E‘-
`
` CLINICAL REVIEW
`
`Clinical Review Section
`
`FIGURE 1: Severity of nausea during Study Day 1, 2, 3, 4, and 5
`PALO-99-03 (top), PALO-99—04 (bottom) (Scanned from figure 7.1.2.4-a,)
`
`Palonosetron 0.25 mg
`
`Palonosetnon 0.75 mg
`
`Ondansetnon 32 mg
`
`I
`
`I1-
`
`Tlme [h]
`
`Dnone Dmild mmoderate Isevere
`
`Palonosetron 0.25 mg
`
`Palonosetron 0.75 mg
`
`Ondansetron 32 mg
`
`8c
`3H
`a.h
`
`oOa 5C §0n
`
`.
`
`Percentageofpatients
`
`a?3‘.
`
`.
`.
`3 :
`
`i
`
`_.:
`1-5.
`'
`
`i
`
`H
`'53;
`q.-
`.1:E3:h
`
`['I.) ——hm:-
`
`Unone Dmild lmoderate Isevere
`
`

`

`
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`Medical Officer Comments: For PALO 99-03, the rate ofpatients without nausea was highest in
`the palonosetron 0.25 mg group and lowest in the ondansetron group. For Day 1 the dtflerence
`was not significant @-value 0.318 using Kruskal- Wallis test). For Days 2, 3, 4,5 there was a
`statistically significant Hiflerence between groups in favor of the 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 ofpalonosetron, which has a longer half-life than
`ondansetron.
`
`For PALO-99-04, the rate ofpatients without nausea was higher in the palonosetron
`groups compared to the dolasetron group. For Day 1 the diflerence was not significant. For
`Days 2,3,4, there was a statistically significant diflerence between groups in favor of the 0.25 mg
`dose ofpalonosetron. When pairwise testing (using the Wilcoxon test) was done with the 0.25
`mg palonosetron group versus dolasetron, statistically significant difiarences were seen on Day
`2, and 3 but not for Day 4 or 5.
`
`Secondarv Efficacv Endpoint — Time to Rescue Medication
`The median time to first use of rescue medication was greater than 120 hours for all
`groups in both studies. However, the sponsor did an analysis of the first quartile of patients and
`found that the time to first administration of rescue medication tended to be shorter in the
`
`dolasetron 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 difference between treatment groups in the number of patients who took rescue
`medication for any study day.
`
`Secondarv Efficacv Endpoint — Time to Treatment Failure
`The median time to treatment failure (time to first emetic episode or administration of
`rescue medication, whichever occurred first) was again greater than 120 hours for all groups in
`both studies. Analysis of the first quartile of patients found that the time to treatment failure was
`longest in the 0.25 mg Palonosetron group.
`
`Secondarv Efficacv End oint —
`
`ualitv of Life
`
`uestionnaire
`
`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. The following tables display the results for
`both PALO-99-O3, and PALO—99-O4 respectively.
`
`Page 43
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`

`

` CLINICAL REVIEW
`
`Clinical Review Section
`
`TABLE 21: PALO-99-03- Quali
`
`LPalonosetron
`
`
`.
`I
`.'
`‘
`_'
`,
`0. 25 mg
`
`of Life VAS scores for nausea and vomiting
`Palonosetron
`Ondansetron .-
`
`'_'
`0.75 mg
`" _ 32 mg
`_
`
`
`
`(News).
`.7
`(N=189)
`‘
`(N=189) _
`.
`'
`Time Perlotl
`
`
`
`_,(hours), _
`
`Median '
`Median -. Median
`- —:)~‘~—-‘h-:J.
`J.._ .-.‘_..__.
`a4. .:-.
`w ..._ a—‘J’.--‘!-h
`
`
`
`
`
`
`II-24 hours
`
`
`
`
`Nausea
`
`
`
`
`872
`
`866
`
`851
`
`
`Vomiting
`900
`897
`899
`Overall score
`1587
`1749
`1721
`
`
`24-96 hours
`
`861
`866
`828
`Nausea
`
`
`Vomiting
`Overall score
`
`
`
`(Reference: Table 7.1.2.8-a ,page 126, Volume 117)
`
`-
`
`:
`
`-
`
`__
`
`
`
`.
`
`
`
`
`
`
`Vomiting
`884
`874
`
`1629
`Overall score
`1686
`1700
`
`24-96 hours
`
`826
`833
`728
`Nausea
`
`
`TABLE 22: PALO-99-04-Qua1itv of Life VAS scores for nausea and vomiting
`_
`' Palonosetron
`Palonosetron
`Dolasetron
`0.25 mg
`0.75 mg
`100 mg
`_
`(N 189)
`(N 1.89)_-
`(N= 191)
`
`_
`
`'
`
`’
`
`.
`Time Period _
`(hours)
`.
`
`aMedian-Medane Medxan
`
`831
`
`84]
`
`.
`
`789
`
`874
`
`0-24 hours
`
`Nausea
`
`
`
`Vomiting
`Overall score
`
`
`
`(Reference: Table 7.1.2.8-a ,page 126, Volume 135)
`
`Medical Officer Comments: For Study PALO-99-03, median quality oflife scores were similar
`in all the treatment groups. Statistical testingfound no difference between the groups for nausea,
`vomiting and the overall score during the 0-24 hours time period. There was statistical
`differencefor the total score for the time period 24-96 hours between palonosetron 0.25 mg and
`ondansetron @=0.014). N0 statistical diflerence was found between the higher dose of
`palonosetron and ondansetron,(a=0.130) nor between the 2 doses ofpalonosetron Ca=0. 369).
`For Stuaji PALO-99-04, again statistical testingfound no diflerenee between the groups
`for nausea, vomiting and the overall score during the 0-24 hours time period. There was
`statistical. diflerencefor the nausea scorefor the time period 24-96 hours between palonosetron
`0. 25 mg and dolasetron @=0.031).
`
`Page 44
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`

