`
`CLINICAL REVIEW STUDY 99—03
`
`PALONOSETRON
`
`2. Secondary Efficacy Endpoints
`There were several secondary efficacy endpoints as listed below:
`Complete response over 120 hours
`
`Complete control (defined as a complete response and no more than mild nausea)
`
`Total response (subjects free from emetic episodes, rescue medication,'and nausea
`over time)
`
`Number of emetic episodes
`
`Time to first emetic episode
`
`Time to rescue medication
`
`Time to treatment failure (time tofirst emetic episode or administration of rescue
`medication, whichever occurred first)
`
`Severity ofnausea (Likert Scale)
`
`Subject global satisfaction with therapy (VAS; visual analog scale)
`
`Quality oflife questionnaire (FLIE; Functional Living Index)
`
`'
`“‘A‘l
`Await-isms .1
`on (imam-AL
`
`18
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-03
`
`Complete Response over 120 hours
`Table 15 on the following page displays one ofthe secondary endpoints — complete response over 120 hours.
`
`TABLE 15- Subjects with Complete Response After Chemotherapy, By Day (Acute and Delayed): (ITT Cohort; N = 663)
`
`
`‘
`Number and Percentage (”/o) of Subjects with
`Difference in Complete Response-Rates,
`i
`.
`97.5% Confidence Intervals
`.,
`--'
`Complete ReSponse -
`
`Palonosetron 0.25 mg
`Palonosetron 0.25 mg
`Palonosetron 0.75 mg
`Palonosetron 0.75 mg
`(N = 139)
`(N = ‘39)
`i Minus 0ndansetron 32 mg Minus Ondansetron 32 mg
`1
`
`Ondansetron 32 mg
`(N = 185)
`
`Time Period
`(Hours)
`Acute'
`
`
`
`‘
`
`
`
`153
`
`(81.0)
`
`139
`
`(73.5)
`
`127
`
`(68.6)
`
`‘
`
`0—24
`
`Delayed”
`i
`(81.5)
`154
`122
`(65.9)
`24—48
`
`
`
`
`
`1
`(85.2)
`161
`124
`(67.0)
`48—72
`
`
`
`
`
`1
`72—96
`168
`(88.9)
`145
`(78.4)
`
`
`
`
`
`96—120
`175
`(92.6)
`161
`(87.0)
`' = Primary efficacy endpoint.
`b = Secondary endpoint.
`.
`‘
`"‘ = 97.5% CIs for the difference between palonosetron and active comparator (ondansetron or dolasetron)
`Medical Officer Comments: During all study days, complete response rates were higher in the 2 palonosetron groups than in the
`ondansetron group. Higher rates were observed in the palonosetron 0. 25 mg group compared to the 0. 75 mg group The lower limit ofthe
`confidence interval ofthe difference ofeach palonosetron dose versus 0ndansetron was above the pre-set threhsold of—1 5%, indicating non-
`inferiority ofpalonosetron to ondansetron. Although the palonosetron seems to demonstrate some eflicacy at 120 hours somefactors need to
`be considered. The p-values were not adjustedfor multiple endpoints. Since there were multiple secondary endpoints, there may be issues
`with multiplicity.
`In addition, the comparator arm Ona'ansetron is not indicatedfor prevention of ClN V at 120 hours. Thus, what the results
`may be demonstrating is that the nausea from the chemotherapy is simply wearing off
`
`
`
`[-6.1%, 15.9%]
`
`[1.8%, 22.8%]*
`
`
`
`[-7.5%,15.2%]
`[4.9%,26.1%]*
`
`
`
`[-0.I%,21.6%]
`[8.0%,28.4%]*
`
`
`
`[1.5%,19.5%]*
`[-2.6%,16.3%]
`[-5.6%,10.4%]
`[-2.0%,13.1%]
`
`
`
`
`19
`
`

`

`133 (70.4)
`
`[63.2%, 76.7%]
`
`124 (65.6)
`
`[58.3%, 72.3%]
`
`
`
`
`[55.9%, 69.8%]
`1 19 (63.0)
`
`
`
`109 (57.7)
`
`[50.3%, 64.7%]
`
`lO](54.6)
`
`[47.1%, 61.9%]
`
`105 (55.6)
`
`[48.2%, 62.7%]
`
`87 (47.0
`
`[39.7%, 54.5%]
`
`102 (54.0)
`
`[46.6%, 61.2%]
`
`101 (53.4)
`
`
`[46.1%, 60.7%]
`
`
`
`
`
`
`
`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99—03
`
`Complete Control
`Table 16 shows the proportion of patients who were considered to have complete control.
`Complete control was another secondary efficacy endpoint and was defined as patient
`who had a complete response and no more than mild nausea.
