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`IND c
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`Page 285
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`Page 287
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`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/5/
`
`Yash Chopra-
`7/11/03 06:23:57 PM
`PHARMACOLOGIST
`
`Jasti Choudary
`7/11/03 06:28:32 PM
`PHARMACOLOGIST
`
`

`

`EXECUTIVE CAC
`
`Date of Meeting: July 8, 2003
`
`Committee: David Jacobson-Kram, Ph.D., HFD-OZ4, Chair
`Joseph Contrera, Ph.D., Member
`Abby Jacobs Ph.D., Member
`C. Joseph Sun, Ph.D., HFD-570, Alternate Member
`Jasti Choudary, B.V.Sc., Ph.D., RFD-180, Supervisory Pharrnacologist
`Yash Chopra, M.D., Ph.D., HFD-l 80, Presenting Reviewer
`
`Author of Draft: Yash Chopra
`
`The following information reflects a brief summary of the Committee discussion and its
`recommendations. Detailed study information can be found in the individual review.
`
`NDA # 21372
`
`Drug Name: Palonosetron Hydrochloride Injection
`Sponsor: Helsinn HealthCare SA
`
`Background: Palonosetron is a serotonin 5-HT; receptor antagonist. It is indicated for the
`treatment of acute and delayed nausea and vomiting associated with emetogenic cancer
`chemotherapy. The sponsor conducted 2-year carcinogenicity studies in CD-1 mice and CD rats
`with palonosetron. The dose selection for these studies was based on maximum tolerated doses
`(MTD) detemiined in 3—month oral toxicity studies in CD—1 mice and Sprague Dawley rats. The
`Ex-CAC provided concurrence for the doses used in both studies. Palonosetron hydrochloride
`solution was prepared in
`
`- 1
`
`Treatments were administered at a volume of 5 ml/kg in mice and rats.
`
`_
`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 mouse micronucleus test. .It was however, positive for clastogenic effects in the Chinese
`hamster ovarian (CHO) cell chromosomal aberration test.
`
`Mouse Carcinogenicity Study:
`
`In the 2-year mouse carcinogenicity study, the animals were treated with oral gavage doses of 0
`(control 1), 0(contr0l 2), 10 (low), 30 (mid) and 60 (high) mg/kg/day. The mortality rates were
`55.4, 48.2, 55.4, 50 and 43.7% among males and, 62.5, 57.1, 53.8, 67.9 and 67.2% among females
`included in control l, control 2, low, mid and high dose treatment groups. The body weights of
`
`

`

`NDA 21-372
`
`Page 2
`
`the animals were not adversely affected during the study. At week 104, the mean body weights of
`males were 99.6, 99.5, 102.2 and 100.2% of the control 1 group males and, mean body weights of
`females were 100.3, 103.2, 102.6 and 108.2% of the control 1 group females. At week 26, the
`plasma exposure (AUC) of the palonosetron in the high dose males and females was about 290
`and 150 times, respectively of the plasma level achieved (AUCmnfm = 29.8 ng.hr/ml) at the
`recommended i.v. clinical dose of 0.25mg. Treatment with palonosetron did not produce new
`tumors or increase the incidences of background tumors.
`
`Rat Carcinogenicity Study:
`
`In the 2-year rat carcinogenicity study, the animals were treated with oral gavage doses of 0
`(control 1), 0 (control 1), 15 (low), 30 (mid) and 60 (high) mg/kg/day in males and 0 (control 1), 0
`(control 2), 15 (low), 45(mid) and 90(high) mg/kg/day in females. A treatment related trend of
`mortality was seen in animals of all groups (p = 0.0087 for males and <0.0001 for females). At
`study week 104, the mortality rates were 53.8, 46.2, 49.2, 58.5 and 72.3% among males and, 52.3,
`64.6, 63.1 and 66.1 and 81.5% among females included in O, 0, low, mid and high dose treatment
`groups. At week 104, the body weights ofmales were 102.4, 108.8, 97.4 and 90.2% ofthe
`control 1 animals. The body weights of females were 95.9, 91.0, 96.9 and 78.3% ofthe control 1
`animals. At week 26, the plasma exposure (AUC) of the palonosetron in the high dose males and
`females was about 137 and 308 times, respectively of the plasma level achieved (AUCMufin) at the
`recommended clinical dose. Palonosetron treatment showed a dose-related increase in the
`incidences of benign pheochromocytoma in males and females. The combined incidences of
`benign and malignant pheochromocytoma were significantly increased in males but not in
`females. Increased incidences of pancreatic islet cell adenoma alone and, combined incidences of
`islet cell adenoma and carcinoma were seen in male rats of all treatment groups as shown in the
`table below. The adenoma of pituitary pars-distalis were increased in males of all treatment
`groups and the incidences were greater than the sponsor’s historical control range of 30.7 to 56%
`in these treatment groups. Treatment with palonosenon produced benign hepatocellular adenoma
`in females of all treatment groups. The combined incidences of benign hepatocellular adenoma
`and carcinoma were increased in these females. The incidences of thyroid C-cell adenoma and
`combined incidences of Cecil adenoma and thyroid carcinoma were increased in females of the
`study. The sponsor did not examine all the animals of the study for the lesions of skin and tail.
`The tumor incidences of the study animals are included shown in the following table.
`
`