`

` CLINICAL REVIEW
`
`Clinical Review Section
`
`Secondarv Efficacy Endpoint -Global Satisfaction with Therapv
`The global satisfaction ofthe patients with the anti-emetic therapy was recorded on a
`VAS for the entire 120-hour interval. Global satisfaction was evaluated daily. The results are
`shown in the following tables
`
`-
`
`l
`
`'
`
`-
`
`'
`
`-_
`
`*
`
`TABLE 23: PALO-99-03 - Global Satisfaction with Anti-emetic therapy
`(ITT cohort, N=563)
`" Palonosetron
`Palonosetron
`0.25 mg
`- 0.75 mg
`..
`(New 1
`-- we»
`
`'-
`
`_.~
`
`Ondansetron ’
`32 mg ‘
`-'
`,
`._>
`(N618?)-
`.-
`
`A.
`'
`2
`
`
`TimePenod
`. '
`than”)
`
`M,MedenmuaMedlan_.ms_Medlan-
`
`
`
`97
`
`
`97
`96
` Delayed
`
`97
`94
`93
`24-48
`
`
`48-72
`98
`96
`94
`
`
`
`
`
`98
`99
`
`97
`98
`
`99
`72-96
`99
`96-120
`(Reference: Table 7.1.2.7-a, page 124, Volume 117)
`TABLE 24: PALO-99-04 - Global Satisfaction with Anti-emetic therapy
`(ITT cohort, N=569
`
`
`‘ .Palonosetron -
`Palonosetron _
`', .
`'Dolasetron '
`
`
`0.25mg 'E " _0.75mg
`.
`100mg -
`
`
`.
`
`.'
`
`'-
`
`.:
`
`WMedxan ‘. Median‘Median
`
`
`
`
`
`
`
`
` 95
`
`90
`
`
`
`93
`
`(Reference: Table 7.1.2.7-a, page 130, Volume 135)
`
`Medical Officer ’5 Comments: For PALO-99-03, a statistical diflerence between treatment
`groups wasfound by Kruskal- Wallis testingfor Day 3 02=0.045) but not the other days (0.05). A
`pair wise test betWeen 0.25 mg ofpalonosetron and ondansetron showed a significant dijference
`(0.015) in favor to palonosetron for Day 3 also. No diflerence was seen between the two
`palonosetron groups or between 0. 75 mg palonosetron and 0ndansetr0n.
`
`Page 45
`
`

`

` CLINICAL REVIEW
`
`Clinical Review Section
`
`For PALO-99-04, a statistical difference between treatment groups wasfound by
`Kruskal- Wallis testingfor Day 2 (p=0. 008) but not the other days). A pairwise test between
`0.25 mg ofpalonosetron and dolasetron showed a significant diflerence (0.022) in favor to
`palonosetronfor'Day 4.
`
`Summafl of Results for Secondary Efficacv Endpoints for PALO-99-03, and 99-04
`The table on the following pages displays a summary of the statistical analysis regarding
`the secondary efficacy endpoints. _
`
`Page 46
`
`

`

`
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`TABLE 25:
`
`Statistical Analysis Results of Secondary Efficacy Parameters for Phase 3 Moderately Emetogenlc CINV
`Pivotal Studies (PALO-99-03 and PALO-99-04)
`
`Slatlsllcal Teal
`
`Overall
`
`PALO 0.25 mg
`vs ONDA 32 mg
`
`PALO 0.75 mg
`vs ONDA 32 mg
`
`PALO 0.25 mg
`vs PALO 0.75 mg
`
`Overall
`
`PALO 0.25 mg
`Vs DOLA i00 mg
`
`PALO 0.75 mg
`vs DOLA 100 mg
`
`PALO 0.25 mg
`vs PALO 0.75 mg
`
`PALO-99-04
`
`Chl square
`
`0.0720-_-% omo
`
`0.0030
`0.00l0
`0-0030
`
`_
`
`
`
`
`
`Parameters
`Complete Control (CC)
`
`24-48 hr
`48-72 hr
`
`72 96 hr
`
`
` o-mr
`
`m_ 0-2050
`mn—— 0-0040
`
`PeUa:e
`
`__
`0.0290
`‘V "
`0.0470
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Number of Emetlc Eplsodes (EE)
`o-zm
`
`72 96 hr
`96 I20 hr
`
`0-120 hr
`Time to First as
`Severity of Nausea
`
`KW/Wilcoxon
`KW/Wilcoxon
`
`KW/Wilcoxon
`Log Rank
`
`0.004
`0.559I
`0.9l l6
`
`POa.A
`
`0.0537m
`‘ 0.0001
`0.0004
`0.0004mm 0.0789
`0.0306
`
`0.0083
`
`xwwncoxon
`
`om _ own
`0-0”
`\l
`'
`'
`0.0488
`0.00:4
`-
`O OO0b
`
`
`0-0'57
`
`m— 0.0253
`PALO = Palonoselron; ONDA = Ondansctron; DOLA = Dolasctron; EE = Emclic Episode; KW = Kruskal-Wallis.
`Le end
`'
`'
`
`
`
`
`
`
`means statistically significant difference (i.e.. p < 0.05).
`means difference in favor of PALO 0.25 mg.
`" means difference in favor of PALO 0.75 mg.
`
`“-0026
`0'69"
`
`Page 47
`
`

