Bachanova: Gamida Cell: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Research Funding.

*signifies non-member of ASH