`

`(‘N
`
`NDA 21-372
`
`Page 3
`
`Tumor lncidences in lO4-Week Rat Carcino enici Stud
`
`Control l
`Observations
`
`
`Control 2
`
`Low Dose
`5 mg/kg/day
`
`W” ---“---
`MALES:
`
`.
`a
`
`Adrenal
` wnE‘Q
`Pheochromoc oma
`
`Phcochromoc
`
`-ma
`
`'
`
`'
`
`
`
` for pooled
`I0/45mg/kg/day
`- l90mg/kyday (Trend Test)
`
` ' ontrol)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Bcni u +Mali- an!
`
`Pancreas:
`Islelcelmdcnoma
`0.029
`0.0125
`10(15.4%
`
`lsleiccllCarcinorna
`700.7% ——1.7-6.2%
`3(4.6%
`2(3.1%
`802.3%
`50.7%
`
`CombincdlslelCcll
`l7(26.l%)
`0.004
`0.005
`5.4—18.0%
`60.2%)
`602%)
`l6(24.6%)
`14(21.5%)
`Adenoma+Carcinoma
`
`Pars~DistalisBcnign
`22(33.s%) 29(44.6%) 45‘(69.2%)
`43'(66.l%)
`43 (66.l%)
`<0.001'
`30.7-56.0%
`Admoma
`
`
`
`
`
`—-----—-_
`Phcochromoc
`oma
`
`—-----_-
`Phcochromoc
`-ma
`Bcni +Mali-am
`'
`
`
`3(4.6%)
`3 (4.6%)
`6 (9.2%)
`0.0002
`<0.005
`0-5.3%
`
`----
` Hepaloccllular
`Carcinoma
`
`Hepatoccllular
`
`- dcnoma +
`
`
`cpatocellular
`
`
`Carcinoma Combined
`
`
`
`Admoma
`
`.
`
`u
`
`x (4.6%)
`
`-
`
`(6.2%)
`
`6(9.2 °/.)
`
`<0.001‘
`
`or all 3 1 o -s
`
`053%
`
`<0.os '
`. 0001—0030)
`
`
`
`”120-0)
`
`
`{Ram—0'03.
`
`
`
`
`6-7-17'0‘V.
`
`
`
`
`
`
`
`
`
`
`
`
`It= pairwise p<0.0$ (for control l). 2 = p<0.05 (for control 2). ' = sponsor's data used, ' =
`" = pairwis: p<0.005 (for pooled comm] group),
`pairwise 1:5! for all muncm groups Vs pooled controls was posixivc; ' = animal # 0502 had both thyroid adenoma and carcinoma
`
`

`

`NDA 21-372
`
`Page 4
`
`Executive-CAC. Recommendations and Conclusions:
`
`]. Mouse Study:
`
`The committee agreed that the study doses were adequate as there was prior concurrence on the
`dose selection. The committee concluded that there were no drug-related tumor findings.
`
`2. Rat Study:
`
`The committee agreed that the study doses were adequate as there was prior concurrence on the
`dose selection. The following tumors were regarded as drug related:
`
`Males: Adrenal benign pheochromocytoma and combined benign and malignant
`pheochromocytomas, pancreatic islet cell adenoma and combined adenomas and carcinoma, and
`adenoma of pituitary pars distalis.
`
`Females: Hepatocellular adenoma and combined hepatocellular adenoma and carcinomas, and
`thyroid C-cell adenoma and combined adenoma and carcinoma.
`
`David Jacobson-Kram, Ph.D.,
`Chair, Executive CAC -
`
`CC:
`
`IHFD-180 Division File
`
`/Jasti Choudary/Supervisory Pharmacologist, HFD-l 80
`/Yash Chopra/Reviewer, HFD-l 80
`/Brian Strongin/CSO/PM, HFD-l80
`IA. Seifn'ed, HFD-024
`
`

`

`This'Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`.-------------—---------------------.----.-.g..------------------------------------—--------------..-------"-——
`
`/S/
`
`David Jacobs'on-Kram
`7/22/03 03:33:58 PM
`
`

`

`STATlSTICAL REVIEW AND EVALUATION — NDA
`CARCINOGENICITY STUDIES
`
`(ADDENDUM)
`
`Medical Division: Castro—Intestinal and Coagulation Drug Products (HOD-180)
`Biometrics Division: Division of Biometrics 11 (RFD—715)
`
`STATISTICAL KEY WORKDS: Carcinogenicity
`
`NDA: 21-372
`
`SERIAL NUMBER:
`
`DATE RECEIVED BY CENTER: September 27, 2002
`DRUG NAME: Palonosetron HCI Intravenous Injection 0.25 mg/S ML
`INDICATION: Prevention of acute and delayed nausea and vomiting associated with
`initial and repeated courses of emetogenic cancer chemotherapy
`SPONSOR: Helsinn Healthcare SA
`
`DOCUMENTS REVIEWED: Volume 1.12, Vol. 1.33-1.41 and 1.48-1.54
`
`STATISTICAL PRIMARY REVIEWER: Milton C. Fan, PhD. (HFD-715)
`STATISTICAL SECONDARY REVIEWER: Karl Lin, Ph.D. (HEB-715)
`STATISTICAL TEAM LEADER: Thomas Pennutt, Ph.D. (HFD-715)
`BIOMETRICS DIVISION DIRECTOR: Edward Nevius, PhD. (HEB-715)
`PHARM