`

`
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`TABLE 25 :Statistical Analysis Results of Secondary Efficacy Parameters for Phase 3 Moderately Emetogenic ClNV Pivotal
`Studies (PALO-99-03 and PALO-99-04) (continued)
`
`Stntlstlcal Test
`Parameters
`Need of Rescue Medleallon
`
`Overall
`
`PALO 0.25 mg
`vs 0nda 32 mt,
`
`PALO 0.75 mg
`vs Onda 32 mg
`
`PALO 0.25 mg
`vs PALO 0.75 mg
`
`Overall
`
`PALO 0.25 mg
`vs Dola 100 mg
`
`PALO 0.75 mg
`vs Dola I00 mg
`
`PALO 0.25 mg
`vs PALO 0.75 mg
`
`PA LO-99-04
`
`—-———_———
`——--___—_—
`———-—-_—_——
`——-—___ _—
`__—____ _—
`——_——__ _—
`———__— 0.200 _—
`Subject Global Satlsfactlon
`mm...
`0.4754
`0.0494
`0.0538
`0.0078
`0.0592
`
`20-00-
`
`——mal
`
`00-0200-
`
`_—
`_—
`0.2628
`0.!393
`_—
`
`0.02l7
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`O .l779
`O
`.5042
`.2I59
`
`0.0307
`
`
`
`0.0159
`
`0.0393
`
`. " '
`
`Function Ltvlng Index-Emmi:
`
`0.0472
`
`0.0130
`
`0.l298
`
`0.3687
`
`PALO = Palonosclron; ONDA = Ondansclron; DOLA = Dolasctron; EE = Emclic Episode; KW = Kruskal-Wallis.
`Le__end
`
`139's!
`means statistically significant difference (i.e.. p < 0.05).
`means difference in favor of PALO 0.25 mg.
`
`hm? mcans_diffcrcnce in favor of PALO 0.75 mg.
`
`(Reference: Table 3.83:6, page 133, Volume 1)
`
`Page 48
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`

`
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`b.) Highly Emetogenic Chemotherapy (Study PALO-99-05)
`For Study PALO-99—05, 76 centers located in Europe, and North America enrolled 680
`patients. Of these 67] Were randomized to one of the three treatment groups.
`There were comparable number of male and female subjects enrolled. This study
`contained slightly more chemotherapy-naive subjects than non-naive subjects. Standard of care
`in patients receiving highly emetogenjc chemotherapy entails the use of corticosteroids. Thus,
`twice as many subjects with concomitant corticosteroid use than without corticosteroid use
`participated in this trial. A large majority of subjects received highly emetogenic doses of
`cisplatin.
`As with the studies related to moderately emetogenic chemotherapy, the primary efficacy
`endpoint was complete response (defined as no emetic episode and no rescue medication) during
`the first 24 hours after administration ofchemotherapy. The following table displays the
`complete response rates for the first 24 hours after chemotherapy.
`
`Complete Response Rates During the First 24 Hours After
`TABLE 26:
`Chemotherapy: Highly Emetogenic CINV Study PALO-99-05
`(ITT Cohort; N = 667)
`
`
`
`Treatment Group
`
`
`Palonosetron 0.25 mg
`
`132 (59. 2)
`
`[52.4%, 65.6%]
`
`[58.8%, 71.6%]
`
`97.5% CI for the Difference in CR Rates
`
`During the First 24 Hours Between
`Palonosetron and 0ndansetron
`
`n (%)
`
`95% CI
`
`
`
`
`Complete Response (CR)
`During the First 24 Hours
`
`
`
`
`Palonosetron
`Palonosetron
`
`0.25 mg Minus
`0.75 mg Minus
`
`
`0ndansetron
`0ndansetron
`
`
`
`
`223
`
`
`
`146 (65.5)
`Palonosetron 0.75 mg
`
`
`
`
`
`
`
`[50.2%, 63.6%]
`126 (57.0)
`Ondansetron 32 mg
`[-8.8%, 13.1%]
`[-2.3%, 19.2%]
`CR = Complete Response (defined as no emetic episode and no rescue medication) during the first 24 hours after
`chemotherapy.
`N = Number of subjects in treatment group.
`n (%)= Number and percentage ofsubjects with CR.
`C1= Confidence interval.
`Source. Final Study Report PALO-99-05; Table 7.1 1.1-a and Table 7 1 l l —b.
`(Reference: Table 3. 8. 3: 7, page 137, Volume 1)
`
`Medical Officer Comment: The palonosetron 0. 75 mg group had the highest proportion of
`subjects (65.5%) with a complete response during thefirst 24 hours after chemotherapy. The
`.palonosetron 0.25 mg group had a complete response rate of59.2% and the complete response
`rate was slightly lessfor the ondansetron group (5 7.0%).
`The lower limit of the 97.5% CIfor the diflerence ofcomplete response rates during the
`first 24 hours after chemotherapy was above the —15%pre-set threshold indicating non-
`inferiority of both palonosetron doses to ondansetron 32 mg in prevention ofhighly emetogenic
`acute CIN V. The comparator drug was an FDA approved medicationfor the prevention of
`highly emetogenic CINV.
`
`Page 49
`
`

