In C2005-01, no clinically significant laboratory abnormalities were reported following APF530 administration. In C2007-01, clinically significant low red blood cell counts and low hemoglobin concentrations were reported in four patients. No clinically meaningful changes in vital signs, physical examinations, or ECGs were reported in either study.
AEs related to APF530 occurred in 28.9% of patients in C2005-01. In addition to injection site reactions, events related to APF530, and occurring in at least two patients, in C2005-01 were mild to moderate constipation (three patients) and mild to moderate headache (two patients). In C2007-01, the only related AEs, other than injection site reactions, were mild or moderate constipation in four patients (11.6%).
Injection site reactions in studies C2005-01 and C2007-01, respectively, included erythema (8.9% and 5.7%), induration (6.7% and 8.9%), bruising (4.4% and 5.7%), and tenderness or pain (2.2% and 2.9%). There were 19 reactions among 80 patients, 17 mild and two of moderate intensity.
Serious AEs in C2005-01 occurred in four patients: one patient died (related to the underlying disease); and among the remaining patients, one had dyspnea, malaise, and hyperhidrosis, one had intractable diarrhea, and one had dysphagia. All patients recovered. None of the events was related to the study drug. In C2007-01, serious AEs occurred in three patients: one had thrombocytopenia and anemia, one had anemia, and one had thrombocytopenia and abdominal pain. None of the serious AEs was considered related to the study drug, and there were no deaths during the study.
Both acute-onset and delayed-onset CINV were controlled at all doses in both the US and European trials (Table 8). Among those treated with APF530 250 or 500 mg, CR was obtained in ≥83% of patients, in both the acute-onset and delayed-onset phases, and complete control was obtained in ≥76%, indicating that nausea was controlled almost as effectively as emesis; the nausea that did occur was mostly mild.
(To view a larger version of Table 8, click here.)
The most important finding of these similarly designed Phase II trials was that granisetron exposure was maintained for 7 days with a single APF530 SC dose. In both studies, granisetron pharmacokinetics were similar and dose proportional with regard to the Cmax; achieved and drug exposure over the acute-onset (24 hours) and delayed-onset (168 hours) phases.
In C2005-01, six of the 45 enrolled patients violated protocol in that they received additional chemotherapy within 14 days after receiving APF530. In the judgment of the medical monitor, chemotherapy received after day 7 would not affect assessment of the primary (pharmacokinetics) objective or efficacy. However, chemotherapy administered from days 7 to 14 could have affected the assessment of AEs in the second week of the study. In C2007-01, six of 35 enrolled patients did not meet the study entry criteria because of their age or participation in another trial within 30 days; these were considered minor deviations unlikely to affect the study outcome.
The granisetron transdermal patch (Sancuso®) is another extended-release form of granisetron but is unlike APF530. It is designed to provide extended release of granisetron for up to 7 days. Unlike APF530, the patch is intended for use with multiday chemotherapy regimens and must be applied 24 to 48 hours before the start of chemotherapy because of the time (48 hours) required to reach the granisetron Cmax. The Cmax achieved with the patch is about half that achieved with APF530 250 mg, and the total exposure over 7 days (AUC at 0 to 168 hours) is comparable with that of APF530 250 mg. Overall, the CR rate was 60% with the patch compared with 65% for oral granisetron.11Detachment of the patch reduces the amount of granisetron delivered and may be the cause of at least some of the broad variability noted in the pharmacokinetic measurements.10