CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-372
`
`Medical Review(s)
`
`

`

`Addendum: Medical Officer Review of
`
`NDA 21-372
`
`Palonosetron
`
`Date Submitted:
`Date Received:
`Date Completed:
`
`10 July 2003
`11 July2003
`11 July 2003
`
`Applicant:
`
`Helsin Healthcare SA
`Via Pian Scairolo
`
`'
`
`6912 Pazzallo (Lugano) - Switzerland
`
`Drug:
`
`Generic Name -
`Molecular Weight -
`Molecular formula -
`Molecular structure —
`
`Palonosetron
`332.87
`C19H24N20.HC1
`
`Drug Class:
`
`S-HT3 antagonists
`
`Formulation: 5-ml vial of palonosetron injection contains 0.25 mg palonosetron base as
`hydrochloride, 207:5 mg mannitol, disodium edetate and citrate buffer in
`water
`
`Route of Administration:
`
`Intravenous-
`
`

`

`I.
`
`Introduction
`
`Helsinn Healthcare submitted a New Drug Application (NDA) for the new
`molecular entity palonosetron on September 26, 2002. The Medical Officer’s Clinical
`Review for this NDA was completed June 6, 2003. Subsequently, it was noted that some
`of the data submitted by the applicant is contradictory and possibly erroneous. This data
`was included in, the initial clinical review unaltered. The purpose of this document is to
`discuss the discrepancies in applicant submission and review the implications for the
`NDA as a whole.
`
`11.
`
`Review of Data
`
`The applicant’s submission consisted of 381 volumes of written material. In two
`places (on page 220 of Volume 1, and page 99 of Volume 96) the following table can be
`found.
`
`Number and Percentage of Patients with Post Dose* Changes in QTc
`Table 11:]
`by Bazett or Fridericia Corrections
`
`Palonosetron
`
`Palonosetron
`
`Ondansetron
`
`Dolasetron
`
`0.25 mg
`(N=605)
`Nt = 594
`
`%
`
`n
`
`5
`
`0.75 mg
`(N=610)
`Nt = 601
`
`%
`
`n
`
`54
`
`3
`
`QTcB
`30 to 60 msec
`
`QTcB
`> 60 msec
`
`QTcB
`> 500 msec
`
`32 mg
`(N=410)
`Nt = 404
`
`%
`
`n
`
`7
`
`100 mg
`(N=194)
`Nt = 192
`
`n
`
`13
`
`2
`
`1
`
`N= Number of patients in specific group.
`Nt= Total Number of patients with ECG parameter.
`n = Number of patients with changes.
`% = Percentage ofpatients with changes.
`QTcF '—' QT interval conected by Fridericia formula
`QTcB = QT interval corrected by Bazett formula.
`msec = Milliseconds
`
`Source: Expert Report PALO—02-04; Appendix A.
`‘ - post dose ECG’s were obtained at 24 hours and 6-8 days afler drug administration. A subset of patients had a ECG
`performed 15 minutes after drug administration. The data for this table was derived from the ECG that had the worst
`value for each patient regardless of the time of the recording.
`The narrative accompanying this table goes on to state “no subject [in the
`palonosetron arms] had > 60 msec change from baseline.” The table with the
`accompanying statement was incorporated in the Medical Officer’s Clinical Review as
`Table 37 on page 77. Subsequently, it was noted that there were inconsistencies in this
`data. Firstly, the numbers and percentages do not correspond to each other. According to
`
`