`

`
`
`CLINICAL REVIEW
`
`- Clinical Review Section
`
`Complete response, by day (0 to 24, 24 to 48, 48 to 72, 72 to 96, and 96 to 120 hours) and
`cumulative time periods (0 to 48, 0 to 72, 0 to 96, O to 120, and 24 to 120 hours) is shown for
`Study PALO-99-05 in the following table.
`
`Page 50
`
`

`

`
`
`
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`Subjects with a Complete Response After Chemotherapy, By Day and Cumulative Time Periods:
`TABLE 27:
`PALO-99-05 (ITT Cohort; N = 667)
`
`- Complete Response at 24 Hours
`97.5% Confidence Intervals
`
`Number and Percentage (%) 0‘ Subjects Wi‘h
`Difference in Complete Response Rates,
`
`
`
`
`Time Period
`(Hours)
`Acute'
`
`Palonosetron 0.25 mg
`(N = 223)
`
`Palonosetron 0.75 mg
`(N = 223)
`
`Ondansetron 32 mg
`(N = 221)
`
`0—24
`
`in (59.2)
`
`
`
`
`
`
`
`
`
`
`127
`137
`149
`165
`
`(57.0)
`(61.4)
`(66.8)
`(74.0)
`
`126
`
`(57.0)
`
`(65.5)
`I46
`
`
`
`129
`(57.8)
`
`
`
`139
`(62.3)
`
`
`164
`(73.5)
`170
`(76.2)
`
`Palonosetron 0.75 mg
`Palonosetron 0.25 mg
`I
`‘ Minus Ondansetron 32 mg Minus Ondansetrori 32 mg
`1
`
`
`
`.
`
`
`
`.
`
`'
`
`[-8.8%, i3.l%]
`
`[-3.4%,18.7%]
`[-2.9%,19.0%]
`[—8.0%,13.i%]
`[-6.6%,l3.4%]
`
`
`[23%, 19.2%]
`
`[-2.5%,19.5%]-
`
`
`[-2.0%,19.9%]
`
`
`[-1.0%,19.5%]
`
`
`[42%,15.5%]
`
`
`
`
`0—24
`0—48
`
`
`
`
`
`
`'
`
`[-2.3%,19.2%]
`(65.5)
`[-8.8%,l3.i%]
`126
`146
`(59.2)
`
`
`[-3.3%,18.7%]
`(49.3)
`[4.2%,17.8%]
`92
`‘
`‘
`110
`(48.4)
`
`
`
`[-2.2%,19.5%]
`(44.4)
`[-2.6%,l9.0%]
`79
`99
`(43.9)
`
`
`
`
`
`
`
`[-2.1%,19.4%]
`(42.6)
`75
`(33.9)
`[-3.0%,i8.5%]
`95
`(41.7)
`
`
`
`
`
`
`
`
`
`(42.2)
`[-l.6%,i9.8%]
`73
`(33.0)
`[-2.9%,i8.5%]
`94
`(40.8)
`
`
`
`
`
`
`
`[-1.9%,20.0%]
`“(433—)“_ “.717"._(48T0‘)"w"
`86
`(38.9)
`[46%,17.3%]
`
`
`
`
`
`
`
`
`
`(57.0)
`(41.6)
`
`132
`108
`98
`93
`91
`101
`
`' = Primary efficacy endpoint.
`" = Secondary endpoint.
`Source: Final Study Repon PALO-99-05; Table 7.l.2.|-a, Table 7.i.2.l-b. Table 7.l.2.l-d, and Table 7.l.2.l-e.
`(Reference: Table 3.83:8, page [39, Volume I)
`
`Page 51
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`

`

`
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`Medical Officer Comments: For all cumulative time periods following thefirst 24 hours, the
`proportion ofsubjects with complete response in the two palonosetron doses were similar. There
`were no statistically significant diflerences between the complete response rate in the
`palonosetron groups cbmpared to the ondansetron group. It is significant to note that
`ondansetron is not indicatedfor delayed treatment ofhighly emetogenic CINV. The applicant
`has demonstrated non-inferiority to ondansetron when using the —15% preset threshold.
`However, the comparator has not been proven to eflicacious in this setting and must be assumed
`to have the same eflicacy as placebo. Thus, to show efficacy ofpalonosetron for delayed
`prevention ofhighly emetogenic CIN V, the applicant should show superiority to ondansetron.
`For all the time periods the lower limitfor the 97.5% confidence intervals for the difference in
`complete response rates was below zero. Palonosetron did not show eflicacyfor delayed
`prevention of highly emetogenic ClN V.
`
`The following table displays other secondary efficacy parameters for PALO-99-05, including
`complete control, number of emetic episodes, time to first emetic episode, severity of nausea,
`need of rescue medication, time to rescue medication, global satisfaction and quality of life
`(Function Living Index-Emesis; FLIE). Statistically significant differences are in bold type.
`
`Page 52
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`

