METHODS

Pharmacokinetics, safety, and efficacy of single SC injections of APF530 were assessed in two open-label multicenter Phase II trials in patients receiving MEC or HEC regimens. The first trial (C2005-01) was a sequential ascending dose study. The second study (C2007-01) was a randomized study with two doses of APF530.

Patients

Inclusion criteria were similar for the two Phase II studies. Eligible patients were at least 18 years old, males or nonpregnant females with cytologically or histologically confirmed cancer, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and scheduled to receive a single-day MEC or HEC regimen. C2005-01 was initially designed to enroll only patients with MEC; however, during the conduct of the trial, the decision was made to enroll patients receiving both MEC and HEC. Emetogenicity was defined according to Hesketh criteria.2 Prior chemotherapy was allowed. In C2005-01, corticosteroids were permitted, although not required, in compliance with the current standard of care and were used in 84% of patients; in C2007-01, patients were required to be able to receive standard doses of dexamethasone as specified in the protocol.


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Patients were not eligible if they received radiation therapy within 7 days prior to receiving APF530 or had scheduled radiation therapy or chemotherapy during the 14 (C2005-01) or 7 (C2007-01) days after receiving APF530. Use of CYP3A4 inhibitors was not permitted. In C2005-01, nausea of greater than mild severity or any vomiting within 24 hours prior to receiving APF530 was exclusionary. Patients with head and neck cancer or upper gastrointestinal cancer were not eligible.

In C2005-01, patients were not eligible if they received antiemetics or other prohibited medications within 10 days prior to receiving APF530. In C2007-01, patients were not eligible if they received granisetron, systemic corticosteroids, or other prohibited medications within 7 days prior to receiving APF530. Patients with a heart rate-corrected QT interval (QTc) interval >500 ms or a cardiac abnormality predisposing them to arrhythmia were also excluded.

The C2005-01 protocol was reviewed and approved by a central institutional review board, the Western Institutional Review Board. The C2007-01 protocol was reviewed and approved by an independent ethics committee for each investigational site. Both studies were conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent. C2007-01 was registered with European Union Drug Regulating Authorities Clinical Trials (EudraCT), as EudraCT number 2008-000469-53. C2005-01 was completed before requirements for trial registration.

Study design

C2005-01 patients were assigned to one of three ascending APF530 dose groups: 250 mg (containing granisetron 5 mg), 500 mg (containing granisetron 10 mg), and 750 mg (containing granisetron 15 mg). The decision to enroll in the next dose-escalation group was based on AEs and laboratory results with the lower dose. Doses were given by SC injection in the abdominal area 30 minutes before the start of chemotherapy. A local anesthetic, usually a lidocaine preparation or ethyl chloride spray, was applied to the area of the injection site prior to study drug administration. The study duration was 14 days. After a 7-day treatment and sample collection period, patients returned for a final follow-up visit 14±3 days after study drug administration. Patients were prescribed rescue medication (excluding granisetron) at the discretion of the investigator, to be used as needed in the event of vomiting.

In C2007-01, patients were randomly assigned to receive APF530 250 or 500 mg by SC injection 30 to 60 minutes before the scheduled chemotherapy. Dexamethasone 8 mg intravenously (IV) was given on day 0, in patients with MEC. Dexamethasone 20 mg IV was given on day 0, and 8 mg twice a day on days 1 to 3, in patients with HEC. The study duration was 14±3 days. Patients were prescribed rescue medication as in the 2005-01 study.

Study objectives

The primary objective of both trials was to define the pharmacokinetic properties of granisetron after a single SC dose of APF530 in cancer patients receiving chemotherapy. Secondary objectives were to assess the safety of single SC injections of APF530 in patients receiving single-day MEC or HEC. Evaluation of efficacy in preventing acute-onset (0–24 hours) or delayed-onset (24–168 hours) CINV was an exploratory objective.

Assessments

Plasma granisetron concentrations were measured predose, prior to chemotherapy infusion (C2005-01), and at 2, 6, 24, 48, 72, 96, 120, 144, and 168 hours after APF530 administration. In C2007-01, additional time points were added at 4, 12, and 18 hours after APF530 administration. Measured pharmacokinetic parameters included area under the concentration–time curve (AUC) at 0 to 24 hours, AUC at 0 to 168 hours, maximum plasma concentration (Cmax), time to Cmax (Tmax), the elimination rate constant, and half-life (t1/2) in both trials; and additionally, apparent total clearance, apparent volume of distribution, and mean residence time, in C2007-01.

Safety was assessed throughout the studies, based on vital signs, physical examination, clinical laboratory tests (only at screening in C2007-01), and 12-lead ECGs at screening (predose) and 168 hours (also at 48 hours in C2005-01), and included AEs, injection site reactions, and concomitant medications.

Efficacy was assessed by the number of emetic episodes, number of retching/dry heave episodes, nausea ratings, and rescue medication use during 7 days following the single dose of APF530, which were recorded in patient diaries and collected at each study visit (C2005-01). Alternatively, patients were interviewed at each visit, regarding the occurrence of nausea and emesis and use of rescue medication, with responses recorded (C2007-01).

Efficacy parameters included complete response (CR) (no emetic episodes and no use of rescue medication), complete control (CR with no more than mild nausea), and total response (CR with no nausea), and were summarized for the acute and delayed phases, for MEC and HEC.

Statistics

Noncompartmental methods and descriptive statistics were used to derive and analyze the pharmacokinetic parameters. Descriptive summaries were used for safety measurements by treatment group and preferred term. Efficacy was summarized by time interval and treatment group. Sample sizes were consistent with a previous pharmacokinetic study of palonosetron in patients with cancer receiving chemotherapy.9