`CLINICAL REVIEW STUDY 99-04
`PALONOSETRON
`
`
`0
`
`47 (24.1%) of the 0.75 mg palonosetron group experienced headache.
`> 30 (15.4%) werejudged to be related to the study drug
`Of those judged-to be related to the study drug:
`> 20 (10.3%) were mild in intensity.
`> 9 (4.6%) were moderate in intensity.
`‘P
`1 (0.5%). was severe in intensity.
`Medical Officer Comments: The Phase [/11 studies reported headache as occurring in
`20.4% ofsubjects. It is unclear what criteria investigators in this study used to determine
`ifa patients headache was related to the study drug. .
`
`Gastrointestinal Disorders
`
`Constipation was the most frequent adverse event in this category
`0
`23 ( l 1.9%) of the 0.25 mg palonosetron group suffered constipation.
`> 14 (7.3%) were judged to be related to the study drug.
`Of those judged to be related:
`> 12 (6.2%) were mild in intensity.
`> 2 (1.1%) were moderate in intensity.
`29 (14.9%) of the 0.75 mg palonosetron group experienced constipation.
`> 18 (9.2%) werejudged to be related to the study drug.
`Ofthose judged to be related :
`> 13 (6.7%) were mild in intensity.
`> 5 (2.6%) were moderate in intensity.
`
`0
`
`Cardiac Disorders
`
`0
`
`Six patients in the palonosetron 0.25 mg group experienced cardiac disorders.
`> Patient #4140 was a 53 year old female who self reponed a brief 15 second
`episode of tachycardia 2 days after receiving the study drug. No ECG was
`obtained at the time ofthe event. This was listed as possibly related to the study
`drug. The adverse event was described as mild in intensity and resolved on
`without treatment. The pulse and blood pressure were normal when checked
`during vital signs screen at all visits.
`> Patient # 2204 was a 54 year old female with a history of breast cancer. She was
`reported to have tachycardia on Visit 3. The adverse event was listed as mild in
`intensity and resolved spontaneously. All vital signs were normal at all visits. No
`further details were given
`> Patient # 2084 was a 62-year-old male with ovarian cancer that was noted to have
`a heart rate of 98 on Visit 3. ECG showed no clinically relevant abnormalities. All
`other vital signs were normal and the patient recovered without treatment.
`> Patient # 2185 was a 73 year old female with a history ofbreast cancer, anemia,
`and hypertension. She was found to have a heart rate of 124 on Visit 3. The
`adverse event was listed as moderate in intensity and not related to the study drug.
`lt resolved without treatment. ECG was unremarkable
`
`> Patient # 4280 was a 83 year old male with a history of lung cancer, prostate
`cancer, and a history of PVC ’5 and arrhythmia. Two days after receiving the
`study drug, he experienced atrial fibrillation for 5 days. This wasjudged as mild
`in intensity and was thought to be unrelated to the study drug.
`
`40
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`0
`
`> Patient # 4464 was a 83 year old male with history of esophageal cancer, prostate
`cancer, hypertension and myocardial infarction. He experienced occasional
`skipped heartbeats for 5 days after receiving the study drug. This was rated as
`mild in intensity and unrelated to the study drug.
`Six patients had arrhythmias in the palonosetron 0.75 mg group.
`> Patient # 4030 was a 80 year old female with a history of breast cancer. She was
`noted to have first degree heart block the day after receiving the study drug. This
`adverse event was categorized as possibly related to the study drug and mild in
`intensity.
`> Patient # 2252 was a 32 year old female with breast cancer. She tachycardia. At
`baseline prior to receiving medication, her heart rate was 96. At Visit 3 it was
`1 16, and at Visit 4 it was 98. This was judged mild in intensity and probably
`related to the study drug.
`'
`> Patient #2079 was a 47 year old male with nasopharyngeal cancer.l-le was noted
`to have tachycardia at Visits 4 and 5 with a heart rate of 96 and 104 respectively.
`ECG was otherwise unremarkable. This was judged mild in intensity and
`probably related to the study drug.
`> Patient # 4433 was a 79 year old female with breast cancer. She was noted to have
`a 151 degree heart block the day after receiving the study drug. This adverse event
`was categorized as not related to the study drug, and mild in intensity.
`> Patient #2082 was a 59 year old female with breast cancer. She was noted on
`Visit 4 to have tachycardia with a heart rate of 120. All other vital signs were
`normal. At Visit 5 her heart rate was 92. This was judged as moderate in intensity
`and probably related to the study drug.
`> Patient #2154 was a 49 year old female with breast cancer. She was noted to have
`a supraventricular arrhythmia on ECG during Visit 4. There apparently was some
`disagreement about interpretation between the investigators. Vital signs remained
`normal and this adverse event was rated as mild in intensity and unrelated to the
`study drug.
`Medical Officer Comments: All cardiac adverse events were reviewed in the
`palonosetron group. There were no incidences of torsades de pointes or any other life
`threatening arrhythmia. Overall, all the cardiac adverse events in the palonosetron
`groups selfresolved and were not severe in intensity.
`
`E. Deaths
`
`There were 3 deaths reported during the study. All occurred in the palonosetron '
`. group. All deaths were judged as either unlikely or unrelated to the study drug.
`
`Patient # 4343 (palonosetron 0.25 mg group) was a 75 year old white female who had
`a history of bilateral lung cancer. Two days after receiving the study medication, the
`patient developed urosepsis and mild dehydration. She died 14 days after receiving
`the study drug. This was judged by the investigator as unrelated to the palonosetron.
`
`Patient # 4007 (palonosetron 0.75 mg group) was a 71 year old Hispanic male with a
`history of gastric and pancreatic cancer. Two days after receiving the study drug; he
`
`41
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`died ofa gastrointestinal bleed. The investigatorjudged his death unlikely to be
`related to the study drug.
`
`Patient #2228 (palonosetron 0.75 mg group) was a 68 year old female with a history
`of non-Hodgkin’s lymphoma. She developed sepsis and septic shock on the day of
`administration ofthe study medication. She died 8 days later. Her death was judged
`unlikely to be related to the study drug.
`
`Medical Officer Comments: All of the deaths were reviewed and were appropriately
`categorized by the investigator. There is no evidence to suggest a relation between
`the study drug and any of these deaths.
`
`Ar’t’t.--;i=."3 MS gm
`N ORlGiiilfilL
`
`——\
`
`42
`
`