`

`
`
`Clinical Review, Section
`
`Statistical Analysis Results of Secondary Efficacy Parameters for
`TABLE 28:
`Phase 3 Highly Emetogenic CINV Pivotal Study (PALO-99405)
`
`'
`
`Parameter
`Complete Control (CC)
`
`Statistical
`Test
`
`Overall
`
`PALO 0.25 mg
`vs 0NDA 32 mg
`
`PALO 0.75 mg
`vs 0NDA 32 mg
`
`PALO 0.25 mg
`vs PALO 0.75 mg
`
`omo ——_
`
`2mm —_———
`
`
`
`=——_—_
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` means statistically significant difference (i.e., p < 0.05).
`
`——_—
`__——
`—_——
`————
`cm-squm __
`
`om
`
`0.0222
`0.2494
`0.1555
`0.1404
`0.5516
`
`KW/Wilcoxon
`KW/Wilcoxon
`KW/Wilcoxon
`KW/Wilcoxon
`KW/Wilcoxon
`KW/Wilcoxon
`E
`
`Log-R
`
`0.1599
`
`:1...- ".2 LL"
`
`._
`
`0.0842
`0.0228
`
`Severity of Nausea
`
`KW/Wilcoxon
`KW/Wilcoxon
`anvucoxon
`KW/Wilcoxon
`72-96 hr
`KW/Wilcoxon
`96-l 20 hr
`Need of Rescue Medication
`
`0.2261
`0.6187
`
`0.218l
`0.2432
`
`0.3360
`
`0.4450
`
`0-120 hr
`
`Chi-square
`0.3310
`
`PALO = Palonosetron; 0NDA = Ondansetron; KW = Kmskal-Wallis; EE = Emetic Episode
`Le - end
`
`means difference in favor of PALO 0.25 mg.
`'_. means difference in favor of PALO 0.75 mg.
`
`'
`
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`

`
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`Statistical Analysis Results of Secondary Efficacy Parameters for
`TABLE 28:
`Phase 3 Highly Emetogenic ClNV Pivotal Study (PALO-99-05) (continued)
`
`Parameter
`
`Test
`
`Overall
`
`vs ONDA 32 mg
`
`vs ONDA 32 mg
`
`vs PALO 0.75 mg
`
`_———_—
`_———_—
`————_—
`——_—
`xwmcoxon _—
`
` Function Living lndex-Emesis
`
`FLlE #1 Nausea
`KW/Wilcoxon
`
`
`
`—-——-
`
`
`
`
`
`
`O 6597
`FLlE #l Vomiting KW/Wilcoxon
`0.829: _—
`mama].
`anvncoxon
`0.9636 _—
`FLlE #2 Nausea
`KW/Wilcoxon
`
`
`0 7070
`LlE #2 Vomiting KW/Wilcoxon
`. _—
`F
`
`
`0.9415
`FLlE #2 Total
`KW/Wilcoxon
`
`PALO = Palonosetron; ONDA = Ondansetron; KW = Knrskal-Wallis.
`Le . end
`
`
`
`
`
`
`——
`
`0.7920
`
`
`
`
`
`
` means statistically significant difference (i.e., p < 0.05).
`
`means difference in favor of PALO 0.25 mg.
`
`— means difference in favor of PALO 0.75 mg.
`_
`(Reference: Table 3.83:9, page 144, Volume 1)
`Medical Officer Comments: The only secondary endpoint with a statistical significant di erence
`in favor ofpalonosetron 0.25 mg was the time to first emetic episode. There was a statistical
`dijference infavor ofthe 0. 75 mg dose ofpalonosetronfor complete control on day 4, number of
`emetic episodes and time to first emetic episode.
`
`Supportive Studv PALO-OO-Ol
`The applicant submitted PALO-OO-Ol as a supportive trial for highly emetogenic ClNV.
`It consisted ofa re-analysis ofefficacy data from Study 2330, a Phase 2 dose-response study that
`:dld not employ a comparator agent. A literature-based meta-analysis (PALO-Ol -23) was
`performed to provide historical placebo control data since the use of placebo is not ethically
`acceptable in the CINV subject population. The study design was similar to the pivotal trials in
`that it was a randomized, multi-center double-blind trial. The endpoints were identical to the
`pivotal trial with the exception being the omission of a' quality of life questionnaire and the time
`assessed was 168 hours versus 120 hours of the pivotal trials. In the original protocol subjects
`received mod the following doses 0.3, l, 3, 10 and 30 pig/kg. In the re-analysis these weight
`based cohorts were converted to fixed milligram doses in the following manners. Subjects were
`assigned to the following groups based on the original dose of medication they received.
`0 < 0.25 mg group included any dose less than 0.1 mg
`0
`0.25 mg group included 0.1 mg to less than 0.5 mg
`
`0
`C
`
`0.75 mg group included 0.5 mg to less than 1.3735 mg
`>O.75 mg group included 1.375 mg or greater
`
`Page 54
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`