`

`this table, five subjects of 594 in the palonosetron 0.25 mg dose group had a change in
`QTcB > 60 msec. Yet, the table displays corresponding percentage as “0” rather than the
`correct percentage of 0.84. This happens several other times in this table for all the
`treatment arms. These instances where a “0" has inappropriately been listed as a
`percentage are shov’vn in boldface type. In addition, the accompanying statement that no
`subjects had a QTc > 60 msec directly contradicts the information provided in the table.
`On July 9, 2003 a telephone conversation was held between the medical officer
`from the Agency and Helsinn's representative Dr. Craig Lehmann to discuss these
`discrepancies. Consequently, Dr. Lehman spoke with Dr.
`~——-—_—
`_
`the cardiologist
`who authored this portion of the NDA submission The applicant provided a replyin the
`form of a phone message and written fax response on July 10, 2003. In the response, Dr.
`Lehmann verifies that the numbers listedin the “n” column of the table are correct.
`
`However, the percentages were not correct due to a rounding error. On review, it seems
`all the percentages for all the treatment arms were rounded down. The corrected version
`of the table is shown below.
`
`Revised Table with Correct Percentages (rounded to nearest tenth)
`
`Ondansetron
`Dolasetron
` Palonosetron Palonosetron
`
`
`0.25 mg
`0.75 mg
`32 mg
`100 mg
`
`
`(N=605)
`(N= 610)
`(N=410)
`(N=l94)
`
`
`Nt = 594
`Nt= 601
`Nt = 404
`Nt = I92
`
`
`11% n
`n
`°/o
`%
`n
`%
`
`
`
`
`
`
`
`QTcB -
`30 to 60 msec
`
`Qch
`> 60 msec
`
`QTcB
`> 500 msec
`
`QTcF
`30 to 60 msec
`
`QTcF
`> 60 msec
`
`QTcF
`> 500 msec
`
`5
`
`27
`
`5
`
`0.2
`
`4.5
`
`54
`
`3
`
`3|
`
`2
`
`0.5
`
`7
`
`32
`
`5.2
`
`0.3
`
`1.7
`
`0.2
`
`7.9
`
`13
`
`2
`
`'
`
`6.7
`
`0.5
`
`5.7
`
`0.5
`
`0.5
`
`
`
`
`
`
`
`
`N= Number ofpatients in specific group.
`Nt= Total Number of patients with ECG parameter.
`n = Number ofpatients with changes.
`% = Percentage ofpatients with changes.
`QTcF = QT interval corrected by Fn'dericia formula
`QTcB = QT interval corrected by Bazett formula.
`msec = Milliseconds
`Source: Expert Report PALO-02—04; Appendix A.
`
`
`The applicant’s response discusses the issues of the contradictory statement as
`follows “Based on discussion today with Dr.
`this statement reflects the zero
`percent incidence values which are incorrect as discussed.” It appears the author referred
`to the erroneous percentage values when he stated that no patients had a change in
`QTc>60 msec. As the table shows 8 subjects in the palonosetron arms had QTcB changes
`> 60 msec and 7 subjects had QTcF changes > 60 msec.
`
`

