Abstract 1025: Phase Ib trial single-arm efficacy estimates via comparison to a historical clinical trial synthetic control arm
Authors: Yin Xiang , Davi Ruthanna , Lamont Elizabeth B. , Thaker Premal H. , Bradley William H. , Leath Charles A. , Moore Kathleen M. , Anwer Khursheed , Musso Lauren , Borys Nicholas 
Published: June 2022

Abstract
Background: Innovations in data science and trial design have catalyzed novel clinical research methods which may inform the future success of new experimental therapies more efficiently than previously believed. To guide development of the novel immune agent GEN-1, we compared endpoints experienced by patients from a recent neoadjuvant single-arm phase Ib study of GEN-1 plus standard chemotherapy to those of similar historical clinical trial patients in receipt of standard chemotherapy alone.
Methods: To compare safety and efficacy endpoints following first-line neoadjuvant weekly GEN-1 immunotherapy and carboplatin and paclitaxel to standard first-line neoadjuvant carboplatin and paclitaxel in women with advanced ovarian cancer, we first applied key OVATION-1 trial (NCT02480374) inclusion and exclusion criteria to the Medidata Enterprise Data Store (MEDS) data to identify candidate historical clinical trial patients for comparison. We standardized and integrated patient-level MEDS data (N=41) from distinct phase I-III trials (enrollment years 2015-2016) with patient-level OVATION-1 data (N=18). Standard propensity score methods were used to identify MEDS patients who appeared similar to OVATION-1 patients to create a synthetic control arm (SCA).
Results: Fifteen OVATION-1 patients (15/18, 83%) were matched to 15 (37%, 15/41) MEDS historical trial control patients. Matching attenuated pre-existing differences in attributes between the OVATION-1 and MEDS patients. The median progression-free survival time was not reached by the OVATION-1 group and was 15.8 months for the SCA. The hazard of progression for the OVATION-1 group relative to the SCA was 0.53 (95% CI 0.16, 1.73). Fourteen of 15 OVATION-1 patients (93.3%) and 15 of the SCA patients (100%, 15/15) had at least one MedDRA toxicity. Compared to SCA patients, OVATION-1 patients had a slightly higher incidence in nausea (OVATION-1 73.3%; SCA 53.3%), fatigue (OVATION-1 73.3%; SCA 33.3%), anorexia (OVATION-1 46.7%; SCA 13.3%), chills (OVATION-1 26.7%; SCA 6.7%), and infusion-related reaction (OVATION-1 26.7%; SCA 0%).
Conclusions: The comparison of patient endpoints from a single-arm phase Ib trial to a historical clinical trial SCA provided informative and relatively reliable estimates of efficacy endpoints which were used to inform GEN-1’s expected effect study size in the phase II setting. This information led to a decrease in the number of planned patients for the subsequent randomized phase II trial. More broadly, this approach supports the ability of historical clinical trial patient comparisons to inform drug development via trial design, something which may further increase the scientific value of early phase trials.
Citation Format: Xiang Yin, Ruthanna Davi, Elizabeth B. Lamont, Premal H. Thaker, William H. Bradley, Charles A. Leath, Kathleen M. Moore, Khursheed Anwer, Lauren Musso, Nicholas Borys. Phase Ib trial single-arm efficacy estimates via comparison to a historical clinical trial synthetic control arm [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1025.