Introduction: Within the tumor microenvironment, CSF1R signaling is thought to play an important role in recruitment and differentiation of tumor-associated macrophages and osteoclasts, promoting disease progression through suppression of anti-tumor immune response, promotion of angiogenesis, tumor cell metastasis and tumor-induced osteolysis. ARRY-382 is a potent, highly selective, oral inhibitor of CSF1R. This Phase 1 dose-escalation study was designed to determine the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of ARRY-382 in patients (pts) with advanced or metastatic cancers refractory to standard treatment.
Methods: Pts received ARRY-382 orally once daily (QD) in 28-day cycles. Study design included an initial accelerated titration phase, followed by 3+3 dose escalation and an expansion phase. Safety was assessed by adverse events (AEs), ECGs, clinical laboratory tests, physical exams and vital signs. PK parameters were estimated based on serial plasma PK samples. Levels of pERK in pt monocytes stimulated with CSF1 ex vivo, circulating CD14dim/CD16+ nonclassical monocytes (NCM) and CSF1 were evaluated as markers of CSF1R inhibition. Urinary collagen type 1 cross-linked N[[Unable to Display Character: ‑]]telopeptide (NTX) was evaluated as a marker of bone turnover.
Results: Twenty-six pts received ARRY-382 at doses ranging from 25 to 500 mg QD. The MTD of ARRY-382 was 400 mg QD. Dose-limiting toxicities were increased creatine kinase (CK), increased AST and pyrexia (1 pt each, all Grade 3). The most common drug-related AEs were fatigue (42%), increased CK (27%), nausea (23%), decreased appetite (15%) and vomiting (12%). Grade 3/4 AEs in >1 pt were increased CK (23%), pneumonia (15%), anemia (8%) and vomiting (8%). Increases in ARRY-382 exposure were approximately dose proportional. At the MTD, a Cmax of 3.06 µg/mL was achieved with a Ctrough > 1 µg/mL after repeated dosing. Doses ≥ 200 mg QD resulted in > 80% mean reduction from Baseline in monocyte pERK, consistent with exposures above the ARRY-382 IC50 value. The PD activity of ARRY-382 was consistent with CSF1R inhibition. Reductions in NCM were observed at doses ≥ 200 mg QD, with a 96% mean decrease from Baseline observed at the MTD. Reductions in urinary NTX were observed at doses ≥ 50 mg QD. Five of 7 pts with elevated urinary NTX at Baseline experienced reductions to within the normal range in the first cycle, including 3 pts with bone metastases. Increases in CSF1 appeared dose-dependent with ∼28-fold maximal increase from Baseline observed at the MTD in the first cycle. No objective responses were observed, although 4 pts (15%) experienced stable disease which lasted > 3 months for 2 pts.
Conclusions: ARRY-382 was generally well tolerated in pts with advanced or metastatic cancers. Exposure and PD activity of ARRY[[Unable to Display Character: ‑]]382 indicate that CSF1R was significantly inhibited at tolerated doses.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A252.
Citation Format: Johanna C. Bendell, Anthony W. Tolcher, Suzanne F. Jones, Muralidhar Beeram, Jeffrey R. Infante, Paul Larsen, Kevin Rasor, Jennifer E. Garrus, Jinfang Li, P. Louann Cable, Christine Eberhardt, Jennifer Schreiber, Selena Rush, Kenneth W. Wood, Emma Barrett, Amita Patnaik. A phase 1 study of ARRY-382, an oral inhibitor of colony-stimulating factor-1 receptor (CSF1R), in patients with advanced or metastatic cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A252.