`

`The initial conclusion of the medical officer’s clinical review in regard to cardiac
`safety was that palonosetron’s effect on QTc was similar to that of other drugs in its
`class These errors are not of a magnitude to alter this conclusion. Furthermore, the errors
`are of a mathematical nature and are present in all the treatment arms. They do not appear
`to be an attempt by the applicant to conceal or alter the side effect profile of this new
`molecular entity
`
`111.
`
`Summary
`
`1. The percentages listed in Table [[Izl entitled “Number and Percentage of
`Patients with PCst Dose Changes in QTc by Bazett or Fridericia Corrections”
`is in error. This table was located on page 220 of Volume 1, and page 99 of
`Volume 96 in the NDA 21-372 submission for palonosetron. The table with
`the incorrect data was also incorporated in the Medical Officer’s Clinical
`Review as Table 37 located on page 77. The corrected table can be found
`above.
`
`The accompanying statement state “no subject had > 60 msec change fi'om
`baseline” is also in error. This statement can be found in the narrative
`
`following the table on page 220 of Volume 1, and page 100 of Volume 96 in
`the NDA 21-372 for palonosetron. This incorrect statement was also
`incorporated into the Medical Officer’s Clinical Review on page 77. The
`correct statement is that 8 subjects in the palonosetron arms had QTcB
`changes > 60 msec and 7 subjects in the palonosetron arms had QTcF changes
`of > 60 msec.
`
`These errors are not of a magnitude to alter the medical officer’s conclusion
`that palonosetron’s effect on QTc is similar to that of other drugs in its class.
`
`The errors appear to be of a mathematical nature, which are present in all the
`treatment arms. They do not appear to be a deliberate attempt by the applicant
`to conceal or alter the side effect profile of this new molecular entity.
`
`APPEARS THIS WAY
`
`0“ ORIGINAL
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Narayan Naif
`7/22/03 02:20:29 PM
`MEDICAL OFFICER
`
`Joyce Korvick
`7/22/03 05:20:33 PM
`MEDICAL OFFICER
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`Detailed Review Of Study PALO-99-04 — A Double Blind Clinical Study To
`Compare Single IV Dose Of Palonosetron, 0.25 Mg or 0.75 Mg And Dolasetron, 100
`mg IV, In Prevention Of Moderately Emetogenic Chemotherapy-Induced Nausea
`And Vomiting
`
`I.
`
`OBJECTIVES
`
`The primary objective of the study PALO-99-04 was to compare the efficacy of
`single IV doses ofpalonosetron O25 mg or O. 75 mg,oto dolasetron 100 mg IVin
`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.
`
`1].
`
`STUDY DESIGN AND METHODOLOGY
`
`This was a double-blind clinical study to compare single IV doses of palonosetron
`0.25 mg or 0.75 mg, and dolasetron 100 mg IV, in the prevention of moderately
`emetogenic chemotherapy-induced nausea and vomiting. The comparator drug
`dolasetron is an FDA approved medication that is indicated for the prevention of
`moderately emetogenic chemotherapy-induced nausea and vomiting. The dose of
`dolasetron is the standard dose used in clinical practice. The table on the following page
`lists the study procedures.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`CLINICAL REVIEW STUDY 99-04
`
`PALONOSETRON
`
`;
`
`,t.,.i
`
`.,,_...
`
`
`
`
`HHHI1,.'_.‘
`
`'
`
`
`
`
`
`:r4'.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`.
`
`EH
`
`_—
`——— x
`———
`——_-
`_--— x
`_——- x
`Patient 5 Diary and was
`filled m frogasngdgagay 1 to Study
`
`X
`
`x
`
`HollerMonitoring" m
`PK ° (Holler Patients) _—
`I_-
`
`H
`
`atients
`8)
`Post study medication administration
`b)
`
`lf Study Day 5 was a holiday or weekend day, patients were contacted the previous/next business day
`If patient was scheduled for a clinic or hospital visit on this day, this information was obtained at that time
`c)
`
`d) Only for those patients who enrolled in the open label protocol (PALO-99-06)
`e) For females of childbearing potential only
`0 After all inclusion/exclusion criteria were met the patient could be randomized to one of three treatment groups
`g) 30 minutes post study mediation administration
`-
`h) At the discretion of the investigator, dexamethasone, 20 mg IV could be given 15 minutes before the start of
`chemotherapy(in the event of a shortage of IV dexamethasone, a single 20 mg oral dose of dexamethasone or a single
`125 mg lV dose of methylpredisolone could be given).
`'
`Limited physical examination only on these days
`i)
`15 minutes post study medication administration in Holter patents only
`j)
`it) See below for efficacy parameters and assessments
`1) Referring to Study Day 1 (0-24 hours)
`m) Referring to Study Days 2-4 (24-96 hours)
`n) Filled in on Study Days 1-5 collected on Study Day 6-8
`0) Patients at selected sites were to have Holter Monitoring from at least 2 hours before to at least 22 hours afler start of
`study medication administration
`Blood sampling for pharmacokinetic analysis
`Blood samlin - for harmacokinetic anal sis should be
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`nerfonned as close as n ssible to Stud Da 6
`
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99—04 '.
`
`(Reference Table 5._5-a , Page 38, volume 135)
`Screening Study Day -7 to 0 (Visit 1)
`Patients signed an informed consent and then had their demographic information
`recorded. The investigator performed an initial history and physical examination.
`Eligibility criteria were examined and the patient underwent laboratory studies. This
`included 12 lead ECG, blood chemistry, complete blood count and urinalysis. A urine
`pregnancy test was done for females of childbearing potential as well. Patients were
`instructed on how to use the diaries to record nausea and episodes of emesis. If patients
`were randomized to get a Holter monitor, this was started 2 hours before the start of the
`study medication administration.
`.
`Study Day 1 (Visit 21
`Study Day 1 was defined as the day the patient received a single dose of a major
`chemotherapeutic agent that was considered the most emetogenic (as classified by
`Hesketh et al., The Oncologist 1999:4zl9l-196). The administration of this agent was not
`to extend greater than 4 hours.
`Each patient was randomized to 1 of 3 treatment groups
`0 Palonosetron 0.25 mg given as a single dose over 30 seconds, 30 minutes prior to
`chemotherapy
`
`o
`