`
`TABLE 16 — Patients with complete control after chemotherapy, overall time
`periods (ITT cohort, N=563)
`
`144 (76.2)
`
`[69.4%, 81.9%]
`
`134 (70.9)
`
`[63.8%, 77.1%]
`
`121 (65.4)
`
`[58.0%, 72.1%]
`
`
`
`
`
`
`
`
`
`
`
`
`84 (45.4)
`[38.1%, 52.9%]
`[37.6%, 52.3%]
`83 (44.9)
`
`
`
`120 (63.5)
`
`[56.2%, 70.3%]
`
`(Reference: Table 7.1.2.2-a, page 109, Volume 117)
`
`Medical Officer Comments: Both palonosetron groups demonstrated higher complete
`control rates at all time periods when compared to ondansetron. The palonosetron 0.25
`mg group had a higher proportion ofpatients that had complete control than the 0.75 mg
`group. The differences between the three groups were statistically significant for the time
`period 0 top 48 hours (p=0. 004), 0 to 72 hours (p=0.001), 0 to 96 hours (p=0. 002) and 0
`to 120 hours (p=0. 002). There was no statistical dIflerence in the 0 to 24 hour time
`period (p=0. 072 using Chi-Square test)
`
`'
`‘l
`APPEARS THlS ‘hA
`0N ORlGli‘l-AL
`
`20
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-03
`
`Number of Emetic Episodes
`Table 17 shows the number of emetic episodes during the observation period.
`’ TABLE 17_— Number ofemetic e.
`isodes durin'
`the observatwn eriod
`
`
`
`
`
`s
`ACUTE
`
`0—24
`
`0 episodes
`
`1 episode
`2 episodes
`
`23 episodes
`DELAYED
`24—48
`
`0 episodes
`
`1 episode
`
`2 episodes
`
`23 episodes
`48—72
`
`0 episodes
`
`1 episode
`2 episodes
`
`23 episodes
`72—96
`
`0 episodes
`
`1 episode
`2 episodes
`
`23 episodes
`96—120
`
`0 episodes
`
`1 episode
`2 episodes
`
`(85.2)
`
`(2.1)
`
`(3.2)
`
`(9.5)
`
`(87.8)
`
`(5-8)
`
`(2.6)
`
`(3.7)
`
`(89.9)
`
`(7.4)
`(1.1)
`
`(1.6
`
`(92.1)
`
`(5.3)
`(1-6)
`
`(1.1)
`
`(94.2)
`
`(3.2)
`
`(1.1)
`
`161
`4
`
`6 1
`
`8
`
`23 episodes
`
`(1.6)
`
`(Reference:Tab1e 7.1.2.3-a, from page 112, Volume 1 17)
`
`Medical Officer Comments: The palonosetron 0.25 mg group hadfewer emetic episodes
`than the other groupsfor days 1,2, and 3. There was no diflerence between the groups on
`day 4 and 5. On these days, most patients did not experience an episode ofemesis.
`However, the palonosetron 0. 75 mg group did have more patients who had 3 or more
`episodes ofemesis on Days 4 and 5 than the other groups. It should be noted that
`multiple analyses were performed, and this result was not aaj'ustedfor multiplicity.
`
`21
`
`

`

`PALONOSETlRON
`
`CLINICAL REVIEW STUDY 99-03
`
`Time to First Emetic Episode
`Table 18 shows the median time to the first emetic episode.
`
`U;-
`TABLE 18 —Median Timeto 'frst emetic eisode
`
`" Palonosetron
`
`30120110113“: 115i
`
`>120
`
`25.2
`
`>120
`
`Q1= first quartile
`(Re'ference:Table 7.2.3—b, page 113, Volume 117)
`
`Medical Officer Comments: The median time to first emetic episode was above 120
`hoursfor all groups. When the applicant performedfurther analysis ofthe first quartile
`ofpatients, theyfound that thefirst quartile showed that time tofirst emetic episode was
`longer in the 0.25 mg group. This was an unplanned analysis that was done after the
`primary analysis failed to show a diflerence. Thus, it is unclear if this is clinically
`significant.
`Severig of Nausea
`The following figure shows the severity of nausea during study Day 1,2,3 and 4
`
`FIGURE 2: Severity of nausea during Study Day 1, 2, 3, 4, and 5
`(ITT cohort N=563) (Scanned from figure 7.1.2.4-a, page 115, Volume 117)
`
`Palonosetron 0.25 mg
`
`Palonosatron 0.75 mg
`
`Ondanselron 32 mg
`
`
`
`
`
`Percentage01patients[7.]
`
`Tlma [h]
`
`Dnone Umild Bmoderate lsevere
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-03
`
`Medical Officer Comments: The rate ofpatients without nausea was highest in the
`palonosetron 0.25 mg group and lowest in the ondansetron group. For Day 1 the
`diflerence was not significant (p-value 0.318 using Kruskal- Wallis test). For Days 2,3, 4,5
`there was a statistically significant dzfi’erence between groups in favor ofthe 0.25 mg
`dose ofpalonosetron. When pairwise testing (using the Wilcoxon test) was done with the
`0.25 mg palonosetron group versus ondansetron statistically significant diflerences were
`seen on Day 2, 3, and 4. This is consistent with the pharmacologic properties of
`palonosetron, which has a longer half-life than ondansetron.
`
`Time to Rescue Medication
`
`The following table shows the time to first use of rescue medication.
