Boccia, R., Cooper, W., & O'Boyle, E. (2015). Sustained antiemetic responses with APF530 (sustained-release granisetron) during multiple cycles of emetogenic chemotherapy. Journal of Community and Supportive Oncology, 13, 38–46. 

To determine if a response to antiemetic APF530 is sustained over multiple cycles of chemotherapy

This study consisted of three treatment arms. During cycle 1, group 1 received 250 mg of subcutaneous APF530, group 2 received 500 mg of subcutaneous APF530, and group 3 received palonosetron at 0.25 mg IV in addition to an subcutaneous placebo before moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC). Patients receiving MEC also received dexamethasone at 8 mg IV 30–90 minutes before chemotherapy. Patients receiving HEC were given 20 mg of IV dexamethasone followed by 8 mg orally twice per day on days 2–4. In cycles 2–4, palonosetron was discontinued, and all patients in the palonosetron group were randomized to receive either 250 mg or 500 mg of APF530 with dexamethasone (dosing as previously stated). Cycles were separated by a range of 3–28 days. Rescue antiemetics were allowed as needed. Local anesthetic was administered to the injection site before the study drugs were administered. Study subjects kept diaries of emetic episodes, the use of rescue medications, and the severity of nausea for each 24-hour period after receiving chemotherapy. Adverse events were documented according to standard toxicity criteria. Complete response (CR) was defined as no rescue medications and no emetic episodes. Complete control (CC) was defined as no more than mild nausea and no rescue medications. Total response was defined as no nausea and no rescue medications.

• N = 580 (four cycles) 
• MEAN AGE = 57 years
• MALES: 25%, FEMALES: 75%
• KEY DISEASE CHARACTERISTICS: Primarily breast, lung, and ovarian cancer; mean time since diagnosis was 0.7 years; scheduled to receive single-day MEC (Hesketh score 3 or 4) or single-day HEC (Hesketh score 5) as defined at the time of study
• OTHER KEY SAMPLE CHARACTERISTICS: The sample size in cycle 1 of the study was 1,389 patients. However, the sample size for subsequent cycles was the number of patients who remained in the study using a modified intent-to-treat population of patients who received the drug and had efficacy data. 

• SITE: Multi-site    
• SETTING TYPE: Not specified    
• LOCATION: United States, India, and Poland

• PHASE OF CARE: Active antitumor treatment

Prospective, multicenter, randomized, double-blinded, placebo-controlled, parallel-group, phase 3 trial with stratification according to the emetogenicity of regimens

• Efficacy measures were assessed from patient diaries which recorded emetic episodes, the use of rescue medication, and the severity of nausea for each 24-hour period after chemotherapy (the specific tool to measure the severity of nausea was not described).
• Adverse events were assessed using standard toxicity criteria.
• Efficacy was measured as the percentage of patients who achieved CR (no emetic episodes and no rescue medication) during the acute and delayed phases of chemotherapy.
• Sustainability over cycles was measured as the proportion of patients with CR during the acute and delayed phases, the time to first emetic episode, the time till the first rescue medication, and the time till the first treatment failure in cycles 2–4.
• Treatment comparisons were based on the Fisher exact test.

In cycle 1, ≥ 75% of both doses of APF530 had acute-phase CR, and ≥ 50% had delayed-phase CR. There was a similar response rate for cycles 2–4 with the HEC group having a slightly better response than the MEC group. Acute phase CR increased over the four cycles of HEC (81%–88%) for APF530 500 mg dose and CR increased from 67% to 83% in the delayed phase for this group. In patients who received palonosetron in cycle 1, ≥ 90% of those who had CR maintained CR in subsequent cycles (with APF530). Half of the of MEC and palonosetron group that did not achieve CR in cycle 1 achieved CR in next cycle (with APF530). No treatment-related serious adverse events were seen. Common adverse events across all cycles included constipation, headache, fatigue, and diarrhea for patients who received APF530. APF530 at 250 or 500 mg caused injection site reactions. Most were mild, and greater than than 3% were moderate.

This study demonstrated sustained responses in the acute and delayed phases of chemotherapy over four cycles in both 250 mg adnd 500 mg oses of APF530. Patients who responded to APF530 in cycle 1 also responded in cycles 2–4. Patients receiving palonosetron for chemotherapy-induced nausea and vomiting had a similar response to APF530 in subsequent cycles. Patients receiving APF530 had mild adverse effects primarily related to injection site reactions.

• Measurement/methods not well described
• Subject withdrawals ≥ 10%  
• Other limitations/explanation: The Hesketh scoring system has changed since the study was conducted. Some regimens considered MEC at the time of the study are now considered HEC, changing the efficacy of MEC versus HEC regimens in the current system. The treatment group size and characteristics varied from cycle to cycle. Patients who no longer received the study drug or who had no data were removed, resulting in a greater than 42% drop in the number of subjects for the final cycle of chemotherapy. It was difficult to read the results of the data in bar graph format. 

APF530 was an effective 5HT3 blocker for the prevention of chemotherapy-induced nausea and vomiting in HEC and MEC regimens, and its efficacy was sustained over multiple cycles. There was no significant benefit in using higher doses over the 250 mg dose. There was a potential for injection site reactions caused by the subcutaneous route of APF530, which may affect patients' quality of life.