`

`PALONOSETIRON
`
`CLINICAL REVIEW STUDY 99-04
`
`F. Serious Adverse Events
`
`The following table displays serious adverse events by body system.
`
`TABLE 31 —-Serious Adverse Events by Body System and Preferred TermI
`
`System organ class
`
`Preferred term
`
`Palonosetron
`
`Palonosetron
`
`Dolasetron
`
`0.25 mg
`
`0.75 mg
`
`100 mg
`
`(MedDRA)
`
`(N = 193)
`
`(N = 195)
`
`(N =194)
`
`%
`
`%
`
`%
`
`Any serious adverse event
`
`Infection and infestations
`
`Pneumonia nos2
`
`Urosepsis
`
`Neutropenic sepsis
`Sepsis nos2
`
`Septic shock
`
`O
`
`NOOO—s—ANAZ
`DOA-ION
`
`O C
`
`Metabolism and nutrition
`
`disorders
`
`Dehydration
`Hyponatremia
`
`Gastrointestinal disorders
`
`Abdominal pain upper
`Diarrhea nos2
`
`Gastrointestinal hemorrhage
`nos2
`
`Small intestinal obstruction
`nos2
`
`Vomiting nos2
`General disorders and
`
`administration site conditions
`
`Chest pain net:2
`
`Pyrexia
`
`Rigors
`
`Neoplasm benign and
`
`malignant
`
`Lung cancer stage
`unspecified
`
`Non Hodgkin's lymphoma nos
`
`(continued)
`
`

`

`. PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`TABLE 31 — Serious Adverse Events by Body System and Preferred Term]
`(Cont’d)
`
`System organ class
`Preferred term
`(MedDRA)
`
`Dyspnea nos2
`Blood and lymphatic system
`disorders
`
`
`
`
`
`
`
`
`Respiratory, thoracic and
`mediastinal disorders
`
`
`
`
`
`Pancytopenia
`Anemia nos2
`Anemia nos2 aggravated
`Febrile neutropenia
`Leucopenia nos.2
`Neutropenia
`
`Cardiac disorders
`Angina unstable
`
`Injury and poisoning
`
`Palonosetron
`0.25 mg
`(N = 193)
`N %
`
`n
`
`1
`
`1
`1
`
`0.5
`
`0.5
`0.5
`
`0.5
`1
`0.0
`0
`0.0
`o
`0 0.0
`0
`0.0
`O
`0.0
`
`0
`0
`
`0
`
`0.0
`0.0
`
`0.0
`
`1
`
`1
`1
`
`1
`o
`o
`O
`o
`O '
`
`O
`0
`
`0
`
`Palonosetron
`0.75 mg
`(N = 195)
`°/o
`
`N
`
`n
`
`0
`
`o
`5
`
`1
`2
`1
`2
`o
`1
`
`1
`1
`
`1
`
`0.0
`
`0.0
`2.6
`
`0.5
`1.0
`0.5
`1.0
`0.0
`0.5
`
`0.5
`0.5
`
`0.5
`
`0.5
`
`O
`
`o
`7
`
`1
`2
`1
`2
`0
`1
`
`1
`1
`
`1
`
`1
`
`030
`
`Dolasetron
`100 mg
`(N =194)
`%
`
`N
`
`0
`
`o
`3
`
`0
`o
`o
`2
`1
`O
`
`0
`0
`
`O
`
`0
`
`0.0
`
`0.0
`1.5
`
`0.0
`0.0
`0.0
`1.0 '
`0.5
`0.0
`
`0.0
`0.0
`
`0.0
`
`0.0
`
`dOOOOO—INOOO
`O-‘O—l—h—LOQJ
`
`O
`
`0
`
`O
`
`0
`
`O
`0
`O
`
`0
`o
`0
`
`O
`
`1
`
`0
`
`0.0
`
`O 0.0
`
`1
`
`1
`O
`- O
`
`2
`1
`O
`
`1
`
`0.5
`
`0.5
`0.0
`0.0
`
`1.0
`0.5
`0.0
`
`0.5
`
`0
`
`0
`
`1
`
`1
`0
`0
`
`2
`1
`O
`
`1
`
`1
`
`1
`
`0
`
`0
`1
`1
`
`0.5
`
`0.5
`
`0.0
`
`0.0
`0.5
`0.5
`
`0.5
`1
`o 0.0
`1
`0.5
`
`O 0.0
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`O
`
`0
`
`0
`
`0
`
`0
`0
`0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`0.0
`0.0
`0.0
`
`0.0
`0
`. o 0.0
`O
`0.0
`
`0
`
`0.0
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Venous thrombosis deep limb
`
`Source: Appendix B-1.3.1. Table 10
`N = number 01 patients
`% = percentage ol patients with adverse events
`n = number 01 adverse events
`‘Multiple answers possxble
`2Not otherwise specified, not elsewhere classified
`
`Subdural hematoma
`
`Muscutoskeletal, connective
`tissue and bone disorders
`
`Back pain
`
`Nervous system disorders
`
`Syncope
`Renal and urinary disorders
`Renal impairment nos2
`
`Vascular disorders
`Phlebitis nos2
`Pulmonary embolism
`
`Scanned from Table 8.1.4-a, page 182-183, Volume 135
`
`Medical Officer Comments: The palonosetron 0. 75 mg group had the highest percentage
`ofadverse events and the 0.25 mg group had the lowest percentage.
`
`The following table gives further detail about serious adverse events.
`
`