`Palonosetron 0.75 mg given as a single dose over 30 seconds, 30 minutes prior to
`chemotherapy
`_
`
`o Dolasetron 100 mg given as a single dose over 30 seconds, 30 minutes prior to
`chemotherapy
`A randomization list was prepared by the firm "m , in the United States. The
`study was extended into Mexico and a randomization list was prepared by a statistician
`not involved with the applicant using a validated SAS program. Randomization was
`blocked by groups of three.
`It was stratified by gender (male or female), previous
`chemotherapeutic history (naive, non-naive). A dynamic adaptive stratification type of
`randomization method was employed to balance the three treatment groups across these
`criteria. It was then checked if the study site had the supply ofthe selected study drug. 1f
`the kit containing the drug and dose to which the patient was randomized was not
`available then they would be randomly assigned to one of the other treatment arms. 1f the
`study site had only one drug available then the patient was automatically assigned to that
`treatment arm. The investigator called an automated telephone line and received a
`randomization code for the patient. Based on this randomization code, the research
`pharmacists would select the appropriate drug. The pharmacist would then prepare the
`drug for administration in unblinded fashion.
`The pharmacist would deliver the drug to the investigator in a blinded fashion. A
`double dummy technique was utilized because the volume of the two study medications
`was different. Each patient received two injections: one containing the active study drug,
`the other inactive normal saline thus ensuring everyone received the same volume
`infusion regardless of treatment arm. The palonosetron or dolasetron was administered as
`an IV bolus over 30 seconds, 30 minutes prior to the chemotherapy. The patient
`remained in the clinic for a minimum of 3 hours after the administration of the study
`
`drug.
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`After randomization, patients were asked if they wished to wear a Holter monitor.
`Holter monitor assignment was blocked if there was a difference of 10 between treatment
`groups or if 20 Holter patients were already in a treatment group; The plan was to have
`95 patients (16.7%) wear a Holter monitor.
`
`Medical Officer Comments: All study sites should have been provided with ample
`supplies of the study drug and the active control. This would have allowed true
`randomization.
`Ifa site only had one drug available, the patient was automatically
`enrolled in that treatment arm. This does not reflect true randomization. However, this
`only occurred in five patients (2 in each of the palonosetron arms, and l in the
`dolasetron arm). Since this is a small number, it does not invalidate the results. In
`addition, the applicant should have considered sending each site an unlabeled kit
`containing the study drug, or active control medication. This would have allowed the
`research pharmacist to remain blinded, and permitted all personnel at each site to be
`blinded to the treatment.
`
`Study Day 2 (Visit 31
`Patients,retumed 24 hours after the study medication administration to the study site.
`They underwent a repeat physical examination, 12 lead ECG, laboratory evaluation and
`documentation of adverse events. For patients who were selected to have a Holter
`monitor it was removed 22 hours after the start of the study medication.
`Study Day 5 jTelephone contact 1 1
`All patients were contacted by telephone for adverse events and concomitant medication
`recording.
`Study Day 6 to 8 {Visit 41
`Patients underwent a repeat physical examination, 12 lead ECG, laboratory evaluation
`and documentation of adverse events. For patients who were selected to have a Holter
`monitor it was removed 22 hours after the start of the study medication. At this visit the
`5-day patient diary was completed.
`Study Day 15 (Telephone contact 21
`All patients were contacted by telephone, and adverse events and concomitant medication
`were recorded.
`
`III.
`
`ELIGIBILITY CRITERIA
`
`Male or females (females of childbearing potential using reliable contraceptive
`measures and a negative pregnancy test), at least 18-years of age, and who provided
`written informed consent were eligible for enrollment if they met the following inclusion
`criteria:
`
`'0 Chemotherapy naive subjects with histologically or cytologically confirmed
`malignant disease
`'
`o Chemotherapy non-naive subjects with histologically proven diagnosis of cancer
`0 Have a Kamofsky index of 2 50%.
`0
`Scheduled to receive a single dose of at least one of the following agents administered
`on Day 1 of the study: any dose of carboplatin, epirubicin, idarubicin, ifosfamide,
`irinotecan or mitoxantrone; or methotrexate > 250 mg/mz; or cyclophosphamide
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`0
`
`0
`
`<1500 mg/m2 IV; doxorubicin > 25 mg/m2 IV; or cisplatin _<_ 50 mg/m2 IV (to be
`administered over 1-4 hours).3
`lfa subject has a known hepatic, renal or cardiovascular impairment and is scheduled
`to receive the above-mentioned chemotherapeutic agents, he/she may be enrolled in
`this study at the discretion of the investigator.
`Ifa subject experienced no more than mild nausea following any previous
`chemotherapy regimen, he/she could have been enrolled at the discretion of the
`investigator.
`
`. The following are exclusion criteria:
`
`0 Unable to understand or cooperate with study procedure
`0 Received any investigational drug 30 days prior to study entry
`0 Received any drug or were scheduled to receive any drug with anti-emetic efficacy
`within 24 hours of the start of treatment until Day 5 of the study
`0 Enrollment in a previous study with palonosetron
`o
`Seizure disorder requiring anticonvulsant medication unless clinically stable and free
`of seizure activity
`
`0 Experienced any vomiting, retching, or NCI Common Toxicity Criteria grade 2 or 3
`nausea in the 24 hours preceding chemotherapy.
`o Ongoing vomiting from any organic etiology
`0 Experienced nausea (moderate to severe or vomiting following any previous
`chemotherapy. At the discretion of the investigator , a patient who experienced at
`maximum mild nausea following any previous chemotherapy might not be excluded
`from this study)
`
`0
`