`

`
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`The following table shows the primary efficacy variable complete response rate during the first
`24 hours.
`
`Complete Response Rates During the First 24 Hours After
`TABLE 29:
`Chemotherapy: Highly Emetogenic CINV Efficacy Analysis PALO-OO-Ol
`(Helsinn Data Set, ITT Cohort; N = 154)
`
`- “m“ -IIEEB:I—I.m-m
`
`N
`
`70
`
`30
`
`27
`
`24
`
`27
`
`46
`
`CR, n (%)
`
`6 (9%)
`
`9 (30%)
`
`12 (44%)
`
`ll (46%)
`
`15 (56%)
`
`23 (50%)
`
`95%C1
`
`99%CI
`
`[3%;18%]
`
`[15%;49%]
`
`[25%;65%]
`
`[26%;67%]
`
`[35%;75%]
`
`[35%;65%]
`
`[2%;21%]
`
`[11%;55%]
`
`[21%;7o%]
`
`[21%;73%]
`
`[30%;79%]
`
`[31%;69%] p-value
`
`0.012
`—
`N = Number of subjecLs in treatment group.
`CR = Complete Response (defined as no emetic episode and no rescue medication).
`n (%) = Number and percentage of subjects with CR.
`C1 = Confidence Interval.
`Note: p-value = Treatment efl'ect versus historical placebo using Fisher’s exact test.
`Source: Final Study Report PALO-OO-Ol; Table 21.
`
`< 0.001
`
`< 0.001
`
`< 0.001
`
`< 0.001
`
`Medical Officer Comments: The palonosetron doses of 0.25 mg to 6 mg were significantly
`superior to the historical placebo group (p < 0.01). Complete response rates rangedfrom 44%
`to 56%for the 0.25 mg to 6 mgfixed-dose groups, compared with a modeled historical placebo
`complete response rate of 9%.
`
`The proportion of subjects who had complete response following highly emetogenic
`chemotherapy for cumulative time periods up to seven days is displayed by fixed dose group in
`the following table.
`
`A“), "'
`We mat
`0N mile at
`
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`

`
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`Complete Control After Chemotherapy: Highly Emetogenic CINV
`TABLE 30:
`Efficacy Analysis PALO-OO-Ol (Helsinn Data Set, ITT Cohort; N = 154)
`
`Palonosetron Fixed Doses
`
`Number and Percentage (%) of Subjects with Complete Control (CC)
`
`
`
`CC = Complete Control (defined as no emetic episode and no rescue medication, experiencing no more than mild
`nausea).
`Source: Final Study Report PALO-OO-Ol; Table 32.
`Medical Officer Comments: The results from this study supported the pivotal trial PALO—99-05,
`that 0.25 mg ofpalonosetroh is efficacious for prevention of CINV in the acute settingfor highly
`emetogenic chemotherapy. The datafiom the supportive trial does not substantiate the claim that
`palonosetron is eflicaciousfor delayedprevention of CINVfor highly emetogenic chemotherapy.
`
`APPEARS iillS WAY
`
`0N ORlGll‘ML
`
`Page 56
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`

` CLINICAL REVIEW
`
`Clinical Review Section
`
`D.
`
`Efficacy Conclusions
`Moderately emetogenic chemotherapy
`The applicant has demonstrated the efficacy of 0.25 mg palonosetron for the prevention of
`moderately emetogenic CINV. This assessment of efficacy is based on two adequate and well
`controlled pivotal Phase 3 efficacy trials, PALO—99-03 and PALO-99-O4, that used standard,
`accepted efficacy and safety endpoints, and FDA-approved active comparators. The primary
`efficacy parameter was complete response within the first 24 hours after chemotherapy that was
`has been used as the basis for approval of other medications for this indication. The results
`demonstrated the non-inferiority of both palonosetron 0.25 mg and 0.75 mg when compared to
`ondansetron and dolasetron. The lower limit of the 97.5% confidence interval for the difference
`
`in complete response rates between the ondansetron and the palonosetron groups during the first
`24 hours after chemotherapy was above the preset 15% delta. These trials also demonstrated that
`palonosetron 0.25 mg was efficacious for delayed prevention (24-120 hours) of moderately
`emetogenic CINV.
`Highly emetogenic chemotherapy
`The applicant has demonstrated the efficacy of 0.25 mg palonosetron for the prevention of highly
`emetogenic CINV. This assessment of efficacy is based on the adequate and well controlled
`pivotal Phase 3 efficacy trial PALO-99-05 and PALO-OO-Ol( a Phase 2 supportive trial). PALO-
`99-05 used standard, accepted efficacy and safety endpoints, and FDA-approved active
`comparators. The trial design and endpoints were identical to PALO-99-03. The results
`demonstrated the non-inferiority of both palonosetron 0.25 mg and 0.75 mg when compared to
`ondansetron. Again, the lower limit of the 97.5% confidence interval for the difference in
`complete response rates between the ondansetron and the palonosetron groups during the first 24
`hours after chemotherapy was above the preset 15% delta. However, these trials did not establish
`that palonosetron 0.25 mg was efficacious for delayed prevention (24-120 hours) of highly
`emetogenic CINV. While the results did show non-inferiority to the comparator arms, the
`comparator drug is not indicated for delayed prevention of CINV. Thus, in order to show
`efficacy the study drug should demonstrate superiority to the comparator drug. It did not do so.
`There was no statistically significant difference between palonosetron and ondansetron for
`delayed prevention of highly emetogenic CINV. The evidence the applicant has presented does
`not substantiate an efficacy claim for this indication.
`
`VII.
`
`Integrated Review of Safety
`A.
`Brief Statement of Conclusions
`_
`The clinical Integrated Summary of Safety (188) of this NDA includes all safety data
`collected in 3137 unique subjects enrolled in the 18 palonosetron clinical trials of whom 2360
`received palonosetron. Review of this data demonstrates that palonosetron when given as single
`dose prior to chemotherapy was well tolerated. A wide dose range was studied (less than 0.25 mg
`'to approximately 6 mg). No deaths occurred that were attributable to the study drug. An
`extensive review of cardiac safety was conducted which included analysis of ECG (performed in
`2172 subjects) and Holter tracings (143 subjects) using high-resolution methods and a
`' centralized review by a blinded cardiologist. No dose response on QTc interval was observed.
`The cardiac safety profile for palonosetron is similar to that of other drugs in this class. No signal
`for adverse effects of the study drug on laboratory or vital signs was detected.
`
`Page 57
`
`