`TABLE 19— Median Time to First Administration of Rescue Medication
`
`
`
`Q1= first quartile
`(Reference: Tables 7.1.2.5-b, from page 118, Volume 117)
`
`Medical Officer Comments: The median time to first use of rescue medication was
`greater than 120 hours for all groups. However, the sponsor did an analysis ofthefirst
`quartile ofpatients andfound that the time to first administration ofrescue medication
`tended to be shorter in the ondansetron group. It is unclear what the clinical relevance of
`this finding is since this was an unplanned analysis. Overall, few patients took rescue
`mediation during this study. There was no statistical diflerence between treatment groups
`in the number ofpatients who took rescue medication for any study day.
`
`Time to Treatment Failure
`
`The median time to treatment failure (time to first emetic episode or administration of
`rescue medication, whichever occurred first) is displayed on the following table.
`x ~- m;
`:1“ 3-.»
`TABLE 20 —Medlantime to Treatment‘failure lTT cohort, N=563
`
`' Ondansetron‘" %
`
`0,1120hours
`
`46.5
`
`>120
`
`211>120
`
`19.5
`
`>12d0
`
`Q1= first quartile
`(Reference: Table 7 l .2 6-a, page 121 Volume 117).
`
`Medical Officer Comments: The median time to treatmentfailure was again greater than
`120 hours for all groups. Analysis of the first quartile ofpatientsfound that the time to
`treatment failure was longest in the 0.25 mg Palonosetron group.
`
`23
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99—03
`
`Qualig of Life Questionnaire
`The quality of life was assessed by using a modified and validated Functional Living
`Index Emesis (FLIE). This consisted of 18 questions divided into 2 domains (nausea, and
`vomiting. The questions were assessed by using a visual analog scale (VAS). A high
`score reflects less impairment from nausea and vomiting.
`
`TABLEVZI — O uali ofLife VAS scores for nausea and vomitin_
`
`
`
`Overall score
`
`24-96 hours
`Nausea
`
`Vomiting
`Overall score
`
`(Reference: Table 7.1.2.8-a ,page 126, Volume 117)
`
`bledical Officer Comments: Median quality of life scores were similar in all the
`treatment groups. Statistical testingfound no diflerence between the groups for nausea,
`vomiting and the overall score during the 0—24 hours time period. There was statistical
`difference for the total score for the time period 24-96 hours between palonosetron 0.25
`mg and ondansetron (p=0. 014). No statistical diyference was found between the higher
`dose ofpalonosetron and ona’ansetron, (p=0. 130) nor between the 2 doses of
`palonosetron (p=0.3 69)
`
`Global Satisfaction with Therapy
`The global satisfaction of the patients with the anti-emetic therapy was recorded on a
`VAS for the entire lZO-hour interval. Global satisfaction was evaluated daily. Again, the
`applicant performed an unplanned analysis of the first quartile. The results are shown in
`the following table.
`
`24
`
`

`

`CLINICAL REVIEW STUDY 99-03
`
`PALONOSETRON
`
`(Reference: Table 7.1.2.7-a, page 124, Volume 117)
`
`Medical Officer’s Comments: A statistical difference between treatment groups was
`found by Kruskal- Wallis testingfor Day 3 (p=0. 045) but not the other days (p=0.05). A
`pair wise test between 0.25 mg ofpalonosetron and ondansetron showed a significant
`difference (0.015) in favor to palonosetron for Day 3 also. N0 diflerence was seen
`between the two palonosetron groups or between 0.75 mg palonosetron and ondansetron.
`
`Summag of Results for Secondagg Efficacy Endpoints
`The table on the following page displays a summary ofthe statistical analysis
`regarding the secondary efficacy endpoints.
`
`APPEARS THIS WAY
`0N ORlGlHAL
`
`/"\
`
`25
`
`

`

`
`
`CLINICAL REVIEW STUDY 99-03
`
`PALONOSETRON
`
`TABLE 23— Statistical Analysis Results of Seconda
`
`Efficacy End oints
`
`Parameters
`Complete Control (CC)
`
`Statistical Test
`.
`
`vs ONDA 32 mg
`
`vs ONDA 32 mg
`
`vs PALO 0.75 mg
`
`—————_
`24-48 hr
`Chi-square —
`48-72 hr
`Chi-square
`72-96 hr
`Chi-square
`96- 120 hr
`Chi-square
`0-48 hr
`Chi-square
`0-72 hr
`Chi-square
`Chi-square
`0-96 hr
`Chi-square
`0-120 hr
`Number of Emetic Episodes (EE)
`0-24 hr
`W/Wilcoxon
`X
`24—48 hr
`W/Wilcoxon
`48a72 hr
`W/Wilcoxon
`72-96 hr
`W/Wilcoxon
`96- l 20 hr
`W/Wilcoxon
`0-120 hr
`KW/Wilcoxon
`
`Time to First [[5
`Severity of Nausea
`
`Log Rank
`
`KW/Wilcoxon
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`a
`.