`Scheduled to receive any dose of a chemotherapeutic agent with an emetogenicity
`level 5 according to Hesl<eth et al Classification (The Oncologist 1999; 42191-196) or
`were scheduled to receive any chemotherapeutic agent with an emetogenicity level 3
`or higher during Days 2-6
`0 Known contraindication to 5-HT; antagonist
`
`0
`
`Scheduled to receive radiotherapy of the upper abdomen or cranium during Study
`Day 2
`
`Medical Officer Comments: The inclusion criteria are adequate. These doses of
`chemotherapy are considered moderately emetogenic according to the classification by
`Hesketh, et al., The Oncologist 1999. The exclusion criteria are adequate with one
`exception. The protocol excludes patients who hadprevious nausea or vomiting with
`previous chemotherapy. This could introduce bias into the study. Patients who are not
`chemotherapy naive and enter the stuay are subjects who tolerate chemotherapy well
`with respect to emetogenicity. This could make the results appear more favorable in this
`subset ofpatients. However, the agency did agree to these criteria in a Special Protocol
`Assessment dated December 1999. The results demonstrated that naive subjects had a
`better response than non-naive.
`
`IV.
`
`STATISTICAL ANALYSIS
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`PALO-99-04 was an active comparator, non-inferiority analysis that employed a
`15% delta. The primary efficacy parameter in these trials was the proportion of subjects
`considered to have achieved a complete response (CR) during the first 24 hours after
`administration of chemotherapy. CR is defined as no emesis and no rescue medication
`during the first 24 hours after chemotherapy.
`The lower bound of 97.5% CI for the difference (palonosetron minus active comparator)
`between the proportion of subjects with a complete response during the first 24 hours
`after administration of chemotherapy was calculated and compared to the pre-set
`threshold (-15% difference) to demonstrate non-inferiority. To demonstrate that the
`two palonosetron doses were equal with respect to CR (0—24 hours), the bounds of the
`two-sided 95% CI of the difference between the proportions of CR (0—24 hours) were
`compared to the pre-set threshold (i 15%). The intent to treat (ITT) population was used
`in the primary analysis. Table 2 displays the various statistical methods used for the
`secondary efficacy parameters at various time intervals.
`TABLE 2 — Statistical Test Utilized for Seconda
`
`Efficacy Parameters
`
`Complete Control (CC)
`
`
`
`
`
`
`—0-96 hr
`0—120 hr
`
`Chi-square
`
`Chi-square
`
`Chi-square
`
`Number of Emetic Episodes (EE)
`EiN
`0-24 hr
`l-Wallis/Wilcoxon
`Kruskal-Wallis/Wilcoxon
`
`24-48 hr
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`48-72 hr
`
`72-96 hr
`
`96-120 hr
`
`Kruskal-Wallis/Wilcoxon
`
`» Kruskal-Wallis/Wilcoxon
`
`Kruskal-Wallis/Wilcoxon '
`
`Kruskal-Wallis/Wilcoxon
`
`0-120 hr
`:3 E (D nO E. aA Fl E1
`' Log Rank
`.
`leverity of Nausea
`0-24 hr
`Kruskal-Wallis/Wilcoxon
`
`
` 48 72 hr
`
`
`24-48 hr
`
`72 96 hr
`
`96-120 hr
`
`Kruskal—Wallis/Wilcoxon
`
`Kruskal-Wallis/Wilcoxon
`
`Kruskal-Wallis/Wilcoxon
`
`Kruskal-Wallis/Wilcoxon
`
`
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`Due to ethical concerns, a placebo-controlled trial was not feasible for CINV.
`Thus to ensure validity, the applicant developed a meta-analysis (PALO-Ol—23) which
`used data from a published literature to predict the complete response for CINV.
`A literature search Was performed to select articles using placebo, dolasetron, granisetron,
`ondansetron and other anti-emetics for CINV). This meta-analysis database consisted of
`78 treatment arms from published trials and included 7274 subjects. Helsinn used this
`database to perform a logistic regression to identify which covariates were relevant in
`predicting complete response for various treatments and produce a model to calculation
`of historical placebo and historical active comparator complete response.
`Validity was demonstrated if:
`‘
`o
`the lower limit of the 95% CI of complete response in the active comparator group
`was greater than the upper limit of the 95% CI of the complete response rate of the
`modeled historical placebo; and -
`
`o
`
`the complete response rate achieved in the active comparator group was similar to
`modeled historical comparator.
`
`Medical Officer Comments: The Agency and the applicant agreed to this approach to
`validation in pre-NDA meetings and end ofPhase 11 meetings held in spring of 1999.
`
`V.
`
`RESULTS
`
`A. Demographics and Disposition of Patients
`Sixty—one centers enrolled 593 patients. Of these, 592 were randomized to one of
`the three treatment groups (1 patient was not randomized and did not receive treatment).
`The following figure shows the disposition of patients.
`
`FIGURE 1 — Disposition of Patients
`
`.
`
`
`
`N = 592
`Randomized
`
`
`
`Treated
`N=l94
`
`Treated
`N= 1 96
`
`Treated
`N=l 93
`
`Not Treated -
`N=9
`
`Palonosetron 0.25 mg
`
`Palonosetron 0.75 mg
`
`Dolasetron 100 mg
`
`
`
`
`
`
`N_=3Drop—outs
`
`
`
`N=l9lCompleters
`
`
`
`N=5Drop-outs
`
`N=l9l —=IN=192Completers _rop—outs Completers
`
`
`
`
`
`
`
`From Figure 6.1-1, Volume 135, pg. 72
`
`’1‘“r"\
`
`Of the eight patients in the palonosetron arms who withdrew from the study:
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`0
`0
`
`0
`
`3 dropped out because of patient decision
`3 dropped out due to serious adverse event or death (1 patient who received 0.25 mg
`and 2 in the 0.75 mg group)
`
`l dropped out because of violation of exclusion criteria
`
`1 patient lost to follow-up.
`0
`One patient who received dolasetron was lost to follow-up.
`
`The following table shows the number ofpatients by region.
`
`TABLE 3 — List of Patients by Region
`
`
`
`‘S'5-
`
`
`
`_-
`,
`LC-o'untr'yv i
`.(Active centers)
`
`g
`
`Us. East (13)
`US. West (15)
`California (13)
`Mexico South (6)
`Mexico Center (10)
`Mexico North (4)
`
`Total (61)
`
`We“ : Chmmp
`
`‘
`“ History”
`.
`.
`_
`|
`: "‘Patient’s
`Randomized: —Male"
`aivel'
`
`"
`
`‘
`
`(Reference: Table 6.1-3, pg. 71, Volume 135)
`
`Mexico Center and California were the regions in which the largest number of patients
`were enrolled.
`
`The following table shows the number of patients by gender, corticosteroid use
`and the number of chemotherapy naive or non-naive patients.
`
`APPEARS nus isI
`OH ORIGINAL M
`
`__.—v\.
`
`

