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

James C Yao, Jennifer A Chan, Alain C Mita, Madan G Kundu, Karina Hermosillo Reséndiz, Ke Hu, Shoba Ravichandran, Jonathan R Strosberg, Edward M Wolin, James C Yao, Jennifer A Chan, Alain C Mita, Madan G Kundu, Karina Hermosillo Reséndiz, Ke Hu, Shoba Ravichandran, Jonathan R Strosberg, Edward M Wolin

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 prelimi-nary 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: Bayesian logistic regression model; MTD; dose escalation with overdose control; pharmacodynamics; pharmacokinetics.

Conflict of interest statement

Disclosure JCY has received consulting or advisory fees from Ipsen, Lexicon, and Novartis and research funding from Novartis. MGK, KHR, KH, and SR are employees of Novartis. JRS has received honoraria from Novartis; consulting or advisory fees from Ipsen, Lexicon, and Novartis; and research funding from Novartis and Pfizer and is on the speaker’s bureau for Bayer and Genentech. EMW has received consulting or advisory fees from Celgene, Ipsen, and Novartis. ACM is a member of the Speaker Bureau for Genentech. JAC has received consulting or advisory fees from Ipsen, Lexicon, Novartis, and Oxigene and has stock in Merck. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Postulated mechanism of action of pasireotide.
Figure 2
Figure 2
Kaplan–Meier estimates of PFS by local radiological review. Abbreviations: CI, confidence interval; NE, not estimable; PFS, progression-free survival; LAR, long-acting release.
Figure 3
Figure 3
Results of the PK/pharmacodynamic analysis. Notes: (A) Mean PK–concentration–time profiles from the PK analysis set. CxDy: Cycle x, Day y. Negative (mean − SD) values were truncated to zero. Below the LLOQ values (<0.15 ng/mL) were set to zero. Day 1 pre-dose concentrations on C2 through C12 represent Cmin concentrations; day 22 concentration from the C1 represents the Cmax concentration. (B) Change from baseline tumor size vs pasireotide trough concentrations. (C) Change from baseline tumor size vs pasireotide trough concentrations. (D) IGF-1 vs pasireotide trough concentrations. (E) CgA vs pasireotide trough concentrations. (F) NSE vs pasireotide trough concentrations. Abbreviations: PK, pharmacokinetic; LLOQ, lower limit of quantitation; C2, Cycle 2; C12, Cycle 12; C1, Cycle 1; CgA, chromogranin A; NSE, neuron-specific enolase; LAR, long-acting release.
Figure 4
Figure 4
Predicted probability of bradycardia vs pasireotide LAR concentration. Abbreviations: CI, confidence interval; LAR, long-acting release; HR, heart rate; bpm, beats per minute.

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