Sustained Release Granisetron

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.

To establish the noninferiority of sustained-release granisetron (APF530) for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) compared with palonosetron following highly emetogenic chemotherapy (HEC) and/or MEC chemotherapy in a subpopulation of patients with breast cancer, and to show the superiority of APF530 for the prevention of delayed CINV following HEC with cycle 1 of chemotherapy.

Patients were stratified based on either moderate or high emetogenicity of the chemotherapy. Patients received both IV and subcutaneous injections. Group 1 received 250 mg of APF530 subcutaneously and placebo IV, group 2 received 500 mg of APF530 subcutaneously and placebo IV, and group 3 received placebo subcutaneously and IV palonosetron 0.25 mg. APF530 was given 30 minutes prior to chemotherapy. At the completion of cycle 1, patients who received palonosetron were offered the option to remain in the study. These patients were then rerandomized 1 to 1 to receive doses of 250 versus 500 mg of APF530 subcutaneously during cycles 2–4. Treatment cycles ranged from 7 days–28 days. Rescue medications were permitted with the exception of granisetron, palonosetron, and aprepitant.

• N = 618   
• MEAN AGE = Moderately emetogenic group (53.3 years in APF 250 mg, 54.3 years in APF 500 mg, 55 years in palonestron only); highly emetogenic group (50.3 years in APF 250 mg, 49.8 years in APF 500 mg, 52.6 years in palonosetron only)
• MALES: Less than 2% (n = 5), FEMALES: 98–100% (n = 603)
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Breast cancer, does not report staging
• OTHER KEY SAMPLE CHARACTERISTICS: Multiple chemotherapy regimens with less than 70% receiving AC; mostly Caucasian and Asian

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: Multiple cancer centers across the United States, India, and Poland

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care, palliative care 

Prospective, multicenter, randomized, double-blind and double-dummy, parallel-group, phase-III noninferiority trial. Groups were broken into highly emetic and moderately emetic based on Hesketh scores.

• Instruments used to measure CINV are not articulated in this paper.  
• Complete response defined as no emesis and no use of rescue medication.

CR rates with the experimental drug at 250 and 500 mg were not significantly different from those with palonosetron for both HEC and MEC regimens. The effectiveness of APF530 improved in later cycles, although at that point, those patients were no longer receiving palonosetron. No significant differences existed between groups in the samples. No noticeable differences existed between the breast cancer group and the overall population of the study.

Safety: Patients receiving APF530 had more complaints of injection site pain compared to palonosetron. No difference in adverse events existed between the breast cancer group and the overall population of the study.

APF530 is effective in acute and delayed CINV in patients with breast cancer. The side effect profile was similar in all arms of the study and included fatigue, constipation, and headache. The trend to better response is not a reflection of palonosetron, as this agent was not used after cycle 1.

• Measurement/methods not well described
• Unknown instruments to measure CINV
• This is a secondary analysis of a previously published paper from 2014.

Sustained-release granisetron can provide another alternative intervention for CINV prophylaxis; however, it does require subcutaneous injection. Further research is needed to establish the comparative effectiveness of this medication within overall CINV antiemetic regimens.

To determine the pharmacokinetics, safety, and efficacy of two dosing regimens of APF530

There were two separate studies reported in this paper. The first study included 45 patients and used three escalating dosing schedules of 250 mg, 500 mg, or 750 mg. The second study included 35 patients with two dosing schedules of 250 or 500 mg. Safety and efficacy were reported. Drug levels were measured from predose to 168 hours after administration. Doses were given via subcutaneous injection in the abdomen prior to chemotherapy. All patients also received dexamethasone.

