Abstract CT082: Phase (Ph) I/Ib study of NIZ985 with and without spartalizumab (PDR001) in patients (pts) with metastatic/unresectable solid tumors
Authors: Conlon Kevin , Leidner Rom , McNeel Douglas , Gupta Sumati , Wang-Gillam Andrea , Waldmann Thomas A. , Pavlakis George , Dostalek Mirek , Kurtulus Sema , Chowdhury Niladri Roy , O'Keeffe Jessica , Parikh Nehal S. , Thompson John A. 
Published: August 2019

Abstract
Background: NIZ985 is a soluble IL-15/IL-15 receptor α heterodimer (hetIL-15) that binds IL-2/IL-15 receptor β/γ and promotes effector T-cell and NK cell expansion and activation. Spartalizumab is a humanized IgG4 mAb that blocks binding of programmed death 1 (PD-1) to programmed death ligand 1/2 (PD-L1/2). In preclinical studies, IL-15 and anti-PD-1/PD-L1 combinations demonstrated synergistic antitumor activity. Here we report dose escalation results from a Ph I/Ib study of NIZ985 as a single agent (SA) and in combination with spartalizumab (NCT02452268).
Methods: Pts with metastatic/unresectable solid tumors received subcutaneous NIZ985 TIW (2 weeks on/2 weeks off); 0.25-4 μg/kg NIZ985 SA or 1 μg/kg NIZ985 with IV spartalizumab (400 mg, Q4W). Ph I endpoints: DLTs, safety, PK, pharmacodynamics (PD), preliminary efficacy, and recommended dose for expansion (RDE), statistically guided by a 3+3 study design.
Results: As of Oct 9, 2018, 14 pts (median age 56.5 y [range 42.0-73.0]) received NIZ985 SA and 11 pts (median age 61 y [range 34.0-75.0]) received NIZ985 + spartalizumab. Treatment was discontinued in 13 (93%) and 10 (91%) pts receiving NIZ985 SA and NIZ985 + spartalizumab, respectively, mainly due to disease progression (57% and 82%); 1 pt in each group is ongoing. No DLTs were reported in the first cycle. AEs suspected to be drug related were reported in 100% of pts (36% grade 3/4) for NIZ985 SA and 100% of pts treated with the combination (27% grade 3/4). Common AEs [all grades; grade 3/4], defined as ≥50% of pts for any grade, were injection site reaction [100%; 7%], chills [64%; 0%], and fatigue [57%; 0%] in NIZ985 SA; and injection site reaction [100%; 9%], fatigue [82%; 0%], diarrhea [64%; 9%], and nausea [55%; 0%] in NIZ985 + spartalizumab. Median duration of NIZ985 exposure (range) across doses was 7.6 weeks (2.6-15.6) in NIZ985 SA and 21.6 weeks (5.6-53.6) in NIZ985 + spartalizumab. In 13 evaluable NIZ985 SA pts, confirmed best overall responses (BORs) were stable disease (SD; n=3, 23%), progressive disease (n=8, 62%), and unknown (n=2, 15%); SD is ongoing in 1 pt with spindle cell ocular melanoma. Confirmed BORs in 11 evaluable NIZ985 + spartalizumab pts were SD (n=5, 45%) and progressive disease (n=6, 55%); SD is ongoing in 1 pt with gastric adenocarcinoma. RDE was declared as 1 μg/kg NIZ985 (TIW; 2 weeks on/2 weeks off) for SA and with spartalizumab (400 mg, Q4W). PD analyses showed NIZ985 induces lymphocyte proliferation in peripheral blood. Preliminary antitumor activity, PK, and PD data from tumors and peripheral blood will be presented.
Conclusions: NIZ985 SA and with spartalizumab was well tolerated in pts with metastatic/unresectable solid tumors, with no DLTs reported. RDEs were NIZ985 1 μg/kg (TIW, 2 weeks on/2 weeks off) for SA and with spartalizumab (400 mg, Q4W). PD data support proof of mechanism. Dose escalation with an alternate NIZ985 schedule is ongoing.
Citation Format: Kevin Conlon, Rom Leidner, Douglas McNeel, Sumati Gupta, Andrea Wang-Gillam, Thomas A. Waldmann, George Pavlakis, Mirek Dostalek, Sema Kurtulus, Niladri Roy Chowdhury, Jessica O'Keeffe, Nehal S. Parikh, John A. Thompson. Phase (Ph) I/Ib study of NIZ985 with and without spartalizumab (PDR001) in patients (pts) with metastatic/unresectable solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT082.