`
`
`
`
`—_-::'i- .
`fir»
`0-7148
`
`oaasa
`,
`Need of Rescue Medication
`
`
`
`
`
`———-—
`
`mam ——_——
`
`
`48-72hr _____
`
`
`mam ———
`
`Nazca
`oaaoo —
`——__
`
`
`—_-—-
`
`
`Subject Global Satisfaction
`
`
`
`
`W72-96 hr
`
`96-120hr
`
`
`
`
`Function Living lndex-Emesis
`mam Naaaa
`
`FLlE #r Vomiting
`mam Taaaa
`ma #2 Naasaa
`
`FLlE #2 Vomiting
`FLlE #2 Total
`
`
`
`0.0565
`
`.0472
`
`
`
`means statistically significant dificrcnce (i.e., p < 0.05).
`means difference in favor of PALO 0.25 mg.
`" means difference in favor of PALO 0.75 mg.
`
`.""«
`
`26
`
`

`

`PALONOSETlRON
`
`CLINICAL REVIEW STUDY 99-03
`
`3. Subgroup Analysis
`
`
`Gender
`
`The primary efficacy parameter was complete response during the first 24 hours after
`chemotherapy. The following table displays complete response by gender for each of the
`treatment arms.
`
`
`
`TABLE 24— Patients with Com lete Res oonse b Gender
`
`'
`Number andPercentage (%) of Subjectswith'
`i
`‘
`
`‘
`'
`Complete Response 6
`
`Palonosetron 0.25
`Palonosetron 0.75
`Ondansetron 32
`
`
`
`
`mg
`mg
`
`(N = 185)
`(N=66/189)
`
`
`
`
`
`
`N* = number of patients with response
`(Reference: Table 7.2.l-a, page 129, Volume 117)
`
`Medical Officer Comments:_Male patients had a higher complete response rate than
`female patients. The applicant does not ofler an explanation why this was so but it has
`been noted in previous studies. The lower limits ofa 97.5% confidence intervalfor the
`difference in complete response rates between both palonosetron doses and ondansetron
`32 mg were above the pre-set threshold of -1 5 % in male andfemale patients.
`
`Chemotherapeutic Histog
`The following table displays complete response stratified by chemotherapeutic
`history during the first 24 hours.
`
`jil‘CompleteResponse
`Ondansetron 32
`Palonosetron 0.75
`Palonosetron‘Oi'ZS
`
`
`
`
`
`
`
`mg
`
`mg
`
`(NN=*189)
`
`0/o
`
`(N = 189)
`N* , %
`
`N
`
`(88. 2)
`
`(68. 8)
`
`6766)
`
`66
`
`6666)
`
`= number of naive or non-naivepatients
`N*= number of patients with response
`(Reference: Table 7.3.l-a, page 144, Volume 117)
`
`mg
`
`(NN=*185)%
`
`
`
`
`(74. 4)
`
`6666)
`
`
`
`27
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-03
`
`Medical Officer Comments: The lower limits of the 97.5 %confidence intervals for the
`difference between palonosetron 0.25 mg and ondansetron were above the preset
`threshold of—l 5 % indicating non-inferiority ofpalonosetron 0.25 mg to ondansetron in
`regard to these subgroups. The palonosetron 0.75 mg dose was only able to
`demonstrate non-inferiority only in the non-naive patients. The exclusion criteria for
`this study excluded non-naive patients who had moderate to severe nausea with prior
`chemotherapy. This could have led to bias with a more favorable response in the non—
`nai‘ve group. However, the results do not demonstrate such a bias. Naive patients had a
`slightly higher complete response rates than non-naive patients in all but the
`palonosetron 0.75 mg group.
`
`VI.
`
`.
`Safety Evaluation
`Most patients were observed for 14 days after the study drug was administered. A
`subset of patients were enrolled in a follow-up study PALO-99-O6, that extended the
`observation period to 27 days. The following table displays treatment emergent adverse
`events.
`
`28
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-03
`
`TABLE 26 — Treatment Emergent Adverse Events overview (Safety cohort, N=562)
`
`Ondansetron
`
`Palonosetron
`0.25 mg
`(N=187)
`N
`%
`114
`61.0
`30
`16.0
`
`Palonosetron
`0.75 mg
`(N=188)
`N
`°/o
`125
`66.5
`30
`16.0
`
`'
`
`32 mg
`(N: 187)
`N.