`

` CLINICAL REVIEW STUDY 99-04
`
`
`
`PALONOSETRON
`
`TABLE 31 — Serious Adverse Events by Patient
`
`
` ___.r _. u ..'__ .....
`
`
`‘ TL
`
`
`
`
`
`
`
`
`
`
`Treatment groupGenderAgePatient No. Event"
`
`
`4280
`
`4059
`4343
`
`82
`
`52
`
`75
`
`Male
`
`Palonosetron 0.25 mg
`
`Pneumonia nos3
`
`Female
`
`Palonosetron 0.25 mg
`
`Abdominal pain upper
`
`Female
`
`Palonosetron 0.25 mg
`
`Dehydration
`Dyspnea nos3
`Lung cancer stage unspecified
`(exc. metastatic tumors to lung)
`Urosepsls
`
`
`
`4348
`
`4002
`
`4007
`
`29
`
`68
`
`71
`
`79
`
`51
`
`67
`
`Female
`
`Palonosetron 0.25 mg
`
`Male
`
`Male
`
`Palonosetron 0.75 mg
`
`Palonosetron 0.75 mg
`
`Anemia nos3
`Gastrointestinal hemorrhage nos3
`
`Female
`
`Palonosetron 0.75 mg
`
`Diarrhea nos;3
`Febrile neutropenia
`
`Female
`
`Palonosetron 0.75 mg
`
`Pneumonia nosz
`
`'
`
`Male
`
`Palonosetron 0.75 mg
`
`Small intestinal obstruction nos3
`
`2
`Dehydration
`Unrelated
`
`
`Unrelated Pancytopenia 1O
`
`Unrelated
`Angina unstable
`
`
`2
`Unlikely
`2
`Unlikely
`
`
`
`
`
`Unrelated
`4
`
`Unrelated
`
`
`4010
`
`4247
`
`4396
`
`4374
`
`46
`
`Female
`
`Palonosetron 0.75 mg
`
`Anemia nos3 aggravated
`Neutropenla
`Syncope
`
`
`Venous thrombosis deep limb
`Palonosetron 0.75 mg
`Female
`70
`E 4210
`£4262
`54
`Male
`Palonosetron 0.75 mg
`Chest pain nec3
` _..—_________._._..
`(cont. mmrt)
`
`Da of
`5/
`onset
`
`.
`.
`Relationship‘
`
`2
`
`8
`
`3
`3
`4
`
`3
`
`Unrelated
`
`Unlikely
`
`Unrelated
`Unrelated
`Unrelated
`
`Unrelated
`
`10
`1 3
`
`7
`
`14
`
`2
`13
`13
`
`Unrelated
`Unrelated
`
`Unrelated
`
`Unrelated
`
`Unrelated _
`Unrelated
`Unrelated
`
`45
`
`

`

` CLINICAL REVIEW STUDY 99-04
`
`PALONOSETRON
`
`
`
`
`
`Patient No.
`
`Age
`
`Gender
`
`Treatment group
`
`Event‘
`
`Day Of
`
`Palonosetron 0.75 mg
`
`Pancytopenia
`
`10
`
`Unrelated
`
` Male
`Unrelated
`7
`Subdural hematoma
`Palonosetron 0.75 mg
`Female
`Male
`Palonosetron 0.75 mg
`Anemia nos3
`10
`Unrelated
`l
`Febrile neutropenia '
`10
`Unrelated
`l
`Hyponatremia
`10
`Unrelated
`'
`
`Female
`
`Female
`
`Palonosetron 0.75 mg
`
`Palonosetron 0.75 mg
`
`.
`
`
`
`
`
`Unrelated
`21
`Phlebitis nos:3
`l
`
`
`‘
`Unrelated
`1
`Non Hodgkin's Lymphoma nos3
`Sepsis nosa
`‘l
`Unrelated
`1
`
`Septic shock
`Unrelated
`
`4008
`
`
`Back pain
`Unrelated
`
`14
`Unrelated
`1
`Unrelated
`
`
`
`
`
`
`4164
`
`4291
`
`2193
`
`2228
`
`74
`
`65
`
`49
`
`68
`
`Male
`
`Dolasetron 100 mg
`
`Female
`
`Dolasetron 100 mg
`
`Pyrexla
`Sepsis nos3
`
`Female
`
`Dolasetron 100 mg
`
`Febrile neutropenia
`
`Female
`
`Dolasetron 100 mg
`
`Vomiting nos3
`
`Female
`
`Dolasetron 100 mg
`
`Febrile neutropenia
`
`Male
`
`Dolasetron 100 mg
`
`Pneumonia nos.J
`
`Female
`
`Dolasetron 100 mg
`
`Leucopcnia nos3
`
`Neutropenic sepsis
`
`-
`
`'
`
`11
`
`22
`
`18
`
`2
`
`6
`
`10
`
`Unrelated
`
`Unlikely
`
`Unrelated
`
`. Unrelated
`
`Unrelated
`
`Unrelated
`
`Rigors
`
`
`Unrelated
`
`
`
`
`
`(continued)
`
`

`

`
`CLINICAL REVIEW STUDY 99-04
`
` PALONOSETRON
`
`TABLE 31- Serious Adverse Events (Cont’d)
`
`._-.- -...- . uvo-uun
`
`
`
`
`Patient No. Age Gender
`Treatmentgroup
`Event1
`Dayof
`Relationship2
`
`
`
`
`Dolasetron 100 mg
`Pulmonary embolism
`21
`Unrelated
`60
`Male
`
`
`
`
`'
`
`
` 50 Female DolasetroniOO mg
`Renal impairmentnos3
`28
`
`
` Unlikely
`
`
`' Preferred term
`2 According to investigators assessment
`1Not otherwise specified. not elsewhere classified
`
`
`
`Scanned from Table 8.1.4—b Page 174, Volume 135
`Medical Oflicer Comments: All the serious adverse events in the palonosetron group were judged to be unrelated or unlikely to be related to
`the study drug. No clear pattern ofserious adverse events is noted.
`
`G. Laboratory Evaluation
`Lab data was collected and analyzed for all patients. This consisted of hematology, chemistry and urinalysis as well as ECG and Holter
`Monitoring for some patients. The following table shows the hematology results. This table displays the changes in hematology
`parameters from below the reference range to within or above the reference range from Visit 1 to Visit 4.
`
`47
`
`

