Phase I dose-escalation study of long-acting pasireotide in patients with neuroendocrine tumors

James C Yao,¹ Jennifer A Chan,² Alain C Mita,³ Madan G Kundu,⁴ Karina Hermosillo Reséndiz,⁴ Ke Hu,⁴ Shoba Ravichandran,⁴ Jonathan R Strosberg,⁵ Edward M Wolin<sup>6

1</sup>GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, ²Gastrointestinal Cancer Center, Dana–Farber Cancer Institute, Boston, MA, ³Experimental Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA, ⁴Oncology, Novartis Pharmaceuticals Corporation, East Hanover, NJ, ⁵Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, ⁶Oncology, Montefiore Einstein Center for Cancer Care, Bronx, NY, USA

Abstract: This phase I study aimed at determining the maximum tolerated dose (MTD) and characterizing the safety, tolerability, pharmacokinetics (PKs), and efficacy of pasireotide in patients with advanced neuroendocrine tumors (NETs). Patients were enrolled in two phases: dose-escalation phase (to determine the MTD) at a starting dose of 80 mg pasireotide long-acting release (LAR) i.m. followed by a dose-expansion phase (to evaluate safety and preliminary efficacy). Associations between PK/pharmacodynamic parameters and clinical outcomes were evaluated using linear regression analysis. A total of 29 patients were treated with 80 mg (n=13) and 120 mg (n=16) doses. Most common primary tumor sites included small intestine (44.8%), pancreas (24.1%), and lung (17.2%). No protocol-defined dose-limiting toxicities were observed in the study; however, in post hoc analysis, a higher incidence of bradycardia (heart rate [HR] <40 beats per minute [bpm]) was observed with 120 mg (31.3%) vs 80 mg (0%). Two partial responses (PRs) were observed, both in the 120 mg dose cohort. Pasireotide concentrations correlated with tumor shrinkage, although the association was not statistically significant (P=0.08). Among the biomarkers analyzed, insulin-like growth factor 1 (IGF-1) showed a decreasing trend with increasing pasireotide concentration, while chromogranin A (CgA) and neuron-specific enolase (NSE) levels did not show any dose–response relationship. The most common adverse events in any dose group were hyperglycemia, fatigue, and nausea. MTD was defined at 120 mg for pasireotide LAR in patients with advanced NETs. Although objective radiographic responses were rarely observed with somatostatin analogs, two PRs were observed among 16 patients in the 120 mg cohort. Bradycardia (HR <40 bpm) appears to be a dose-limiting effect; however, the mechanism and clinical significance are uncertain. This study was registered with clinicaltrials.gov (NCT01364415).

Keywords: pharmacokinetics, pharmacodynamics, MTD, Bayesian logistic regression model, dose escalation with overdose control