`%
`120
`64.2
`26
`13.9
`
`Number of patients with AEs
`
`All
`
`Related‘
`
`
`By category
`
`All AEs/Non-Lab, Non-ECG
`An AEs/Laboratory
`An AEs/ECG
`Related‘ AEs/Non-Lab, Non-ECG
`Related‘ ABS/Laboratory
`Related1 AEs/ECG
`Serious adverse events
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`All SAEs
`Related SAEs
`Withdrawn due to AEs
`
`80
`65
`9
`22
`4
`6
`
`5
`1
`
`42.8
`34.8
`4.8
`11.8
`2.1
`3.2
`
`2.7
`0.5
`
`86
`61
`8
`26
`1
`5
`
`5
`0
`
`45.7
`32.4
`4.3
`13.8
`0.5
`2.7
`
`2.7
`0.0
`
`86
`62
`7
`23
`3
`2
`
`5
`0
`
`46.0
`33.2
`3.7
`12.3
`1.6
`1.1
`
`2.7
`0.0
`
`
`
`
`
`
`
`
`
`0.5
`1
`'
`0.5
`1
`0.0
`0
`All
`
`0.0
`0
`0.5
`1
`0.0
`0
`Related'
`~_~%N'N%~'
`
`%
`N
`
`
`Subgroup: gender
`54
`30 55.6
`51
`29 56.9
`52
`33 63.5
`AliAEs/maie
`
`
`All AEs/fernale
`133
`34 63.2 137
`96 70.1
`135
`87 64.4
`
`
`52
`5
`9.6
`Related‘ AEs/maie
`54
`_5
`9.3
`51
`6 11.8
`
`
`135
`21 15.6
`Related1 AEs/female
`133
`25 18.8
`137
`24 17.5
`
`
`
`Subgroup: chemotherapeutic
`history
`
`
`
`75
`45 60.0
`80
`52 65.0
`79
`49 62.0
`112
`69 61.6
`108
`73 67.6 108
`71 65.7
`
`
`75
`12 16.0
`80
`19 23.8
`79
`11 13.9
`
`
`
`112
`
`
`
` 1816.1 108
`11
`
` 24 57.1
`42
`40
`28 70.0
`40
`27 67.5
`42
`2
`4.8
`40
`512.5
`40
`2
`5.0
`
`All AEs/nawu
`AllAEs/non-naive
`Related1AEs/naive
`Related1 AEs/non—naive
`
`
`
`
`
`Germany
`All AEs
`
`Related1 AEs
`
`‘H‘In'innnd\
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99703
`
`TABLE 26 - Treatment Emergent Adverse Events (Cont’d)
`
`
`Palonosetron
`
`Palonosetron
`
`Ondansetron
`
`0.25 mg
`(N = 187)
`
`0.75 mg
`(N = 188)
`
`32 mg
`(N = 187)
`
`Number of patients with AEs
`
`N’
`
`N
`
`% N"
`
`N
`
`%
`
`N'
`
`N
`
`%
`
`
`
`Italy
`
`All AEs
`
`Related1 AEs
`
`United Kingdom! The Netherlands
`
`'
`
`All AEs
`
`Related1 AEs
`
`Arkhangelsk
`
`All AEs
`
`Related1 AEs
`
`Moscow
`
`All AEs
`
`Related‘ AEs
`
`St. Petersburg
`
`All AEs
`
`Related‘ AEs
`
`Source: Appendix 8-1.3.1. Tables 1 and 3
`‘ Adverse events which had a definite. possible. probable or unknown relationship to study mediation
`N = number of patients with events
`N' = number of patients in the specific group
`% = percentage of patients with events
`
`(Scanned from Table 8.1.1, page 161-162, Volume 162)
`
`Medical Officer Comments: There was a high rate of treatment adverse events in all
`three study arms. The rate was highestfor the patients in the palonosetron 0.75 mg
`group. Cancerpatients undergoing chemotherapy generally have a high rate of
`complications and co-morbid illness so the high rate is not unexpected Adverse events
`that were rated by the investigator as definite, possible, probable or unknown -
`relationship to the study drug were characterized as related adverse events. The number
`ofserious adverse events was equal in all groups. Female patients had a higher rate of
`adverse events versus males particularly in the palonosetron 0. 25 mg arm.
`Chemotherapy naive and non-naive patients had a similar rate ofadverse events. The
`three Russian sites reported less adverse events than the other sites. The applicant does
`not ofler an explanation for these diflerences.
`
`30
`
`"\
`
`

`

`PALONOSETIRON
`
`. CLINICAL REVIEW STUDY 99-03 '
`
`B. Adverse Events by Body System
`The following table displays adverse events by body system.
`
`System organ class2
`Preferred term2
`
`Blood and iymphatic
`system disorders
`
`Headache nos3
`
`General disorders and
`
`Pyrexia
`
`Investigations
`
`Skin & subcutaneous
`
`tissue disorders
`
`Vascular disorders
`
`TABLE 27'— Treatment Emergent Adverse events by body System and preferred
`terml (Safety Cohort, N=562)
`
`
`
`
`Palonosetron
`Palonosetron
`Ondansetron.