`

`
`
` CLINICAL REVIEW STUDY 99-04
`
`PALONOSETRON
`
`
`TABLE 33 -Hematology values changing from normal to abnormal or abnormal to normal between Visit 1 and Visit 4
`
`
`
`.
`
`27 (13.9)
`
`15(77)
`
`0 (0.0}
`
`' 1 (0.5)
`
`74 (38.1)
`
`
`Palonosetron 0.75 mg
`Palonosetron 0.25 mg
`Dolasetron 100 mg
`(N = 193)
`(N = 195)
`(N = 194)
`
`
`Vislt1
`
`N (11,)
`N M)
`
`
`N (‘70)
` =
`#-
`
` Hematocrit
`
` 18 (9.3)
`
`
`
`
`17 (8.8)
`0 (0.0)
`18 (9.2)
`22 (11.3)
`0 (0.0)
`
`
`
`2 (1.0)
`78 (40.4)
`11 (5.7)
`0 (0.0)
`74 (37.9)
`9 (4.6)
`
`
`11 (5.7)
`
`
`4.
`
`0 (0.0)
`0 (0.0)
`0 (0.0)
`0 (0.0)
`o (0.0)
`4 (2.1)
`
`
`
`
`1 (0.5)
`0 (0.0)
`3 (1.5)
`
`
`Erythrocytes
`
`
`
`
`
`
`
`28 (14.5)
`16 (8.3)
`0
`21 (10.8)
`24 (12.3)
`0 (0.0)
`32 (16.5)
`21 (10.8)
` V'N-‘V
`77 (39.9)
`
`
`‘1 (0.5)
`76 (39.2)
`
`0 (0.0)
`0 (9.0)
`1
`0 (0.0)
`0 (0.0)
`2 (1.0)
`
`
`
` 4 (2.1)
`
`
`74 (38.3)
`0 (0.0)
`0 (0.0)
`62 (31.8)
`. o (0.0)
`
`1 (0.5)
`46 (23.8)
`1 (0.5)
`
`2 (1.0)
`61 (31.3)
`2 (1.0)
`
`39 (20.1)
`1 (0.5)
`
`+
`
`
`
`0 (0.0)
`0 (0.0)
`o (0.0)
`
`o (0.0)
`0 (0.0)
`0 (0.0)
`
`0 (0.0)
`0 (0.0)
`0 (0.0)
`
`
`
`
`Eosinophils
`
`
`
`
`
`0(0.0)
`0(0.0)
`0(0.0)
`0 (0.0)
`0 (0.0)
`o (0.0)
`0 (0.0)
`0 (0.0)
`0 (0.0)
`0(0.0)120(62.2)
`
`124 (63.6)
`2 (1.0)
`0 (0.0)
`
`
`0 (0.0)
`
`0 (0.0)
`2 (1.0)
`
`
`
`0 (0.0)
`0 (0.0)
`1 (0.5)
`
`1 (0.5)
`0 (0.0)
`
`
`
`1 (0.5)
`(con: mued :1
`
`2 (1.0)
`
`2
`
`4 (2.1)
`
`73 (37.4)
`
`3 (1.5)
`
`0 (0.0)
`
`0 (0.0]
`
`3 (1.5)
`
`86 (44.3)
`
`0 (0.0)
`
`1 (0.5)
`
`1 (0.5)
`
`1 (0.5)
`
`2 (1.0)
`
`4(21)
`
`129 (66.5)
`
`1 (0.5)
`
`48
`
`

`

` CLINICAL REVIEW STUDY 99-04
`
`PALONOSETRON
`
`TABLE 33 -Hematology values changing from normal to abnormal or abnormal to normal between Visit 1 and Visit 4 (Cont’d)
`
`Paformsatron 0.25 mg
`(Ix = 193;:
`
`Palcnosetron 0.75 mg
`{N = 135;.
`Visll 1
`
`Doasetrcr. 130 mg
`(N = 194)
`
`Visit 4
`
`-
`
`*1 {as}
`=
`
`+
`
`-
`
`N (53;.
`—
`
`_
`
`-
`
`N <39]
`=
`
`g.
`
`
`
`
`
`
`
`‘ Basophlls
`
` _
`
`
`
`
`-
`o (-3.-Z-
`:1 (0.1:)
`c. 23.0;
`3 031::-
`0:11.33
`0 :13;
`a (C123
`0 (0.9;.
`0 (=13;
`
`
`
`=
`.
`3 {0.0) 1250345)
`11-15).
`“cc:- 127(651]
`owe-:-
`'32(ES.-3fl
`0:13;
`0:03)
`
`
`
`
`
`*
`1' (013)
`I
`.
`0022-?)
`3
`013.0;
`
`00.3}
`-0(C-.C'ju C(03)
`
`
`Snare: Amt-an: x 8-1 3 2. ‘atle 3
`- = batm- t’atewce mrge
`= = o: :1i1 rafen: $93 mus
`4 = above I'E'B‘B'Ki‘: tarp;
`N = n. 'rba.’ 3f p31 arm or :1 :1ervgss
`a} - pe‘oartz-gn of pa". B1ls Jim’s-urges
`Visit I = xreewin; 'u'asil d = Sluflj; Day 3-3
`
`Scanned from Table 8.2.1-b, page 188-189, Volume 135
`
`Medical Officer Comments: Most hematology parameters changed to below the reference range at Visit 4. This is likely secondary to
`chemotherapy. Overall, diflerences in all treatment groups are not likely clinically significant and more likely due to chemotherapy than the
`study drug
`
`49
`
`

