Palonosetron Hydrochloride (Page 4 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of palonosetron hydrochloride at 10, 30 and 60 mg/kg/day. Treatment with palonosetron was not tumorigenic. The highest tested dose produced a systemic exposure to palonosetron (Plasma AUC) of about 150 to 289 times the human exposure (AUC= 29.8 h•mcg/L) at the recommended intravenous dose of 0.25 mg. In a 104-week carcinogenicity study in Sprague-Dawley rats, male and female rats were treated with oral doses of 15, 30 and 60 mg/kg/day and 15, 45 and 90 mg/kg/day, respectively. The highest doses produced a systemic exposure to palonosetron (Plasma AUC) of 137 and 308 times the human exposure at the recommended dose. Treatment with palonosetron produced increased incidences of adrenal benign pheochromocytoma and combined benign and malignant pheochromocytoma, increased incidences of pancreatic Islet cell adenoma and combined adenoma and carcinoma and pituitary adenoma in male rats. In female rats, it produced hepatocellular adenoma and carcinoma and increased the incidences of thyroid C-cell adenoma and combined adenoma and carcinoma.

Palonosetron was not genotoxic in the Ames test, the Chinese hamster ovarian cell (CHO/HGPRT) forward mutation test, the ex vivo hepatocyte unscheduled DNA synthesis (UDS) test or the mouse micronucleus test. It was, however, positive for clastogenic effects in the Chinese hamster ovarian (CHO) cell chromosomal aberration test.

Palonosetron hydrochloride at oral doses up to 60 mg/kg/day (about 1894 times the recommended human intravenous dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

14 CLINICAL STUDIES

14.1 Prevention of Nausea and Vomiting Associated with MEC and HEC in Adults

Efficacy of a single intravenous dose of Palonosetron Hydrochloride injection in preventing acute and delayed nausea and vomiting associated with MEC or HEC were studied in 4 trials. In these double-blind studies, complete response rates (no emetic episodes and no rescue medication) and other efficacy parameters were assessed through at least 120 hours after administration of chemotherapy. The safety and efficacy of Palonosetron Hydrochloride injection in repeated courses of chemotherapy was also assessed.

Moderately Emetogenic Chemotherapy

Two double-blind trials (Study 1 and Study 2) involving 1132 patients compared a single dose of Palonosetron Hydrochloride injection with either a single dose of ondansetron (Study 1) or dolasetron (Study 2) given 30 minutes prior to MEC, including carboplatin, cisplatin ≤ 50 mg/m² , cyclophosphamide < 1500 mg/m² , doxorubicin > 25 mg/m² , epirubicin, irinotecan, and methotrexate > 250 mg/m². Concomitant corticosteroids were not administered prophylactically in Study 1 and were only used by 4 to 6% of patients in Study 2. The majority of patients in these studies were women (77%), White (65%) and naïve to previous chemotherapy (54%). The mean age was 55 years.

Highly Emetogenic Chemotherapy

A double-blind, dose-ranging trial evaluated the efficacy of a single intravenous dose of Palonosetron Hydrochloride injection from 0.3 to 90 mcg/kg (equivalent to < 0.1 mg to 6 mg fixed dose) in 161 chemotherapy-naïve adult cancer patients receiving HEC, either cisplatin ≥ 70 mg/m² or cyclophosphamide > 1100 mg/m². Concomitant corticosteroids were not administered prophylactically. Analysis of data from this trial indicates that 0.25 mg is the lowest effective dose in preventing acute nausea and vomiting associated with HEC.

A double-blind trial involving 667 patients compared a single intravenous dose of Palonosetron Hydrochloride injection with a single intravenous dose of ondansetron (Study 3) given 30 minutes prior to HEC, including cisplatin ≥ 60 mg/m² , cyclophosphamide > 1500 mg/m² , and dacarbazine. Corticosteroids were co-administered prophylactically before chemotherapy in 67% of patients. Of the 667 patients, 51% were women, 60% White, and 59% naïve to previous chemotherapy. The mean age was 52 years.

