PII-054 - EVALUATION OF PHARMACOKINETICS (PK), SERUM CYTOKINES, AND SAFETY FOLLOWING INTRAVENOUS (IV) OR SUBCUTANEOUS (SC) STEP-UP DOSING OF UBAMATAMAB, A MUC16XCD3 BISPECIFIC ANTIBODY, IN PATIENTS WITH RECURRENT OVARIAN CANCER (OC)

P. Madia¹, D. Conrado¹, S. Yoo¹, B. Wang¹, J. Brouwer-Visser¹, Q. Qin¹, J. Davis¹, T. Uldrick¹, M. Peterman¹, E. Miller¹, M. Zhu¹; ¹Regeneron Pharmaceuticals, Inc..

Background: Ubamatamab is a MUC16xCD3 bispecific antibody that promotes T cell–mediated cytotoxicity by binding MUC16-expressing OC cells and CD3+ T cells. Safety, PK, pharmacodynamics (PD), and efficacy of ubamatamab in patients with OC (NCT03564340) were evaluated in the ongoing first-in-human study with once weekly (QW) administration. Step-up dosing in Week (W) 1–2 prior to full treatment doses was employed to minimize acute adverse events (AEs) like cytokine release syndrome (CRS) and pain. SC administration of ubamatamab during step-up dosing was explored as an approach to better mitigate CRS due to expected lower peak concentration (Cmax) and delayed time to Cmax (Tmax) compared with IV administration.

Methods: Step-up doses of ubamatamab IV at 1 mg in W1 and 20 mg (split over 2 days) in W2 prior to full doses in ≥W3 (20–800 mg QW, N=95) were evaluated during dose escalation. A population PK model was developed with IV data and used to predict the SC PK profile with 0.8 bioavailability (BA) in monkey and 0.28/day absorption rate constant for monoclonal antibodies. Patients (n=12) were studied with SC step-up doses at 2 mg in W1 and 25 mg in W2 prior to IV dosing from W3. PK, PD, and AEs from this cohort were compared with the pooled data from IV cohorts.

Results: The observed Cmax (mean ± SD) of SC ubamatamab (0.107 ± 0.031 mg/L at 2 mg W1 and 1.27 ± 0.743 mg/L at 25 mg W2) was 25% lower than the predicted Cmax. BA was lower than expected. Compared with the observed IV Cmax at 1 mg and 20 mg, SC Cmax at 2 mg and 25 mg was 62% and 72% lower in W1 and W2, respectively. Median Tmax was delayed with SC (3.05 days) compared with IV (0.18 days). Serum IL-6 increased from baseline (2.47 pg/mL) and peaked within 24 h after IV or SC doses. Median peak IL-6 was substantially lower with SC than IV in W1 (10.3 vs. 110 pg/mL) and modestly lower in W2 (56.6 vs 113 pg/mL). The median CRS onset time was within 24 h of the IV or SC dose. Frequencies of AEs (CRS/pain) after SC were lower than after IV in W1 but not W2. With either IV or SC step-up dosing, cytokine elevation and acute AEs were less frequent at full treatment doses at ≥W3.

Conclusion: SC step-up dosing decreased the incidence of AEs and cytokine elevation after the initial dose in W1. The data support further optimization of SC step-up dosing and strategies to help mitigate AEs.