A phase I study of LY3022855, a colony-stimulating factor-1 receptor (CSF-1R) inhibitor, in patients (pts) with advanced solid tumors.

Abstract

2523 Background: Binding of CSF-1 to the CSF-1 receptor (CSF-1R) results in proliferation, differentiation, and migration of monocytes/macrophages. Intratumoral infiltration with macrophages correlates with increased invasiveness, growth, and immunosuppression. LY3022855 (LY) is a human IgG1 antibody (mAb) targeting CSF-1R. Methods: Eligible pts (ECOG 0-2) with advanced solid tumors were enrolled. Mandatory pre and post-treatment biopsies were obtained. LY was given on a 6-week cycle. Two escalation regimens (Part A: weight-based dosing; Part B: flat dosing) were investigated in a 3+3 design. Primary objective was to establish the safety and characterize the pharmacokinetics (PK) of LY. Secondary objectives were to establish recommended phase 2 dose (RP2D) and to characterize pharmacodynamics (PD). Results: As of Sept 6, 2016, 35 cancer pts (colorectal 14; lung 4; pancreas 3; others 14) were treated (29 in Part A; 6 in Part B) with median treatment duration 4 weeks (range 1-21). Common treatment-emergent adverse events (TEAEs) were fatigue (54%), hypoalbuminemia (40%), nausea (37%), AST increase (37%), anemia (34%), anorexia (34%), creatine kinase elevation (29%), and constipation (23%). Most common grade (G) 3/4 TEAEs were anemia (11%), fatigue (11%), ascites (9%), and lymphocyte count decrease (9%). 3/28 evaluable pts had DLTs: G3 left ventricular systolic dysfunction (1), G4 rhabdomyolysis and G4 acute renal failure (1), and G3 pancreatitis (1). Eight treatment unrelated deaths were reported. One pt (adenoid cystic carcinoma) had stable disease (~3 mo as of last visit), 19 pts had progressive disease, and 15 pts were non-evaluable for response assessment. PK profile of LY was consistent with IgG1 mAbs. An interim analysis following completion of Part A demonstrated a lack of relationship between weight and clearance, prompting evaluation of non-weight based dosing. PD analyses revealed dose-dependent increases in serum CSF-1 levels as well as suppression of circulating non-classical monocytes (CD14dim CD16bright), indicating biologic activity at studied doses. Conclusions: RP2D for LY monotherapy has been determined. Detailed PK and PD data will be presented. Clinical trial information: NCT01346358.

Clinical Development of Colony-Stimulating Factor 1 Receptor (CSF1R) Inhibitors

“…(IMC-CS4) [38,39] LVEF decrease, rhabdomyolysis þ AKI, pancreatitis None 100 mg None Durvalumab RG7155 [42] Emactuzumab None None 1000 mg 2 CRs þ 22 PRs in TGCT Avelumab SNDX6532 [45,46] Axatilimab None None 6 mg/kg None Durvalumab CSF1 MCS110 [47] Lacnotuzumab There was reduction in nonclassical (CD14 þ CD16high) monocytes and increase of PD-L1-expressing, CD4 or CD8-positive cells in on-treatment tumor biopsies. [35] FPA008 (cabiralizumab) FPA008 is a humanized immunoglobulin G4 (IgG4) MAB that blocks ligand binding, receptor signaling, and therefore depletes TAMs.…”

“…The RP2D of LY3022855 monotherapy is 100 mg once weekly. [38] Patients with advanced refractory metastatic breast cancer (n ¼ 22) and metastatic castration-resistant prostate cancer (n ¼ 12) received LY3022885 in 6-week cycles in cohorts: 1.25 mg/kg every 2 weeks; 1.0 mg/kg on weeks 1, 2, 4, and 5; 100 mg once weekly; and 100 mg every 2 weeks. Common treatment-related AEs were fatigue (38%), decreased appetite (27%), nausea (27%), increased lipase (24%), and increased CK (21%).…”