`

`CLINICAL REVIEW STUDY 99-04
`
`PALONOSETIRON
`
`34 (18.0)
`155 (82.0)
`
`33 (17.5)
`156 (82.5)
`
`35 (18.3)
`156 81.7)
`
`124 (65.6)
`65 (34.4)
`
`131 (69.3)
`58 (30.7)
`
`125 (65.4)
`66 (34.6)
`
`Chemotherapeutic
`History
`Naive
`Non-naive
`
`Corticosteroid Use
`
`
`
`Yes
`No
`
`11( 5.8)
`178 (94.2
`
`12 (6.3)
`l77(93.7
`
`(Reference: Table 6.3-b, pg. 76, Volume 135)
`
`Medical Officer Comments: The distribution ofpatients by gender, corticosteroid use
`and chemotherapeutic history is similar across treatment groups. The majority of
`patients were female and naive. This is because moderate emetogenic chemotherapy is
`mostfrequently given for breast cancer. The number ofpatients who received
`corticosteroids Was small. This is because its use was allowed by amendment to the
`protocol that was implemented 5 months prior to the study ended
`
`The next table displays the type of cancer for which chemotherapy was given.
`
`APPEARS THIS WAY
`ii ORIGINAL
`
`

`

`CLINICAL REVIEW STUDY 99-04
`
`PALONOSETRON
`
`W: was". {LI-F:
`'s‘e‘tron?‘
`
`Breast Cancer female— nos
`
`106 (54.9)
`
`95 (48.7)
`
`110 (56.7)
`
`(2.1)
`
`Breast Cancer invasive —nos
`
`22
`
`(11.4)
`
`20
`
`(10.3)
`
`Lung Cancer
`
`.
`
`8
`
`(4.1)
`
`10
`
`(5.1)
`
`Non—Hodgkins lymphoma- nos
`
`Non-small cell lung cancer
`
`Ovarian cancer- nos
`
`Breast Cancer stage II
`
`Cervical cancer carcinoma
`
`Small cell lung cancer stage unspecified
`
`Colon Cancer nos
`
`Prostate cancer nos
`
`Acute lymphocytic leukemia
`
`(4.1)
`
`(2.6)
`
`(2.1)
`
`(1.6)
`
`(1.6)
`
`(1.6)
`
`(1.0)
`
`(0.5)
`
`(0.0)
`
`13
`
`(6.7)
`
`(1.0)
`
`(4.6)
`
`(0.5)
`
`(1 .0)
`
`(3.1)
`
`(1.5)
`
`(0.5)
`
`(1.0)
`
`(9.8)
`
`(3.6)
`
`(4.1)
`
`(1.0)
`
`(1.5)
`
`(1.0)
`
`(1.0)
`
`(2.1)
`
`(0.0)
`
`(1 .5)
`
`(Reference: Table 6.4.2-a, pg. 89, Volume 135)
`
`Medical Officer Comments: Breast cancer was the mostfrequently reportedprimary
`cancer in all treatment groups. A higher number ofsmall cell lung cancer and colon
`cancer was seen in the palonosetron groups versus the dolasetron group. However, these
`differences should not have affected the results ofthe study.
`
`The following table gives detailed information about the demographic data of the patients
`enrolled.
`
`10
`
`

