Interpreting the findings with APF530 SC in the context of granisetron IV is not straightforward because a minimal effective concentration of granisetron in prevention of CINV has not been defined. The recommended dose of granisetron for prevention of CINV is 10 μg/kg,12 which achieves a Cmax of 4.9 ng/mL.13 In an APF530 Phase I safety and pharmacokinetics study in normal volunteers in which granisetron IV (50 μg/kg) was used as a control, granisetron concentrations at 24 and 48 hours were 3.67 and 0.890 ng/mL, respectively. Assuming that an effective granisetron concentration is maintained for at least 48 hours, the minimal effective concentration is <1.0 ng/mL.13 With APF530 500 mg in C2005-01, the granisetron concentration at 168 hours was 1.96 ng/mL; it appears that an effective concentration of granisetron was maintained over at least 7 days with APF530 500 mg.
The dose of granisetron in APF530 SC raised no safety issues. Regulatory concerns regarding potential prolongation of the QTc by 5-HT3 inhibitors resulted in labeling changes regarding potential cardiac safety for granisetron.14 The labeling change was based on individual incidents of QT prolongation.12,15 However, no effect on QTc intervals had been seen in several earlier trials with IV and oral granisetron,16–20 and a recent study with transdermal granisetron also reported no significant effects on QTc or other ECG variables.13 The effect of high-dose APF530 on the QTc interval (QTc) was assessed in a blinded, placebo-controlled study in normal volunteers with APF530 SC 1,000 mg. No clinically significant QTc prolongation was seen with APF530 SC or granisetron IV.8
Based on the findings in these Phase II trials, a Phase III trial was conducted to assess the efficacy of APF530 SC 250 mg and APF530 SC 500 mg in comparison with the second-generation 5-HT3 inhibitor palonosetron. For the 500 mg dose of APF530, the CR rate was noninferior to that of palonosetron in the control of acute emesis following administration of MEC or HEC, and in control of delayed emesis following administration of MEC. In control of delayed emesis following HEC, CR rates with APF530 SC 500 mg were numerically superior to those of palonosetron, although superiority to palonosetron in this setting was not demonstrated.6,21
The pharmacokinetic properties of APF530 have been defined in two Phase II trials in cancer patients receiving a MEC or a HEC regimen. An effective plasma concentration of granisetron was maintained for 7 days with a single dose of APF530. APF530 was well tolerated, exhibiting AEs expected with granisetron. Injection site reactions occurred in fewer than 10% of patients and were mild in most patients. Preliminary efficacy data suggest that APF530 is an expanded option for prevention of acute and delayed CINV. APF530 is a novel delivery system that could particularly benefit chemotherapy patients in the outpatient setting, where convenience and patient compliance are important concerns. On the basis of the findings in this study, APF530 SC 250 mg and APF530 SC 500 mg were carried forward in a Phase III trial.
Nashat Gabrail,1 Ronald Yanagihara,2 Marek Spaczyński,3 William Cooper,4 Erin O’Boyle,5 Carrie Smith,1 Ralph Boccia6
1Gabrail Cancer Center, Canton, OH, USA; 2St Louise Regional Hospital, Gilroy, CA, USA; 3Department of Gynecology, Obstetrics and Gynecologic Oncology, University of Medical Sciences, Poznan, Poland;4TFS International, Flemington, NJ, USA; 5FibroGen, Inc., San Francisco, CA, USA; 6Center for Cancer and Blood Disorders, Bethesda, MD, USA
NG, RY, MS, and RB were the study site investigators, EO was the clinical representative, CS was the clinical study nurse at the Gabrail Cancer Center, and WC performed the statistical analysis. All authors were involved in study conception and design, data acquisition, and the drafting and critical revision of the manuscript’s intellectual content. All authors have read and approved the final manuscript, and agree to be accountable for all aspects of the work’s accuracy and integrity.
This study was sponsored by Heron Therapeutics, Inc. (formerly AP Pharma, Inc.). Medical writing support was provided by Richard McCabe, PhD, of SciStrategy Communications, supported by Heron Therapeutics, Inc. The authors would like to thank the many investigators and their clinical staff, who made this study possible.
Dr Nashat Gabrail has received research funding from Heron Therapeutics, Inc. (formerly AP Pharma, Inc.). for the conduct of the clinical trial. Dr Ronald Yanagihara has received research funding from AP Pharma, Inc. for the conduct of the clinical trial. Dr Marek Spaczyński has received funding and honoraria from AP Pharma, Inc. for the conduct of this clinical trial. William Cooper is a consultant for TFS International, the clinical research organization contracted to provide work for AP Pharma, Inc. Erin O’Boyle was previously an employee of, held stock options in, and is currently a consultant for AP Pharma, Inc. Carrie Smith has received funding from AP Pharma, Inc. as a consultant. Dr Ralph Boccia has received clinic funding for the trial only. The authors declare that they have full control of the primary data and agree to allow the journal to review these data. The authors report no other conflicts of interest in this work.
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Source: Cancer Management and Research.
Originally published on March 17, 2015.