`

`
`CLINICAL REVIEW STUDY 99-04
`PALONOSETRON
`
`
`The investigator rated each abnormal lab finding whether it was clinically relevant. This
`was based on whether the value changed more than one toxicity grade (NCI criteria).
`The following table shows the number of clinically relevant abnormalities in hematology
`for each treatment arm.
`
`TABLE 34 — Clinically relevant abnormalities in hematology according to the
`investigator.
`
`(N = 194)
`
`(N = 193)
`
`(N = 195)
`
` Dolasetron
`
` Palonosetron Palonosetron
`
`
`0.25 mg
`0.75 mg
`100 mg
`
`%
`N
`%
`N
`N i %
`
` Hemoglobin
`
`
`Visit 1 (Screening)
`Visit 3 (Study Day 2)
`
`Visit 4 (Study Day 6-8)
`
`Hematocrit
`
`
`
`Visit 1 (Screening)
`Visit 3 (Study Day 2)
`
`
`Visit 4 (Study Day 6-8)
`
`
`
`Erythrocytes
`
`
`Visit 1 (Screening)
`
`Visit 3 (Study Day 2)
`
`\
`
`
`
`Visit 4 (Study Day 6-8)
` Leukocytes
`Visit 1 (Screening)
`
`
`
`
`Visit 4 (Study Day 8-8)
`
`
`Lymphocytes
`
`
`Visit 1 (Screening)
`
`
`Visit 4 (Study Day 6-8)
`
`
`Neutrophils
`
`
`Visit 1 (Screening)
`
`
`Visit 4 (Study Day 6-8)
`
` Eosinophils
`
`
`Visit 1 (Screening)
`Visit 3 (Study Day 2)
`
`
`Visit 3 (Study Day 2)
`
`Visit 3 (Study Day 2)
`
`Visit 3 (Study Day 2)
`
`Visit 4 (Study Day 6-8)
`(continued)
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`TABLE 34- Cont’d
`
`Palonosetron
`
`Palonosetron
`
`0.25 mg
`(N = 193)
`
`N
`
`"/0
`
`0.75 mg
`(N = 195)
`
`N
`
`"/0
`
`Dolasetron
`
`100 mg
`(N = 194)
`
`N
`
`°/o
`
`
`
`Basophfls
`
`Visit 1 (Screening)
`Visit 3 (Study Day 2)
`Visit 4 (Study Day 6-8)
`Platelets
`
`Visit 1 (Screening)
`Visit 3 (Study Day 2)
`Visit 4 (Study Day 6—8)
`Source: Appendix C—8, Listings
`N = patients with abnormalities
`‘71: = percentage of patients with abnormalities
`
`Scanned from page 195-196, Volume 135,
`
`Medical Officer Comments: The number of clinically relevant lab abnormalities was low
`in all treatment groups. An overall trend was noted that there were more clinically
`relevant abnormalities in Visit 4 and this is consistent with the eflects of chemotherapy.
`
`Blood Chemistry values were also judged whether to be clinically relevant. The
`following table displays clinically relevant blood chemistry values from all three
`treatment arms.
`
`APPEARS THIS WAY
`0“ ORIGINAL
`
`51
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`TABLE 35 - Clinically Relevant Abnormalities in Blood Chemistry
`
`Palonosetron
`
`Palonosetron
`
`Dolasetron
`
`0.25 mg
`(N = 193)
`
`N
`
`"/o
`
`0.75 mg
`(N = 195)
`
`N
`
`°/o
`
`100 mg
`(N = 194)
`
`N
`
`%
`
`
`
`SGOT
`
`Visit 1 (Screening)
`
`Visit 3 (Study Day 2)
`
`Visit 4 (Study Day 6-8)
`
`SGPT
`
`Visit 1 (Screening)
`
`Visit 3 (Study Day 2)
`
`Visit 4 (Study Day 6~8)
`
`Alkaline phosphatase
`
`Visit 1 (Screening)
`
`Visit 3 (Study Day 2)
`Visit 4 (Study Day 6-8)
`Total bilirubin
`
`Visit 1 (Screening)
`
`Visit 3 (Study Day 2)
`
`Visit 4 (Study Day 6—8)
`
`Calcium
`
`Visit 1 (Screening)
`Visit 3 (Study Day 2)
`
`ViStt 4 (Study Day 6—8)
`
`. Albumin
`
`'
`
`Visit 1 (Screening)
`
`Visit 3 (Study Day 2)
`
`Visit 4 (Study Day 6-8)
`
`Glucose
`
`Visit 1 (Screening)
`
`Visit 3 (Study Day 2)
`
`Visit 4 (Study Day 6—8)
`(continued)
`
`52
`
`

`

`CLINICAL REVIEW STUDY 99-04 PALONOSETRON
`
`TABLE 36 -C0nt’d
`
`Palonosetron
`
`Patonosetron
`
`Dolasetron
`
`0.25 mg
`
`(N = 193)
`
`0.75 mg
`
`(N = 195)
`
`100 mg
`
`(N = 194)
`
`N
`
`%
`
`N
`
`%
`
`N
`
`%
`
`Bicarbonate
`
`Visit 1 (Screening)
`
`Visit 3 (Study Day 2)
`
`Visit 4 (Study Day 6—8)
`
`Creatinine
`
`.
`
`Visit 1 (Screening)
`
`Visit 3 (Study Day 2)
`
`Visit 4 (Study Day 6—8)
`
`Blood urea nitrogen
`
`Visit 1 (Screening)
`
`Visit 3 (Study Day 2)
`
`Visit 4 (Study Day 6-8)
`
`Potassium
`
`Visit 1 (Screening)
`
`' Visit 3 (Study Day 2)
`
`Visit 4 (Study Day 6-8)
`
`Sodium
`
`Visit 1 (Screening)
`
`Visit 3 (Study Day 2)
`
`Visit 4 (Study Day 6-8)
`Source. Appendix C-8, Listing 3
`N = patients with abnormalities
`% = percentage of patients with abnormalities
`
`Scanned from Table 8.2.2c, pg. 195—196, Volume 135
`
`Medical Officer Comments: There werefew diflerences between the groupsfor blood
`chemistries. There were no clinically relevant values ofSGOT and SGPT in the
`palonosetron group at Visit 4.
`
`The following table displays vital sign information.
`
`53
`
`._._-‘
`
`