Efficacy Results

Studies 1, 2 and 3 show that Palonosetron Hydrochloride injection was effective in the prevention of nausea and vomiting associated with initial and repeat courses of MEC and HEC in the acute phase (0 to 24 hours) [Table 5]. Clinical superiority over other 5-HT3 receptor antagonists has not been adequately demonstrated in the acute phase. In Study 3, efficacy was greater when prophylactic corticosteroids were administered concomitantly.

Studies 1 and 2 show that Palonosetron Hydrochloride injection was effective in the prevention of nausea and vomiting associated with initial and repeat course of MEC in the delayed phase (24 to 120 hours) [Table 6] and overall phase (0 to 120 hours) [Table 7].

Table 5: Prevention of Acute Nausea and Vomiting (0 to 24 Hours) in Adults with Nausea and Vomiting Associated with MEC or HEC in Studies 1, 2 and 3: Complete Response Rates

* Intent-to-treat cohort † 2-sided Fisher’s exact test. Significance level at α=0.025. ‡ These studies were designed to show non-inferiority. A lower bound greater than -15% demonstrates non-inferiority between palonosetron hydrochloride injection and comparator.
Chemotherapy	Study	Treatment Group	N *	% with Complete Response	p-value †	97.5% Confidence Interval Palonosetron Hydrochloride injection minus Comparator ‡ (click image for full-size original)
ModeratelyEmetogenic	1	Palonosetron Hydrochloride injection 0.25 mg intravenously	189	81	0.009
		Ondansetron 32 mg intravenously	185	69
	2	Palonosetron Hydrochloride injection 0.25 mg intravenously	189	63	NS
		Dolasetron 100 mg intravenously	191	53
Highly Emetogenic	3	Palonosetron Hydrochloride injection 0.25 mg intravenously	223	59	NS
		Ondansetron 32 mg intravenously	221	57

Table 6: Prevention of Delayed Nausea and Vomiting (24 to 120 Hours) Associated with MEC in Adults in Studies 1 and 2: Complete Response Rates

* Intent-to-treat cohort † 2-sided Fisher’s exact test. Significance level at α=0.025. ‡ These studies were designed to show non-inferiority. A lower bound greater than -15% demonstrates non-inferiority between palonosetron hydrochloride injection and comparator. § Ondansetron 32 mg intravenous was used in the clinical trial. Although this dose was used in the trial, it is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose.
Chemotherapy	Study	Treatment Group	N *	% with Complete Response	p-value †	97.5% Confidence Interval Palonosetron Hydrochloride injection minus Comparator ‡ (click image for full-size original)
ModeratelyEmetogenic	1	Palonosetron Hydrochloride injection 0.25 mg intravenously	189	74	<0.001
		Ondansetron 32 mg intravenously §	185	55
	2	Palonosetron Hydrochloride injection 0.25 mg intravenously	189	54	0.004
		Dolasetron 100 mg intravenously	191	39

Table 7: Prevention of Overall Nausea and Vomiting (0 to 120 Hours) Associated with MEC in Adults in Studies 1 and 2: Complete Response Rates

* Intent-to-treat cohort † 2-sided Fisher’s exact test. Significance level at α=0.025. ‡ These studies were designed to show non-inferiority. A lower bound greater than -15% demonstrates non-inferiority between palonosetron hydrochloride and comparator. § Ondansetron 32 mg intravenously was used in the clinical trial. Although this dose was used in the trial, it is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose.
Chemotherapy	Study	Treatment Group	N *	% with Complete Response	p-value †	97.5% Confidence Interval Palonosetron Hydrochloride injection minus Comparator ‡ (click image for full-size original)
ModeratelyEmetogenic	1	Palonosetron Hydrochloride injection 0.25 mg intravenously	189	69	<0.001
		Ondansetron 32 mg intravenously §	185	50
	2	Palonosetron Hydrochloride injection 0.25 mg intravenously	189	46	0.021
		Dolasetron 100 mg intravenously	191	34