• N = 80
• MEAN AGE = 64 years (SD = 12.5 years [trial 1]), 55.7 years (SD = 8.7 years [trial 2])
• MALES: 40% (trial 1), FEMALES: 60% (trial 1), 100% (trial 2)
• KEY DISEASE CHARACTERISTICS: Ovarian cancer, breast cancer, lung cancer, lymphoma, leukemia, endometrial cancer, cervical cancer, vulvar cancer, colorectal cancer, bladder cancer, thymoma, and myeloma
• OTHER KEY SAMPLE CHARACTERISTICS: Chemotherapy regimens included carboplatin and combinations of cyclophosphamide-anthracycline, cyclophosphamide combinations, irinotecan, topotecan, cisplatin combinations, anthracycline, and gemcitabine-vinorelbine, among others.

• SITE: Multi-site    
• SETTING TYPE: Outpatient  
• LOCATION: Gabrail Cancer Center in Canton, OH; St. Louise Regional Hospital in Gilroy, CA; Department of Gynecologic Oncology at the University of Medical Science in Poznan, Poland

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care and palliative care

Prospective

• Plasma concentrations were measured.  
• Safety was assessed by vital signs, physical examinations, and clinical laboratory tests.  
• Twelve lead electrocardiograms were completed at screenings.  
• Symptoms were assessed with patient diaries.  
• Effectiveness was measured using diaries, information about the use of rescue medications, the number of emetic episodes, the number of retching episodes, and the number of nausea episodes for a seven-day period after the administration of medications.  
• Noncompartmental methods and descriptive statistics were used.

Both studies met the primary objective by defining pharmacokinetics. Adverse events did not appear to be dose-related. Most were mild to moderate and were unrelated to the study drug. Injection site reactions were low and were not associated with dosing, and 17.7% of erythema was reported in the 250 mg arm. No erythema was reported in the 750 mg arm. The plasma concentrations of granisetron were maintained for seven days with a single dose of the drug. Preliminary data demonstrated another option for the prevention of acute and delayed chemotherapy-induced nausea and vomiting. Patients treated with APF530 at 250 or 500 mg obtained complete response 83% of the time in the acute-onset and delayed-onset phases. Complete control was obtained in 76%. Nausea was controlled almost as well as emesis. Nausea reports were mostly mild.

Granisetron exposure was maintained for seven days with a single dose of subcutaneous AFP530. Mild injection site irritation was noted. Nausea was mild, and nausea and vomiting were controlled in the acute and delayed phases.

• Small sample (< 100)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment) 
• Risk of bias (no appropriate attentional control condition)  
• Findings not generalizable

This could be another option for treating chemotherapy-induced nausea and vomiting, but it is possible that this treatment causes unnecessary discomfort when oral and transdermal approaches are available. This is very preliminary data, and the study did not compare this treatment to standard care. Additional research to determine the usefulness of this drug for chemotherapy-induced nausea and vomiting is needed.

To examine whether the post hoc analysis presented here confirms the original findings of the APF530 phase III trial, that APF530 is an alternative to palonsetron for preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV) after moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC)

In the original study, patients were randomized 1:1:1 to receive APF530 500 mg subcutanous plus placebo IV, APR530 250 mg subcutaneous and palonosetron 0.25 mg plus placebo. The first objective was to establish noninferiority of APF530. For the second cycle, the placebos were dropped, and individuals who had been randomized to the palonsetron were randomly assigned to either 250 or 500 mg of APR530.

• N = Original study: 1,341 patients, secondary analysis: 1,299 patients (609 in the MEC group and 690 in the HEC group). Forty-two patients were dropped because they were reclassified as receiving regimens now considered less emetogenic than MEC. Of the remaining subjects, almost 50% were reclassified from MEC to HEC or HEC to MEC.  
• MEAN AGE = 60.3 years (MEC group), 53.4 years (HEC group)
• MALES: 24.8%, FEMALES: 75.2%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: The most common tumors were lung, ovarian, and breast.

• SITE: Multi-site   
• SETTING TYPE: Multiple settings    
• LOCATION: International study—United States, Europe, India

ACUTE PHASE OF CARE: Active antitumor treatment

Secondary analysis of a randomized, controlled study

Complete response (CR) was measured by no emetic episodes and no use of rescue medications during the acute and delayed phases of CINV after cycle one. Noninferiority was established if the confidence interval for the difference in CR was greater than 15%.