`

` CLINICAL REVIEW STUDY 99-04
`
`PALONOSETRON
`
`
`
`TABLE 37- Cont’d
`
`Changes from
`
`'
`
`Respiratory rate
`[breathsfmin]
`
`Visii 1
`Changes from
`
`Visit 1' to Visit 32
`, Visit 1 to Visit 4’
`5 Wm! 1 to Visit 5‘
`
`Heart rate [beatslmin]
`
`Visil 1
`Changes from
`
`Visit 1‘ to Visit 32
`Visil110 Visit 4’
`VISil 1 to Visit 5‘
`So..~rco: .Aupendix 8-1.3.3. Tab 9 1
`‘l - rumae! :9 patierts w-Ir :ala
`: scrnan fig
`‘ SIJdv Day 2
`, Slucv Day 5-8
`' 51:11:17 Day 15—25
`
`Palono selron
`
`0.25 mg
`(N = 193)
`
`Palonosetron
`
`0. 75 mg
`{N = 195)
`
`Dolasetron
`
`100 mg
`(N =194)
`
`Max
`
`N
`
`Min Mean Max
`
`Min Mean
`
`Min ' Mean
`
`Max
`
`185
`
`177
`179
`103
`
`192
`
`185
`190
`109
`
`10.9
`
`0.0
`-00
`0.2
`
`79 9
`
`0.8
`-0.7
`0.1
`
`-
`
`186
`
`174
`176
`103
`
`194
`
`187
`187
`112
`
`-
`.
`.
`
`19.2
`
`-0.2
`-0.0
`-o.1
`
`79.9
`
`-1.5
`-1.1
`-1.1
`
`181
`
`175
`
`178
`
`103
`
`191
`
`186
`
`190
`
`110
`
`19.0
`
`0.1
`
`0.1
`
`-O.2
`
`79.9
`
`-1.5
`
`0.1
`
`-‘1.2
`
`Scanned from Table 8.3.1-a , page 216-217. Volume 135
`
`55
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`filedical Oflicjer Comments: There was no significant change or trend seen in vital signs
`from visits 1 to 4.
`
`H. ECG Evaluation
`
`A 12 lead ECG was performed for all patients at Visit 1 (screening), Visit 3 and
`Visit 4. The interpretation ofthe ECG’s was performed by a cardiologist at a central
`location who was blinded to the patient’s treatment. In addition, the investigator also
`interpreted the ECG.
`A subset of patients were randomized to receive a Holter monitor. The numbers
`are listed in the following table.
`
`TABLE 38— Number of Patients who underwentHolter Monitor __
`
`.
`
`Palonosetro
`
`(Reference: Table 6.3—d, page 78, Volume 135)
`
`At Visit 1 the majority of patients had normal ECG (range 65.6% to 74.2%).The
`following table displays Changes in ECG findings between the visits.
`
`56
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`TABLE 39 - Changes in ECG findings between the visits
`
`
` Paionosetron
`Palonosetron
`
`
`0.25 mg
`-
`0.75 mg
`100 mg
`(N=193)
`. (N=195)
`(N=194)
`
`
`N
`%
`N
`
`
`°/o
`
`N
`
`%
`
`Changes from
`
`Dolasetron
`
`
`Study Day 1) Hotter
`
`
`patients only‘
`
` No change
`
`
`improved
`Deteriorated
`
`Missing
`Normal to normal
`
`Visit 1 to 2 (screening to
`
`'
`
`
`
`Normal to abnormal
`
`Visit 1 to 3 (screening to
`
`Study Day 2)
`
`Normal to normal
`
`Normal to abnormal
`
`Visit 1 to 4 (screening to
`
`
`
`
`No change
`159
`82.4
`'
`153
`81.0
`170
`87.6
`
`
`
`Improved
`4
`2.1
`6
`3.1
`-
`2
`1.0
`
`
`
` Deierioraied
`15
`7.8
`15
`7.7
`12
`6.2
`
`
`
`
`Missing
`10
`5.2
`14
`7.2
`7
`3.6
`
`
`
`115
`60.1
`116
`59.0
`133
`68.6
`
`3.6
`7
`3.1
`6
`52
`10
`
`_,
`
`
`Study Day 6-8)
`
`
`
`
`
`
`
`
`
`5.7
`6
`3.1
`7
`3.6
`
`
`12.9
`
`
`12.4
`24'
`28
`14.4
`25
`
`57,0
`113
`57.9 '
`127
`65.5.
`.110
`
`
`‘9
`4.7
`3
`1.5
`2
`1.0'
`
`
`
`No change
`
`improved
`
`Deteriorated
`
`Missing
`
`149
`
`77.2
`
`3.6
`
`7
`
`11
`
`147
`
`75.4
`
`10
`
`5.1
`
`155
`
`79.9
`
`5
`
`2.6
`
`_
`
`Normalionormal
`Normal to abnormal
`Source: 'Appendix 8-1.3.3. Tables 2 and 3
`N = number of patients in the specific group,
`' Calculation oi percentages based on Nm(palonosetron. 0.25 mg N"... = 12. palonosetmn. 0.75 mg N1... = 12. dolasetron
`100mg NM=6).
`’
`
`I Scanned from Table 8.3.2-a: page 207, Volume 135
`
`57
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`Medical Officer Comments: The majority ofpatients had no change in ECG. Between
`Visit 1 and 3, a higher proportion of the 0.25 mg palonosetron group had worsening
`ECG as rated by the reading cardiologist. The diflerences were relatively small and no
`distinct pattern could be delineated.
`
`The QT interval was evaluated also for any change after receiving treatment. The
`following table shows the changes in QT and QTc.
`
`A
`
`"
`1
`F1173“
`lb lid/AV
`PP..1li\-:) Ta
`Oi‘sl ORI‘GWAL
`
`58
`
`