`
`
`0.25 mg
`0.75 mg
`32 mg
`
`(MedDRA)
`(N = 187)
`(N = 188)
`(N = 187)
`
`
`n
`70
`°/o
`%
`N
`N
`n
`N
`n
`
`
`Any adverse event
`114_61.0 273
`66.5
`125
`
`
`63
`23.9
`45
`73
`25.1
`47
`
`
`
`
` LymphOpenia 27 14.4 27 23 12.2 23 20 10.7 20
`
`
`
`
`
`
`
`
`
`
`Leucopenia nos3
`24
`12.8
`24
`21
`11.2
`21
`21
`11.2
`21
`
`
`
`Neutropenia
`15
`8.0
`15
`8
`4.3
`8
`15
`8.0
`15
`
` Gastrointestinal disorders
`28
`15.0
`29
`32
`17.0
`46
`26
`13.9
`31
`
`Nervous system disorders
`
`28
`15.0
`30
`28
`14.9
`34
`37
`19.8
`48
`
`
`
`19
`10.2
`20
`23
`12.2
`26
`28
`15.0
`33
`
`
`
`27
`14.4
`35
`19
`10.1
`21
`26
`13.9
`31
`administration site
`
`conditions
`
`
`
`
`
`Metabolism and nutrition
`disorders
`
`
`
`
`Cardiac disorders
`
`
`
`
`
`
`
`Source: Appendix 8-1 .3.1 Table 4
`MedDRA = Medical Dictionary tor Regulatory Activities
`N=—number of patients
`%= percentage of patients with adverse events
`n= number of adverse events
`‘Multiple answers possible
`:lnddence or at least 5% of patients in any treatment group
`’Not otherwise specified
`
`.
`
`
`
`
`
`
`
`
`
`
`31
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-03
`
`(Scanned from Table 8.1.2.2—c, page 166, Volume 1 17)
`
`Medical Officer Comment: Adverse events ofthe blood and lymphatic system were most
`common in all treatment groups. These were equally spread out in all treatment groups
`and were secondary to chemotherapy. Following the blood and lymphatic disorders,
`headache was the mostfrequently reported adverse event. This also was balanced in all
`treatment arms. The percentage ofpatients with headache is less than the Phase 1/11
`palonosetron studies where it occurred in 20% of the patients.
`
`D. Adverse Events by Severity and Relationship to Treatment
`The following table shows adverse events by treatment group and severity.
`
`TABLE 28—— Number of Adverse Events b Intensi
`.1 ‘ “2'7,"
`r 1n
`~
`J‘g'x”mu9-5.1"
`‘Palonosetro
`' W
`'1'” 2‘3
`
`
`
`Ondansetron
`
`'
`
`(60.8)
`(34.8)
`
`(4.4)
`
`V169
`90
`
`16
`
`U
`
`(61.5).
`(32.7)
`
`(5.8)
`
`190
`97
`
`7
`
`(64.6)
`(33)
`
`(2.4)
`
`166
`95
`
`12
`
`273
`
`(Reference: Table 8.1.2.2-a, page 167, Volume 1 17)
`
`Medical Officer Comments: The majority ofadverse events in all treatment arms were of
`mild intensity. The rate ofsevere-adverse events was higher in the palonosetron groups
`compared to the 0ndansetr0n group. The body system mostfrequently involvedfor severe
`adverse events was neutropenia (2/1 8 7, l .1 %) for the 0.25 mg palonosetron group and
`leukopenia (2/188, 1. l %) for the 0.75 mg palonosetron group.
`
`32
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-03
`
`The following table displays the Number of displays by relationship to treatment.
`
`TABLE 29— Number of Adverse Events bv Relationshi n to Treatment
`
`:Palonosetro
`
`
`
`157m
`73
`32
`' 7
`
`._
`
`'
`
`'
`
`-
`
`(56)
`(29.3)
`(8.8)
`(3.37)
`(0)
`'('2.6')""
`
`'
`
`'
`
`Unrelated
`Unlikely
`Possible
`Probable
`Definite
`Unknown
`
`153
`80
`24
`”'9'” '
`O
`7
`273
`
`(Referencefable 8.1.2.2-b, page 168, Volume 117)
`
`Medical Officer Comments: The majority of adverse events were judged by the
`investigator to be unrelated to the study drug in all three treatment groups. The
`incidence ofpossibly related adverse events was slightly higher in the 0.75 mg
`palonosetron group than in the 0.25 mg group.
`
`The following table shows the treatment emergent related adverse events by body system.
`
`Alji't1.1i)g.3.J ”Al.
`0N Oi‘iiuiniAi.
`
`',4-.\_
`
`33
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-03
`
`
`
`TABLE 30 — Treatment Emergent Related Adverse Events by Body System and
`Preferred Term2 (Safety cohort, N=562)
`
`
` System organ class3
`
`Palonosetron
`Palonosetron
`Ondansetron.
`
`Preferred term
`0.25 mg
`0.75 mg
`32 mg
`
`
`
`(MedDRA)
`(N = 187)
`(N = 188)
`(N = 187)
`
`
`
`
`
`
`n%N n N % n N %
`
`
`
`
`
`
`
`
`
`
`
`Any related adverse event
`
`
`
`Nervous system disorders
`Headache nos‘
`
`
`
`Dizziness
`
`Somnolence
`
`
`Gastrointestinal disorders
`Constipation
`
`
`Metabolic disorders nos‘
`
`
`
` Metabolism and nutrition
`disorders
`
`
`
`
`General disorders and
`administration site
`conditions
`Cardiac disorders
`Bradycardia nos4
`
` In vestigations
` Skin 8. subcutaneous
`
`tissue disorders
`
`Source: Appendix 8- 1.3.1 Table 9
`
`MedDRA= Medical Dictionary tor Regulatory Activities
`N= number of patients
`%= percentage of patients with adverse events
`n: number of adverse events
`'Adverse events which the investigator considered to have a definite.
