Abstract CT145: A first-in-human phase 1 study in patients with advanced and/or refractory solid malignancies to evaluate the safety of ATOR-1015, a CTLA-4 x OX40 bispecific antibody
Authors: Yachnin Jeffrey , Ullenhag Gustav J. , Carneiro Ana , Nielsen Dorte L. , Rohrberg Kristoffer Staal , Kvarnhammar Anne Månsson , Bågeman Erika , Wennersten Camilla S. , Russell Charlotte Astrid 
Published: September 2020

Abstract
ATOR-1015 is evaluated in this first-in-human phase 1 study for safety and tolerability, as well as pharmacokinetics, immunogenicity and clinical efficacy (NCT03782467). ATOR-1015 is a human CTLA-4 x OX40 targeting IgG1 bispecific antibody developed as a next generation CTLA-4 antibody with enhanced immune activation and tumor-directed activity for improved clinical efficacy and reduced toxicity. The primary objective of the study is to determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) in patients with advanced solid malignancies. Safety and tolerability of ATOR-1015 are assessed by adverse events (AEs), vital signs, ECG, laboratory evaluations and physical examinations. Secondary objectives include pharmacokinetics (PK), immunogenicity and clinical efficacy. Clinical efficacy is assessed with CT scans using Response Evaluation Criteria in Solid Tumors (iRECIST) for immune-based therapeutics. The study is designed with single patient cohorts for doses less than 100 mg. Thereafter, the study follows a modified 3+3 design. Intra-patient dose escalation is allowed. After the dose escalation, there is an option for expansion at or below the MTD. A total of up to 53 patients will be enrolled in the study. ATOR-1015 is administered intravenously biweekly as a single agent. Patients will receive ATOR-1015 treatment until confirmed progressive disease, unacceptable toxicity or withdrawal of consent. The first patient was dosed in March 2019. Sixteen patients have been enrolled, one screen failure and 15 exposed to ATOR-1015. The following dose levels have been evaluated; 0.043 mg; 0.137 mg; 0.438 mg; 1.4 mg; 4.4 mg; 14 mg; 42 mg and 100 mg. Dose escalation is ongoing, and the 200 mg dose level is under evaluation. The following cancer types have been included; colorectal cancer (n=9), uveal melanoma (n=2), pancreatic cancer (n=2), ovarian cancer (n=2), and cholangiocarcinoma (n=1). The median age of the patients is 52 years (range 40-72). Patients received a median of 6 prior lines of therapy (range 3-16). The median time on study was 7.4 weeks (range 0.1-32.1). Six patients are on study and nine patients have discontinued treatment. Reasons for discontinuation include clinical deterioration (n=6), death due to disease progression (n=2) and confirmed disease progression (n=1). Six patients out of 15 experienced drug-related AEs that were all grade 2 or less. Four patients had infusion-related reactions (IRR), and one of those four also had abdominal pain, one patient had vitiligo, and one patient had rash. The IRR symptoms were predominantly rash. No Dose-Limiting Toxicities have occurred. Preliminary PK data show dose-proportional kinetics up to 100 mg. Conclusion: The dosing of ATOR-1015 has been safe and well-tolerated up to 100 mg. Dose escalation continues and the current dose level is 200 mg.
Citation Format: Jeffrey Yachnin, Gustav J. Ullenhag, Ana Carneiro, Dorte L. Nielsen, Kristoffer Staal Rohrberg, Anne Månsson Kvarnhammar, Erika Bågeman, Camilla S. Wennersten, Charlotte Astrid Russell. A first-in-human phase 1 study in patients with advanced and/or refractory solid malignancies to evaluate the safety of ATOR-1015, a CTLA-4 x OX40 bispecific antibody [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT145.