`

` CLINICAL REVIEW STUDY 99-04
`
`PALONOSETRON
`
`TABLE 40 — Changes in QT and QTc at Visits
`
`____.____~_.____-. ._...._.. _.._. _......__..
`
`
`
`
`
`Palonosetron 0.75 mg
`(N = 195)
`Moan
`Min
`
`N
`
`Max
`
`Dolasetron 100 mg
`(N = 194)
`
`Mean
`Min
`N
`'Max
`
`
`
`
`
`
`
`
`Palonoselron 0.25 mg
`(N = 193)
` M In
`
`Mean
`
`
`
`176
`368
`
`10
`386
`183
`373
`
`169
`369
`
`188
`371
`
`OT
`
`Visil 1'
`Vi51t 2’
`V151! 3’
`Visit 4‘
`Visit 2. 3 and 4
`Changes from
`
`
`
`
`
`Visi‘i 1
`lo 2
`
`V'siz 1 to 3
`
`v=si:
`1 to 4
`
`
`Visii 1 10 2. 3. 4
`Maximum change
`
`
`
`
`
`
`
`
`
`
`
`Visit 22
`
`Visit 33
`
`QTc by Bazett
`Visit 1‘
`
`Visii4‘
`Visit 2, 3 ant: 4
`
`
`
`Changes from
`
`
`Visit 1 to 2
`
`Visit 1 to 3
`
`
`
`Visit 1 to 4
`{conliruem
`
`10
`
`169
`
`157
`
`174
`174
`
`178
`
`10
`
`183
`
`169
`188
`
`1o
`
`169
`
`157
`
`9.3
`
`5.8
`
`0.7
`
`3.4
`12.2
`
`414
`
`419
`
`419
`
`414
`417
`
`~5.6
`
`5.5
`
`1.2
`
`3
`
`
`
`
`
`
`
`
`
`182
`4
`1 B7
`169
`.191
`
`365
`381
`373
`370
`372
`
`
`
`
`
`
`4
`
`177
`
`160
`
`16.8
`
`6.9
`
`4.3
`
`5.7
`
`
`
`.48.
`
`60
`
`