`study medication
`:Muttiple answers possible
`:lncidence of at least 1.5% of patients in any treatment group '
`‘Not otherwise specified
`
`possible, probable or unknown relationship to
`
`Scanned from Table 8.1.2.2.2-c, page 169, Volume 1 17
`
`Medical Officer Comments: The rate ofpatients with related adverse everzts wa;hh1gher
`in the 2 palonosetron groups than in the ondansetron group (16/0 vs. 13.9%») .
`e ,1
`nervous system was the most often involved in all 3 treatment arms. The most commo
`
`0
`
`.
`
`34
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-03
`
`related adverse events were headachefor all treatment groups. Metabolism and
`nutrition disorders occurred more often in the palonosetron 0.25 mg group (3.2% vs 1%
`and 1.6 %) . General disorders and administration site conditions occurred more in the
`palonosetron groups compared to the ondansetron group (2. 7% and 3.2% versus 1.1%).
`Bradycardia was reported in 3 patents in the palonosetron 0.25 mg group and in 2
`_ patients in the ondansetron group.
`The individual case report tabulation forms were reviewed for the treatment
`related adverse events. The following are the highlights of this review.
`Nervous System Disorders
`Headache was the most common adverse event.
`
`0
`
`0
`
`19 (10.2%) of the 0.25 mg palonosetron group suffered headaches.
`> 9 (4.8%) werejudged to be related to the study drug.
`> 13 (7%) were mild in intensity.
`> 6 (3.2%) were moderate in intensity.
`23 (12.2%) ofthe 0.75 mg palonosetron group experienced headache.
`> 10 (5.3%) were judged to be related to the study drug.
`> 18 (9.6%) were mild in intensity.
`> 5 (2.7%) were moderate in intensity.
`Four patients (3 in the 0.25 mg palonosetron group and 1 in the 0.75 mg palonosetron
`group) experienced somnolence. All were judged as related to the study drug. In one of
`the patients who received 0.25 mg ofpalonosetron, it was judged as moderate in severity.
`The others were reported as mild.
`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 but even counting all headache
`patients in this study as related to the study drug the percentage is much less
`( 10.2%,12.2%) than seen in the Phase [/11 studies.
`
`Gastrointestinal Disorders
`
`Constipation was the most frequent adverse event in this category
`0
`4 (2.1%) of the 0.25 mg palonosetron group suffered constipation.
`> 3 (1 .6%) were judged to be related to the study drug.
`> 2 (1.0%) were mild in intensity.
`> 2 (1.1%) were moderate in intensity.
`7 (3.7) of the 0.75 mg palonosetron group experienced headache.
`> 6 (3.2%) were judged to be related to the study dr'ug.
`> 3 (1.6%) were mild in intensity.
`.
`> 3 (1.6%) were moderate in intensity.
`
`0
`
`Metabolic Disorders
`
`The most common metabolic disorder was recorded as metabolic disorder not
`
`otherwise specified. 3 (1 .6%) of the 0.25 mg palonosetron group experienced metabolic
`disorder not otherwise specified. All three were seen at the same investigative site in
`Arkhanglesk, Russia. They were all listed as having a worsening of metabolic pattern in
`the myocardium on ECG. This was judged as mild in intensity and of unknown or
`possibly related to the study drug. All recovered without treatment.
`
`35
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99—03
`
`The remainder of patients consisted of2 patients with hypocalcemia and 1 patient
`with hypokalemia. These were not considered severe adverse events and it is unclear if
`they are related to the study drug.
`
`Cardiac Disorders
`
`0 Three patients in the palonosetron 0.25 mg group experienced bradycardia.
`Interestingly all three were seen at the same investigative site in Arkhanglesk, Russia.
`> Patient #1 115 was a 40 year old female who was noted to have a heart rate of 47
`of ECG on Visit 3. This was listed as probably 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 #‘ 1240 was a 68 year old female with a history of hypertension and breast
`cancer. She was noted to have bradycardia on her ECG from Visit 3. The adverse
`event was listed as mild in intensity and resolved spontaneously. All vital signs
`were normal at all visits.
`
`> Patient #1248 was a 28-year-old male with Hodgkin’s disease that was noted to
`have an ECG on visit 4 that showed a heart rate of 55. All other vital signs were
`normal and the patient recovered without treatment.
`
`0 Three patients had episodes of extra-systole in the palonosetron groups. The
`following 2 patients were rated as possible or of unknown relation to the study drug.
`> Patient #1 137 was a 58 year old female with a history of breast and thyroid
`cancer. She received 0.25 mg of palonosetron. She was noted to have a single
`extrasystolic beat on her Visit 3 ECG. She had no further episodes and her vital
`signs remained normal. The investigator recorded this mild in intensity and
`unknown in terms of relation to the study drug.