The results of this secondary analysis did not find significance difference between APF530 and palonsetron for acute and delayed CINV in patients receiving HEC and MEC regimens. There were no notable differences in the results of this study and the original analysis, except they found numerically higher CR rates in patients receiving MEC and lower CR rates in patients receiving HEC for all study arms.

The post hoc analysis presented here confirms the original findings of the APF530 phase III trial, that APF530 is an alternative to palonsetron for preventing acute and delayed CINV after MEC and HEC.

Post hoc analysis

The results of this study will not change the current use of slow-release granisetron (noninferior to palonsetron) for acute and delayed CINV after HEC and MEC, but confirms previous knowledge with new ASCO emetogenicity criteria.

To compare two dose levels of AFP530 and palonosetron in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV) after moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC)

Eligible patients were 18 years of age or older with a confirmed malignancy scheduled to receive single-day MEC or HEC defined by the Hesketh algorithm. Patients were stratified according to their chemotherapy emetogenicity (MEC or HEC) and randomized 1:1:1 to receive APF530 at 250 mg subcutaneously (granisetron 5 mg) plus a placebo IV; APF530 at 500 mg subcutaneously (granisetron 10 mg) plus a placebo IV; or palonosetron IV at 0.25 mg plus a placebo subcutaneously prior to chemotherapy. After cycle 1, all patients were invited to continue in the study. If they consented, they were rerandomized to maintain blinding, but only patients who received IV palonosetron in cycle 1 were actually randomized 1:1 to receive APF530 at 250 or 500 mg subcutaneously for less than or equal to three subsequent cycles. Efficacy measures were determined from patient diaries in which patients recorded emetic episodes, rescue medications, and the severity of nausea for each 24-hour period after chemotherapy.

• N = 1,396 (653 received MEC, 742 received HEC)
• MEAN AGE RANGE = 54.8–58.1 years 
• MALES: 27.2%–12.25%, FEMALES: 62.8%–87.75% (across treatment arms and emetogenicity strata)
• KEY DISEASE CHARACTERISTICS: 63.3%–69.5% patients with breast cancer receiving MEC; 25.4%–32.8% patients with lung cancer; and 25.4%–27.6% patients with breast cancer receiving HEC
• OTHER KEY SAMPLE CHARACTERISTICS: Greater than half of the patients received prior chemotherapy. Eastern Cooperative Oncology Group performance statuses were greater than or equal to 2.

• SITE: Multi-site    
• SETTING TYPE: Not specified    
• LOCATION: 103 centers in the United States, Poland, and India

• PHASE OF CARE: Active antitumor treatment

Prospective, multicenter, randomized, double-blinded, double-dummy, parallel-group, phase 3 trial

• Efficacy measures were determined from diaries in which patients recorded emetic episodes, rescue medications, and the severity of nausea for each 24-hour period after chemotherapy.

The original analysis under the Hesketh criteria for emetogenicity demonstrated that AFP530 at 250 and 500 mg subcutaneously was noninferior to palonosetron as assessed by complete response (CR) in the control of acute CINV after MEC (CR rates of 74.8% and 76.9%, respectively, versus 75% for palonosetron). The result was similar for patients receiving HEC with acute CR rates of 77.7% and 81.3% for APF530 at 250 mg and 500 mg, respectively, versus 80.7% for palonosetron. APF530 at 500 mg subcutaneously also was noninferior to palonosetron in preventing delayed CINV after MEC with a CR rate of 58.5% versus 57.2% for palonosetron. The superiority of APF530 at 250 or 500 mg subcutaneously versus palonosetron at 0.25 mg IV in preventing delayed CINV after HEC in cycle 1 was not determined. However, CR rates were similar for APF530 at 500 mg subcutaneously and palonosetron at 0.25 mg IV. In a post hoc analysis, patients receiving chemotherapy regimens whose antiemetic risk had been revised according to the updated antiemetic practice guidelines (notably cyclophosphamide plus anthracyclines [reclassified from MEC to HEC] and carboplatin-based regimens [reclassified from HEC to MEC]) were reclassified at the request of the U.S. Food and Drug Administration. The results of this reanalysis showed no notable statistic or clinical difference in response rates between APF530 and palonosetron.