`

`
`
`Clinical Review Section
`
`The most common adverse reactions seen with palonosetron (2 2%) were constipation and
`headache. Incidences of these reactions were similar across all palonosetron dose groups and the
`active comparator 5-HT; receptor antagonists, ondansetron and dolasetron. All other adverse
`reactions were seen at incidences equal to or less than 1%. Nearly all episodes of constipation
`were self-limiting and not severe. However, two subjects who took palonosetron in Phase 2 trials
`suffered from constipation that required treatment in a hospital. The current package insert for
`another already approved 5—HT; antagonists ondansetron states that constipation occurred in
`1 1% of chemotherapy patients receiving multiday ondansetron. The package insert for
`dolasetron reports a 3.2% incidence of constipation in chemotherapy patients.
`C.
`Description of Patient Exposure
`This Integrated Review of Safety is comprised of data from 16 studies with 3125 subjects
`in the palonosetron clinical development program. It consists single-dose administration of
`palonosetron by the intravenous and oral. routes in healthy volunteers, special populations, and
`PONV and CINV patients. The 16 studies included nine controlled studies (active or placebo)
`and seven uncontrolled studies (no comparator). A total of 2348 palbnosetron-treated subjects
`were in these 16 studies: 198 in Phase 1; 937 in Phase 2; and 1213 in Phase 3 studies.
`The following table summarizes the number of subjects exposed to palonosetron and
`comparators in the 16 clinical trials in the Integrated Safety Database
`
`Enumeration of Subjects Exposed to Palonosetron (All Doses)
`TABLE 31:
`and Comparators in Various Analysis Populations in the Integrated Summary
`of Safety
`
`
`
`Palonosetron (all doses)
`IV
`Oral
`Total
`
`Active Comparators
`Ondansetron
`Dolasetron
`
`Placebo
`
`Total
`
`No. subjects
`
`Allt 'als
`n
`
`on
`M)
`
`1838
`(100)
`
`N
`M)
`
`510
`(100)
`
`on
`(/o)
`
`2348
`(100)
`
`n
`(%)
`
`410
`(100)
`
`n
`(%)
`
`194
`(100)
`
`n
`(%)
`
`173
`(100)
`
`on
`U0)
`
`3125
`(100)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Ph
`
`3t'al
`" s
`as“
`Phase 2/3
`
`Pivotals'
`Phase 2/3
`
`trials
`
`1213
`(66.0)
`1374
`
`(74.8)
`1693
`
`(92.1)
`
`b
`
`480
`
`1213
`(51.7)
`1374
`
`(58.5)
`2150
`
`(91.6)
`
`937
`
`457
`
`(89.6)
`
`457
`
`410
`(100)
`410 .
`
`(100)
`410
`
`(100)
`
`-194
`(100)
`194
`
`(100)
`194
`
`(100) -
`
`1817
`(58.1)
`1978
`
`(63.3)
`2881
`
`(92.2)
`
`1064
`
`127
`
`(73.4)
`
`127
`
`145
`
`'
`
`53
`
`198
`
`46
`
`244
`
`.
`
`.
`
`' includes studies PALO-99-03, PALO-99-04, PALO-99-05 and 2330.
`b Study 2330 is included in Phase 2 trials and Phase 2/3 Pivotal trials.
`(Reference: Volume 1, Table 3.8.4:], page 165).
`
`2348 subjects in the Integrated Safety Database received palonosetron while 410, 194,
`and 173 received ondansetron, dolasetron, and placebo, respectively. A total of 1838 (78.3 %) of
`
`Page 58
`
`