`

`CLINICAL REVIEW STUDY 99-04
`PALONOSETRON
`
`.
`
`_' ”
`
`Female
`
`(17.6)
`34
`159 (82.4)
`
`34
`161
`
`(17.4)
`(82.6)
`
`(18.6)
`36
`158 (81.4)
`
`(4.6)
`
`Ethnic Group
`White
`Black
`
`Hispanic
`Asian
`Other
`
`Tobacco Use
`Non-smoker
`Ex-smoker
`Smoker
`
`Alcohol
`
`consumption
`No
`Rarely
`Occasionally
`Regularly
`
`(31.6)
`61
`(6.2)
`12
`115 (59.6)
`3
`(1.6)
`2
`(0.0)
`
`(34.9)
`68
`(4.1)
`8
`114 (58.5)
`4
`(2.1)
`5)
`
`(32.0)
`62
`(5.2)
`10
`115 (59.3)
`6
`(3.1)
`1
`(0.5)
`
`128 (66.3)
`38
`(19.7)
`27
`(14.0)
`
`114 (58.5)
`52
`(26.7)
`29
`(14.9)
`
`114 (58.8)
`51
`(26.4)
`29
`(14.9)
`
`126 (65.3)
`26
`(13.5)
`32
`(16.6)
`9
`(4.7)
`
`128 (65.6)
`31
`(15.9)
`26
`(13.3)
`9
`
`(Reference: Table 6.41—a, pg. 80, Volume 135)
`
`Aledical Officer Comments: Overall the treatment arms were balanced in regard to
`baseline demographic characteristics. Due to the many ofthe clinical sites being located
`in Mexico a large number ofsubjects were Hispanic.
`
`The following table gives physical characteristics ofthe patients in each treatment arm.
`
`11
`
`

`

`CLINICAL REVIEW STUDY 99-04
`
`PALONOSETRON
`
`sis-mac;-
`
`rot):
`
`-
`
`«$3.13. 1.:
`.
`951-.“ "‘,~—~Ilfv"l(
`
`osetronr'
`'
`tron
`
`18.5
`
`Age(years)rv‘
`
`'
`
`i
`
`i
`
`55.7
`
`Height(cm)
`
`159.7
`
`9.5
`
`160.3
`
`8.9
`
`160.6
`
`9.1
`
`Weight(kg)
`
`71.6
`
`17.3
`
`71.0
`
`16.0
`
`72.5
`
`Karnofs
`
`94.7
`
`8.2
`
`93.6
`
`9.9
`
`94.3
`
`8.8
`
`(Reference Table 6.4.1-a, pg. 80, Volume 135)
`
`Medical Officer Comments: Each treatment arm was similar in regards to age, height
`and weight. They also were balanced in regards to Kamofiky index.
`
`TABLE 8 —Risk Factors for Patients
`
`185(96.9)
`
`187 (98.9)
`
`188 (99.5)
`
`189 (99.0)
`
`2(1.l)
`187 (98.9),
`
`4(2.l)
`185 (97.9)
`
`3(l.6)
`188 (98.4)
`
`7 (3.7)
`182 (96.3)
`
`7 (3.7)
`182 (96.3)
`
`6 (3.1)
`
`héiim 1
`Yes
`
`No
`
`Hepatic Impairment
`Yes
`No
`
`Cardiac Impairment
`Yes
`No
`
`(Reference: Table 6.4.l-b, pg.‘ 85, Vol. 135)
`
`Medical Officer Comments: There were small numbers ofpatients with organ
`impairment. The most common organ impairment was cardiac.
`
`The protocol defined prior diseases as those starting before Visit 1 and not ongoing after
`Visit 1. Concomitant diseases were defined as those starting before Visit 1 and ongoing
`
`12
`
`