A single, subcutaneous APF530 injection offered a convenient alternative to palonosetron for preventing acute and delayed CINV after MEC or HEC with similar safety profiles.

• Measurement/methods not well described
• Other limitations/explanation: Patient diaries and ratings were not clearly described. Chemotherapy was single-day only, and nausea and vomiting was measured for only a 24-hour period.

Single-dose APF530 subcutaneously was noninferior to palonosetron at 0.25 mg IV for controlling acute CINV in patients who received single-day MEC or HEC as determined by CR. This provides another option for antiemetic chemotherapy premedication. Because of changing emetic classifications, antiemetic study interpretation can be a complicated process. The findings of this study cannot be generalized to multiday chemotherapeutic regimens because multiday chemotherapeutic regimens were not included in the design of the study.

To compare the efficacy and safety of granisetron injection extended-release (APF530) versus ondansetron for delayed chemotherapy-induced nausea and vomiting (CINV) after highly emetogenic chemotherapy, following a guideline-recommended three-drug regimen

Patients receiving highly emetogenic chemotherapy were randomized into either the APF530 or ondansetron arm for the study. Patients in the APF530 arm received APF530 500 mg subcutaneously and saline placebo in place of ondansetron. Patients in the ondansetron arm received ondansetron 0.15 mg/kg intravenously and a saline placebo subcutaneously in place of APF530 on day 1. All patients also received fosaprepitant 150 mg IV and dexamethasone 12 mg IV on day 1; dexamethasone 8 mg orally once daily on day 2 and twice daily on days 3–4. A topical anesthetic was applied to the injection site before APF530 or its placebo were administered. On day 1, all study medications were administered 30 minutes before the start of chemotherapy.

• N = 902   
• MEAN AGE = 55.7 years and 55.6 years for the APF530 and placebo arms, respectively
• MALES: 20.4% and 17.5% of patients enrolled in the APF530 and placebo arms, respectively; FEMALES: 79.6% and 82.5% of patients enrolled in the APF530 and placebo arms, respectively
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: No specific tumor types were recruited.
• OTHER KEY SAMPLE CHARACTERISTICS: Men and women aged 18–80 years receiving the first cycle of a single-day highly emetogenic chemotherapy for a histologically or cytologically confirmed malignancy

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: Seventy-seven medical centers across the United States

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care

• Prospective, randomized, double-blind, double-dummy, parallel-group, multicenter, phase-III trial

Patients were monitored during four clinic visits:

• screening: day –21 to –1
• baseline/day 1 
• day 6 
• final safety follow up on the day of the patient’s next chemotherapy administration

Patients completed symptom diaries during days 1–6 to self-report nausea, vomiting, retching, and rescue medication usage.

A higher percentage of patients receiving APF530 had delayed-phase complete response when compared to patients receiving ondansetron. The absolute treatment difference was 8% (95% CI [1.7, 14.4], p = 0.014). Delayed-phase CR rates for the cisplatinum arm were 65.3% with the APF530 regimen and 54.7% with the ondansetron regimen. The absolute treatment difference here was 10.6% (95% CI [–1.4, 22.7]). For the non-cisplatinum arm, the delayed-phase CR rates were 64.4% for APF530 and 57.4% for ondansetron regimens. This absolute treatment difference was 7% (95% CI [–0.9, 12.1], unadjusted p = 0.092).

APF530 provided superior control of delayed-phase CINV after highly emetogenic chemotherapy when compared with standard three-drug regimens.

• Short follow-up time

APF530 was found to be a well-tolerated  extended-release granisetron formula with clinical benefit for the control of CINV after highly emetogenic chemotherapy.