044: The Role of Exposure-Response Analyses in Determination of Recommended Dose for Expansion in a Phase I/Ib Study of NIZ985 Alone & in Combination With Spartalizumab in Cancer Patients

Statement of Purpose: A Phase I/Ib, open-label, multicenter, dose-escalation/-expansion study has been conducted in adult patients with advanced solid tumors or lymphoma for NIZ985, an investigational recombinant heterodimer of interleukin (IL)-15 and IL-15 receptor alpha (NCT04261439). Following completion of the dose escalation phase, an integrated data analysis was performed to determine the recommended dose for expansion (RDE).

Description of Methods & Materials: In this Phase I/Ib study, eligible patients had previously responded and progressed on a checkpoint inhibitor treatment. Dose escalation phase was comprised of 2 arms: Arm 1- single agent, subcutaneous NIZ985 at 2, 4, 8, 12 or 16 μg/kg once a week, 3 weeks on/1 week off every 28 days; and Arm 2- NIZ985 in combination with 400 mg spartalizumab (PDR001, monoclonal antibody targeting PD-1) intravenously on Day 1 of each 28-day cycle. Evaluation of safety and tolerability were the primary objectives, and the secondary objectives were to assess antitumor activity, pharmacokinetics (PK) and immunogenicity. Exploratory objectives included pharmacodynamic (PD) biomarker assessment in the tumor and peripheral blood samples. Integrated data analysis was performed in an exploratory manner to elucidate the PK/PD relationships in safety, tolerability and PD effects of NIZ985.

Data & Results: At data cut-off (Aug 15, 2022) a total of 56 patients had been treated in Arm 1 (n=27) and Arm 2 (n=29). NIZ985 alone and in combination with spartalizumab were generally well tolerated and the maximum tolerated dose (MTD) was not identified. The best overall response was partial response (n=2) across the dose levels in both arms (n=1 in Arm 1 NIZ985 8 µg/kg; n=1 in Arm 2 NIZ985 2 µg/kg + PDR001 400 mg). Dose-proportional exposure was observed up to 12 μg/kg but the exposure overlapped at 16 μg/kg. Exposure-response analysis showed positive PK/PD relationship for peripheral immune activation of CD8+ and NK cells. It indicated that maximum PD effect could be anticipated at 12 μg/kg accounting for the overlapping exposure at 16 μg/kg. For safety and tolerability, a positive exposure-response relationship was observed for probability of adverse events causing dose modification. Moreover, the above-mentioned probability also showed a positive correlation with average daily dose. Overall, it was demonstrated that the top dose of 16 μg/kg would not provide any better PD effects but only add risks in terms of safety and tolerability. Therefore, RDE was declared at 12 μg/kg for both NIZ985 alone and in combination with spartalizumab.

Interpretation, Conclusion or Significance: Following completion of the dose escalation phase, MTD had not been identified and a clear correlation of efficacy with dose or exposure was not observed. Principles of clinical pharmacology were applied to determine the RDE with exploratory PK/PD analyses for both PD biomarkers and safety endpoints. As a result, an RDE that appropriately balances safety, tolerability and pharmacological activity was identified for evaluation in the expansion phase.

Disclosures: All authors are employees and may be stockholders of Novartis.