`

`-.
`
`CLINICAL REVIEW STUDY 99—04 -.
`
`PALONOSETRON
`
`after Visit 1. The following table lists prior and concomitant diseases. Diseases are listed
`by the system organ class followed by preferred term according to MedDRA.
`
`5 Comrum»
`
`
`
`'.
`12
`43
`44
`
`(64.9)
`(22.2)
`(22.7)
`.
`
`143 (73.7)
`46
`(23.7)
`15
`(7.7)
`50 (25.8)
`38 (19.6)
`65
`(33.5)
`50
`(25.8)
`52
`(26.8)
`
`(21.1)
`(16.5)
`(15.5)
`(14.9)
`(15.5)
`(11.3)
`
`41
`32
`30
`29
`30
`22
`23
`33
`
`.
`«a
`Any prior Disease
`Infections and infestations
`Gastrointestinal disorders
`Reroductive s stern and breast disorders
`
`Any concomitant diseases
`Metabolism and nutrition disorders
`Diabetes mellitus nos
`Reproductive system and breast disorders
`Menopause
`.
`Vascular disorders
`I
`Hypertension nos
`Musculo-skeletal, connective tissue and
`bone disorders
`
`Gastrointestinal disorders
`Immune system disorders
`Drug hypersensitivity
`Respiratory disorders
`Blood and lymphatic system
`Anemia
`Cardiac disorders
`Nervous s stem disorders
`I Multiple answers possible
`2
`Incidence at least 14% ofpatients in treatment group
`3 Incidence at least 10% of patients in treatment group
`(Reference: Table 6.4.4-a, pg. 94, Vol. 135)
`
`.
`
`. -/.o
`129. (66.8)
`46
`(23.8)
`43
`(22.3)
`25
`(13.0
`
`156 (80.8)
`60
`(31.1)
`18
`(9.30)
`50
`(25.9)
`41
`(21.2)
`48
`(24.9)
`41
`(21.2)
`43
`(22.3)
`
`41
`32
`24
`32
`30
`24
`27
`24
`
`(21.2)
`(16.6)
`(15.5)
`(16.6)
`(15,5)
`(12.4)
`(14.0)
`.
`
`.,
`130 (66.8)
`47
`(24.1)
`44
`(22.6)
`29
`14.9
`
`163 (83.6)
`55
`(28.2)
`23
`(11.8)
`48
`(24.6)
`40
`(20.5)
`62
`(31.8)
`48
`(24.6)
`56
`(28.7)
`
`46 (23.6)
`40 (20.5)
`35 (17.9)
`22 (11.3)
`24 (12.3)
`16 (8.2)
`22 (1 1.3)
`34 (17.4
`
`Medical Officer Comments: There were no significant differences between treatment
`groups with regard to prior and concomitant disease. Hypertension was the most
`frequently reported concomitant disease in all treatment groups.
`
`The next table displays concomitant medications (defined as intake between receiving the
`study drug and the last date of contact or intake before randomization that continued after
`receiving the study drug).
`
`13
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`
`
`TABLE 10 — Concomitant Medication]
`’
`W ' " :Pal'b‘ribs‘é'
`"
`‘
`‘
`
`
`:oncomitant Medication
`
`’
`
`Any concomitant medication
`Analgesics
`'
`Opioids
`Other analgesics and antipyretics
`Antacids
`drugs for treatment peptic ulcer
`Antianemic preparations
`Antibacterial for systemic use
`Anti—inflammatory and anti-rheumatic
`products
`Non-steroid anti-inflammatory/anti-
`rheumatic products
`Antithrombotic agents
`
`-
`
`145 (75.1)
`58
`(30.1)
`10
`(5.2)
`50
`(25.9)
`44
`(22.8)
`38
`(19.7)
`16
`(8.3)
`18
`(9.3)
`27
`(14.0)
`
`
`
`140 (64.1)
`76 (39.0)
`22
`(11.3)
`57
`(29.2)
`43
`(22.1)
`36
`(18.5)
`16
`(8.2)
`32
`(16.4)
`22
`(11.3)
`
`144 (74.2)
`64
`(33.0)
`12
`(6.2)
`55
`(28.4)
`51
`(26.3)
`46 (23.7)
`22
`(11.3)
`19 .(9.8)
`25
`(12.9)
`
`(14.0)
`
`(1 1.3)
`
`25
`
`(12.9)
`
`(6.2)
`
`(11.3)
`
`18
`
`(9.3)
`
`-
`
`1 Multiple answers possible
`2
`Incidence at least 10% ofpatients in treatment group
`(Reference: Table 6.4.5-a, pg. 96, Vol. 135)
`
`Medical Officer Comments: The treatment groups were comparable in regards to
`concomitant medication. The most common medication in all 3 treatment groups was
`analgesics.
`Prior anti-emetic treatments were defined as intake within 12 months before
`
`randomization. By this criteria 70 (36%) patients of the 0.25 mg palonosetron group, 71
`(36.4%) patients ofthe 0.75 mg palonosetron group, and 65 (33.5%) of the dolasetron
`group had prior anti-emetic treatment. Concomitant anti-emetic treatment included all
`medication taken after Study Day 5. Anti-emetic treatment taken between the
`administration of the study drug and Study Day 5 was considered rescue therapy and is
`included in the efficacy results. Concomitant anti—emetic treatment was seen in 26
`(13.5%) patients of the 0.25 mg palonosetron group, 28 (14.4%) patients ofthe 0.75 mg
`palonosetron group, and 29 (14.9%) of the dolasetron groUp. Dexamethasone was the
`most common concomitant anti-emetic teatment in the palonosetron groups (4.7% and
`6.2%) while ondansetron was most frequently taken by patients in the dolasetron group
`(3.6%).
`
`14
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-04
`
`The following table displays the chemotherapy agent administered on Study Day 1, the
`day the patients received either palonosetron or dolasetron.
`
`Cyclophosphamide
`
`138 (73.0)
`
`129 (68.3)
`
`146(764)
`
`(0.0)
`
`91
`
`(48.1)
`
`77
`
`(40.7)
`
`93
`
`(48.7)
`
`39
`
`(20.6)
`
`44
`
`(23.3)
`
`43
`
`