`

` CLINICAL REVIEW STUDY 99-04
`
`
`
`PALONOSETRON
`
`TABLE 40 — cont’d
`
`
`
`..__. ._-___..-___.._._t-.._.... .
`.. 3
`_ . .-....;__.__.._
`Palcnoselron 0.75 mg
`(N =1951
`
`
`
`l————___—.__...__ _
`Dolasetron 100 mg
`(N=194)
`'
`
`7
`3
`
`Min
`
`Max
`
`
`
`Visit 1"
`
`
`
`
`
`Visit 2"-
`. Visit 33
`l
`'5 Visit 4‘
`1 Visit 2. 3 and 4
`1
`1 Changes from
`
`
`
`10
`153
`1139
`188
`
`407
`403
`398
`401
`
`8
`181
`167
`187
`
`391
`398
`395
`397
`
`1'
`!
`Palonosotron 0.25 mg
`(11:19.3)
`2
`
`
`Mean
`N
`Max
`Min
`Mean
`N
`Mean
`N
`Min
`Mann:
`
`
`
`
`
`
`
`Visit 1 to 2., 3, 4
`.-.. __131
`1731 w 3.3
`— h 175
`2.7
`'
`_
`5.3
`_
`
`
`Maximum change
`174
`10.3
`1 76
`10.1
`12.9
`
`
`I
`QTc by Friderlcla
`
`i
`178
`393
`180
`394
`393
`
`4'08
`
`401
`
`
`
`397
`
`399
`
`
`
`
`8
`-3.s
`19.3
`
`
`
`172
`4.5
`177
`74
`
`
`
`
`
`157
`1.5
`—
`160
`'
`3.5
`
`
`176
`3.2
`5.4
`
`
` 9.9
`
`
`Visn 1 to 2
`-0.6
`10
`
`Visit 1 to 3
`5.6
`159
`
`Visit 1 ton
`1.1
`157
`
`
`Visit 1 to 2. 3.11
`3.4
`174
`9.7
`Maximum cha nge
`
`
`Soume' Ao:encix 8.1.3.3. ‘1an:: 4
`N = nalerls MU‘ changes
`'Vtsn 1 = 521991151";
`;.'JIS“ 2. Study Dr; 1 (15 mirules aflor stLdy medicaficn admifiislraffifi for Hotter patterns only. calcula‘iio'I 01 person
`pa msselron D 75 mg k... = 12. dolasuzrcn 100 mg Nm. = 6,1
`' 'v-sil 3 = Study Day 2
`' 'v'ISH d = Study Day 6-8
`
`Scanned form Table 8.3.2-b, page 220-221, Volume 135
`
`age: based on N...(pn:o1osnllon 3 25 mg M... = 12.
`
`6!
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`Medical Officer Comments: There were no relevant differences seen between treatment
`groups for the mean duration of QTc. The 0.25 palonosetron group showed a mean
`change in QTc interval that was less than was seen in the dolasetron arm. However, the
`maximal change in QTc was highest in the palonosetron 0.25 mg arm, although the
`mean change was lower than the a’olasetron arm.
`
`When the QT and QTc intervals are averaged there can be regression to the mean. Thus,
`it can be more clinically relevant to examine the number of patients with critical changes
`for QT and QTc ECG findings. The following table displays this information.
`
`TABLE 4] — Critical Changes for QT and QTc ECG findings at Visits
`
`Palonosetron
`
`Palonosetron
`
`Dotasetron
`
`0.25 mg
`(N = 193)
`
`N
`
`%
`
`0.75 mg
`(N = 195)
`
`N
`
`%
`
`100 mg
`(N = 194)
`
`N
`
`%
`
`Changes from
`
`Visit 1' to Visit 2“ (Holler
`patients only)
`OT 30 to 60 msec
`QT > 60 msec
`
`OTC by B 30 to 60 msec
`OTC by B > 60 m'sec
`OTC by F 30 to 60 msec
`OTC by F > 60 msec
`Visit 1‘ to Visit 3‘
`OT 30 to 60 msec
`QT > 60 msec
`
`OTC by B 30 to 60 msec
`OTC by B > 60 msec
`OTC by F 30 to 60 msec
`QTC by F > 60 msec
`Visit 1' to Visit 45
`OT 30 to 60 msec
`OT > 60 msec
`
`
`
`OTC by B 30 to 60 msec
`QTC by B > 60 msec
`OTC by F 30 to 60 msec
`OTC by F > 60 msec
`Source: Appendix (3-1.3.3, Table 7
`N = patients with changes
`% = percentage of patients with Changes
`8 = Bazcu
`F = Fridoncia
`' Screening
`:Calculation ol percentages based on N....(patonoselron 0.25 mg N...i = 12. palonosetron 0.75 mg Ni... = 12. dotaselron
`100mg~....=6)
`.
`_'
`_
`.
`’ Study Day 1 (15 rrunules after study medication administration)
`' Study Day 2
`‘ Study Day 6-8
`
`Scanned from Table 8.3.2-c, page 224, Volume 135,
`
`62
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`Medical Officer Comments: It is generally accepted that a change in QTc of greater
`than 60 msec is ofconcern and greater than 30 msec is potentially concerning. The 0.25
`mg palonosetron group hadfewer patient or equal number ofpatients in this group. Only
`one patient in the palonosetron group had a change in QTcfi'om S 5 00 msec to >500
`msec. Three patients in the dolasetron group had such a change.
`
`ECG’s were rated by the cardiologist as to whether they had clinically relevant findings
`The following table displays the clinically relevant abnormalities for each treatment
`group.
`
`TABLE 42 — Clinically relevant abnormalities detected by ECG assessed by
`cardiologist
`-
`
`Palonosetron
`
`Palonosetron
`
`Dolasetron
`
`0.25 mg
`
`(N=193)
`
`0.75 mg
`
`(N=195)
`
`100 mg
`
`(N=194)
`
`N
`
`%
`
`N
`
`°/o
`
`N
`
`%
`
`
`
`Visit 1 (screening)
`Visit 2 (Study Day 1)1
`
`Visit 3 (Study Day 2)
`
`Visit 4 (Study Day 6-8)
`
`Source: Appendix 8-1.3.3. Table 3
`N = patients wuth abnormalities
`f/o = percentage of patients with abnormalities
`‘Calcuiatron ot pe'centages based on NW (palonosetron 0.25 mg NR.- = 12, palonosetron 0.75 mg NM. = 12. dotasetron
`100 mg NM = 6)
`
`Medical Officer Comments: A slightly higher percentage ofthe palonosetron 0.25 mg
`group had ECGfindings which were assessed to be clinically relevant. Thejudgement of
`clinical relevance was based on the subjective opinion ofa blinded cardiologist. There
`were a relatively small number ofpatients who had ECG ’s available for Visit 2 (30
`patients). Thus the percentage with abnormalities is high in the 0.25 mg palonosetron
`group despite only 3 patients having abnormal ECG 's.
`
`A subset of patients underwent Holter monitoring from 2 hours prior to receiving the
`medication to 22 hours after getting the study drug. The results of this were analyzed by
`a blinded cardiologist at a central location. The cardiologist assessed whether the
`
`63
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`findings were abnormal or normal and ifthey were clinically relevant. The results are
`displayed in the following table.
`
`
`
`Holter
`
`Interpretation
`
`Normal
`
`Abnormal
`Clinical
`'
`Relevance
`
`" "
`
`8
`
`4
`,,
`
`(66.7)
`
`.
`
`(33.3)
`
`'
`
`10
`
`2
`
`'
`
`'
`
`(83.3)
`
`(16.7)
`
`5
`
`2
`
`'
`
`(83.3)
`
`(16.7)
`
`(0.0)
`2'
`(8.3)
`'l'
`"ma—5.0)
`3
`7
`'Relevanutm
`' (16.7)"
`0
`'
`'
`(8.3)
`i
`” (23.3)""”'"'
`' m1 '
`lrrelevant
`' Patients with data available: Palonose—tro'n'025 mg #19, palonosetron 0.75 mg =14,
`dolasetron = 12
`
`'
`
`(Reference: Table 8.3.3—a, page 227,Volume 135)
`
`The following are details about the patients with abnormal Holter monitor results that
`were judged to be clinically relevant in the palonosetron group.
`
`0
`
`0
`
`0
`
`0
`
`Patient #4026 (palonosetron group 0.25 mg) was a 46 year old female with breast
`cancer. She had non-sustained ventricular tachycardia note on Study Day 3 with a
`heart rate of 73. She had no cardiac history.
`
`Patient #4174 (palonosetron group 0.25 mg) was a 62 year old female with breast
`cancer. She had a history ofhypothyroidism. She had transient second degree heart
`block on Study Day 3.
`
`Patient #4464 (palonosetron group 0.25 mg) was a 86 year old male with a history
`esophageal and prostate cancer.
`lung cancer. He had a history of myocardial
`infarction in the past. On Study Day 2, he had a non-sustained ventricular
`tachycardia with a heart rate of 82
`
`Patient #4267 (palonosetron group 0.75 mg) was a 79 year old male with a history of
`congestive heart failure, coronary artery disease, and hypertension. He experienced
`non-sustained ventricular tachycardia on Study Day 2 (prior to receiving the study
`drug) and at Study Day 3.
`
`Two patients had abnormal a Holter monitor in the control group. This was judged as
`clinically relevant by the reviewing cardiologists.
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`Medical Officer Comments: It is likely that Patients #4464 and #4267 had abnormal
`Holter monitor readings due to underlying medical conditions unrelated to the study
`drug. This is less certain for Patients #4026 and #41 74. However, both these
`abnormalities were self—limiting and apparently did not result in clinical symptoms.
`
`VII. Conclusion
`
`The primary objective ofthe study PALO-99-O4 was to compare the efficacy of
`single IV doses ofpalonosetron 0.25 mg or 0.75 mg, to dolasetron 100 mg IV in
`preventing moderately emetogenic CINV.
`The secondary objectives were to evaluate
`the safety and tolerability of palonosetron and its relative safety in comparison with
`dolasetron. In addition, the effect of anti-emetic control with palonosetron or dolasetron
`on the quality of life of patients receiving moderately emetogenic chemotherapy was
`evaluated. The study achieved these objectives
`A. Efficacy
`The primary efficacy parameter was complete response within the first 24 hours
`after chemotherapy. The results demonstrated the non—inferiority of both palonosetron
`0.25 mg and 0.75 mg when compared to dolasetron. The lower limit of the 97.5%
`confidence interval for the difference in complete response rates between the dolasetron
`and the palonosetron groups during the first 24 hours after chemotherapy was above the
`preset 15% delta. There were multiple secondary endpoints. Pairwise testing between
`palonosetron 0.25 mg and dolasetron revealed differences in favor of palonosetron in the
`following parameters:
`0 Complete control for all time periods except Study Days 1 and 5
`0 Number of emetic episodes