`> Patient #1 116 was a 64 year old male with a history of coronary artery disease,
`metastatic carcinoma ofunknown primary and multiple other medical problems.
`He received 0.75 mg of palonosetron. He apparently underwent l-lolter monitor
`and was noted to have extra-systolic beats intermittently. The CRT does not
`clarify what exact arrhythmia he suffered but he did receive riboxinum, a cardiac
`medication not approved in the US. This adverse event was categorized as
`probably related to the study drug and mild in intensity.
`0 Two patients who received 0.75 mg palonosetron experienced first degree AV block.
`These were classified as possibly'related to the study drug, however, both patients
`had this ECG finding prior to receiving the study drug.
`0 Patient #3138 was a 63 year old female with metastatic breast cancer. She received
`0.75 mg of palonosetron. She suffered lower extremity edema that was judged to
`be mild in intensity and of unknown relationship to the study drug.
`Patient #1080 was a 63 year old female with metastatic ovarian cancer. She was noted
`to have tachycardia with a heart rate of 92 at Visit 3 and 4 that decreased to 80 at
`her final visit. This wasjudged mild in intensity and possibly related to the study
`drug.
`
`0
`
`Medical Officer Comments: All cardiac adverse events were reviewed in the
`palonosetron group. The bradycardia episodes were mild in intensity and spontaneously
`
`36
`
`

`

`PALONOSETJRON
`
`CLINICAL REVIEW STUDY 99—03
`
`resolved. Patient #1248 may not have had true bradycardia rather a physiologic slow
`heart rate due to relative young age. Patient #1116 had a pre-existing cardiac condition
`that may have contributed to his arrhythmia. Overall, all the cardiac adverse events in
`the palonosetron groups selfresolved and were not severe in intensity.
`
`E. Deaths
`
`There were 4 deaths reported during the study. Three occurred in the palonosetron
`0.75 mg group and 1 in the ondansetron group. All deaths were judged as either
`unlikely or unrelated to the study drug.
`
`Patient # 3219 (palonosetron 0.75 mg group) was a 55 year old white female who had
`a history of disseminated gastric cancer with ascites, constipation, vomiting and
`depression. Two days after receiving the study medication, the patient suffered an
`intemiittent severe obstruction ofthe gastric outlet. The patient underwent parenteral
`nutrition and received a gastric tube but died approximately 31/2 months after
`receiving the study drug. This was judged by the investigator as unlikely related to
`the palonosetron
`
`Patient # 3145 (palonosetron 0.75 mg group) was a 63 year old white male with a
`history of gastric cancer, small cell lung cancer with wide spread metastasis. One
`week after receiving palonosetron he developed severe pneumonia with severe
`atelectasis and ple°ural effusion. He died three weeks later and the investigatorjudged
`his death unlikely to be related to the study drug.
`
`Patient #1263 (palonosetron 0.75 mg group) was a 76 year old female with a history
`of breast cancer, hypertension, coronary artery disease and diabetes. She developed
`diabetic ketoacidosis 20 days after receiving the study drug. She was hospitalized and
`treated but expired 27 days after receiving palonosetron. Her death was judged
`unlikely to be related to the study drug.
`
`Patient #3328 (ondansetron group) was a 66 year old white male who developed a
`pulmonary embolism 1 day after receiving ondansetron. He was intubated and placed
`on a ventilator but died one day later. This death was judged to unrelated 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.
`
`F. Serious Adverse Events
`
`The following table displays serious adverse events by body system.
`
`37
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-03
`
`TABLE 31 : Serious Adverse Events by Body System and Preferred Terml
`
`System organ class
`
`Palonosetron
`
`Palonosetron
`
`Ondansetron
`
`Preferred term
`(MedDRA)
`
`025 mg
`(N = 187)
`
`%
`
`0.75 mg
`(N = 188)
`
`%
`
`32 mg
`(N =18?)
`
`%
`
`Nervous system disorders
`
`.a.t.a<3.3.5(nI!
`
`Addo—n-soi:
`
`ooc—n—Lnoiz
`
`coo—senor):
`
`oocooomz
`
`oooooom:
`
`Any serious adverse event
`
`Infection and infestations
`
`Pneumonia nos2
`
`Periodontitis
`
`Injury and poisoning
`Accident nosz
`
`Neoplasms benign and
`
`malignant
`
`Placental polyp
`
`Psychiatric disorders
`
`Acute psychosis
`
`Renal and urinary disorders
`
`Urinary retention
`
`Urinary tract disorders nos2
`
`Blood and lymphatic system
`disorders
`
`Thrombocytopenia
`
`Gastrointestinal disorders
`
`Gastrointestinal obstruction
`nos2
`
`General disorders and
`
`administration site conditions
`
`Condition aggravated
`
`Metabolism and nutrition
`
`disorders
`
`Diabetic ketoacidosis
`
`Convulsion nos2
`
`(confinued)
`
`38
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-03
`
`TABLE 3] — Serious Adverse Events by Body System and Preferre