`

`
`
`Clinical Review Section
`
`subjects received IV palonosetron while 510 (21.7 %) received the oral formulation.
`The following table displays the exposure in the CINV patients.
`
`Exposure in CINV in Integrated Safety Database
`TABLE 32:.
`
`
`Phase3
`
`
`
`Phase 2/3 pivotal'
`
`I,
`
`IV
`
`IV
`
`IV
`
`1213
`
`163
`
`
`
`1545
`Overall exposure in CINV
`‘ Includes PALO-99-O3, PALO-99-04, PALO-99-OS and 2330.
`b Study 2330 and Study 2120 for IV and 2332 for P0.
`(Reference Table 3.84:2, Volume 1, page 165)
`
`
`
`
`
`
`1817
`
`1978
`
`332
`
`2149
`
`Two-thousand one hundred and fifty subjects were exposed to palonosetron in the Integrated
`Phase 2/3 trials. Seventy-two percent were treated for CINV, including 763 subjects in
`moderately emetogenic studies (PALO—99—03, PALO-99-O4) and 782 in highly emetogenjc
`studies (PALO-99-05, 2330, 2332, and 2120). The remaining 28% were enrolled in post-
`operative nausea and vomiting (PONV) trials (2500 and 2502).
`The applicant proposes a dose of 0.25 mg IV in this NDA. In the Integrated Review of
`safety database most subjects received either 0.25 mg or 0.75 mg doses, (38% and 33.8 %,
`respectively). The following table summarizes exposure in clinical trials according to
`palonosetron dose level
`
`TABLE 33:
`Dose
`
`Exposure in the Integrated Safety Database of Palonosetron by
`
`Numberof
`
`Palonosetron (mg)
`
`Subjects
`
`<o.25
`
`0.25
`
`0.75
`
`>0.7s
`
`Total
`
`Comparators
`Dola
`100 mg
`
`I Onda
`32 mg
`
`
`
`"an
`278
`
`_---n
`Tm" Phase
`329
`817
`726
`278
`2/3
`
`Total all
`integrated
`trials
`
`341
`
`347
`
`2348
`
`2150
`
`-
`
`Onda = Ondanseu'on; Dola = Dolfietmn.
`(Reference: Table 3.8.4.3, page 166, Volume 1)
`
`A total of 2150 subjects were exposed to palonosetron in the Phase 2/3 trials.'0f these, 1693
`(78.7%) received IV doses (in studies PALO-99-03, PALO-99-04, PALO-99-05, 2330, 2120,
`and 2500) and 457 (21.3%) received oral doses (in studies 2332 and 2502).
`The mean age of palonosetron-treated subjects was 49.7 years. Four-hundred and
`
`seventeen subjects (18%) subjects were 2 65 years. More females (64%) than males (36%) were
`
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`

`

` CLINICAL REVIEW
`
`Clinical Review Section
`
`exposed to palonosetron. The majority of subjects were Caucasian, with 785 (33%) subjects
`representing non-Caucasian races. Fifty-six percent of the subjects were from North America.
`C.
`Methods and Specific Findings of Safety Review
`The applicant did not include two trials in the Integrated Safety Database that
`investigated repeated dosing of palonosetron. These were PALO-99—O6, a repeat-cycle, open-
`label, extension trial involved 895 patients from the Phase 3 pivotal trials and PALO-99—34
`comprised 12 healthy subjects. They did, however, include deaths and serious adverse events
`from these studies with the other data.
`1. Deaths
`
`In
`Of subjects who received palonosetron in all Phase 1, 2 and 3 trials, 31 (1.3%) died.
`the studies with comparator arms, four (0.7 %) subjects who had received ondansetron died and
`no deaths occurred among dolasetron or placebo subjects. Fifleen of the deaths in the
`palonosetron group occurred during the Phase 2 studies including two deaths in subjects
`receiving palonosetron for PONV. The remaining 16 deaths occurred during Phase 3 studies in
`subjects receiving moderately or highly emetogenic chemotherapy for cancer.
`Twenty-three subjects who died received intravenous formulation ofpalonosetron and the
`remaining 8 subjects received the oral formulation. The dose was > 0.75 mg in six deaths, 0.75
`mg in 14 deaths, 0.25 mg in eight deaths and < 0.25 mg in three deaths. Sixteen ofthe 31 deaths
`occurred within 2 weeks of receiving the dose ofpalonosetron, nine deaths occurred more than 2
`weeks after receiving the palonosetron and the timing was unknown for six of the deaths. Below
`are listed a summary of the case reports for all subjects who died within two weeks of receiving
`palonosetron or for those in which the time of death was uncertain.
`Study PALO-99-O4
`
`0
`
`0
`
`Subject #2228 was a 68 year old female with Non-Hodgkins lymphoma who died of
`septic shock. She received 0.75 mg ofpalonosetron IV. The death was thought to be
`unlikely related to the study drug by the investigator and the sponsor.
`Subject #4007 was a 71 year old male who suffered from pancreatic cancer. He
`experienced gastrointestinal bleeding and died 2 days after receiving 0.75 mg
`palonosetron IV. The death was thought to be unlikely related to the study drug by the
`investigator and the sponsor.
`Subject #4343 was a 75 year old female who suffered from lung cancer. She was
`hospitalized for pleural effusion secondary to her cancer 3 days after receiving 0.25
`mg palonosetron IV. She died of urosepsis tWo weeks after receiving the
`palonosetron. The death was assessed to be unrelate