Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`
`Treanda (bendamustine)
`
`consists of individual reports, a report of a 398 patient postmarketing study, and an Overall
`Safety Update Report (SUR). According to Astellas, approximately .1 patients were
`exposed to bendamustine during this time period. Reliance on postmarketing reports for
`estimation of adverse reaction incidence and severity is limited due to the passive nature of the
`collection of spontaneous reports, the voluntary nature of reporting, the insufficient detail
`contained in these reports, and difficulty calculating event rates due to the relatively unknown
`safety population denominator.
`
`Demographics
`
`The demographics presented below in Table 7-6 are from the major study used for the safety
`analysis (02CLLIII). All patients had histologically—confirrned chronic B-cell lymphocytic
`leukemia and symptomatic Binet stage B or Binet stage C disease. Patients were predominantly
`men (62% vs. 38%), with an average age of 63.3 years, exactly half were less than 65 years of
`age versus 265 years of age. In study 02CCLLIII, patients in each treatment group were well-
`matched for age, gender, race, and body height. The data in Table 7-6 below were confirmed
`using the raw datasets provided by the Applicant in the application.
`
`Table 7-6 Demographic Information (Treated Analysis Set; Applicant Table)
`
`Total
`Bendnnmslinc Chlommbmfl
`Demographic Information
`.\'=30|
`N=153)
`.\‘=l48
`Variable/Stalhlk
`
`Age, (years)
`Mm
`63.0
`63.6
`63.3
`so
`763
`8.6:
`$15
`Median
`63.0
`66.0
`64.0
`Min. max
`45.0. 77.0
`53.0. 78.0
`38.0. 78.0
`.-\ge grou
`7- 65 yen];
`265 yms
`Sex. n (”M
`Men
`Women
`Race. 11 (“/0)
`01th
`mm:
`Weight (kg)
`“
`Menu
`Median
`SD
`Min. max
`"eight (em)
`11
`Mm
`31)
`Median
`Min. max
`SOURCE: Summary 15.3]. Listing 4.
`’ Race for paxicm lOSlé in the chlommbucil treatment group 11m not specified.
`Mineminimum: nnwnwtimmm SD=xumdard deviation.
`
`DU
`(D
`a,~0-
`1
`0
`(5
`m
`—'
`9:
`(D
`
`0
`0
`'0
`<
`
`151 (so)
`150(50)
`187 (62)
`114 (38)
`
`ll'~|)
`500099)
`
`397
`76. 1
`750
`14.35
`48.3, 133.0
`298
`103.7
`8.80
`1690
`“7.0. l‘)0.0
`
`s: (54)
`71 (46)
`97 (63)
`56 (37)
`
`69 (47)
`79 (53)
`90 (61)
`58 (39)
`
`0
`153 (100)
`
`l(<‘l)
`147 ( >99)
`
`15:
`78.:
`77 4
`15.06
`50.0. 133.0
`153
`169.0
`8.60
`170.0
`147.0. 190.0
`
`HS
`74.0
`72.0
`13.26
`43.8. 11s.0
`145
`163.4
`9.04
`mm
`149.0. 189.0
`
`Data in above table was confirmed by review of raw and derived datasets and CRFs.
`
`75
`
`

`

`Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`
`Treanda (bendamustine)
`
`:Rev1ewerComments The bendamustmeand chlorambucfltreatmentgroups appearto ;
`Elbewell-balancedfordemographlc cr1ter1athat Could potentlallyimpactthesafety analys1s
`forbendamustme Age genderand welght didnotSignlficantlyvarybetweengroups
`:1 An insufficwntnumber ofnon-cauca31an patlents were enrolled to addresspotentlal
`.lmpactsuponrace
`,
`-
`.
`-
`~
`,
`--
`9"
`'
`1 " '
`' The demograph1cs ofthlsstudy populatlon maynotmirror thoseofthe potent1al
`populat1onWho Will be treatedWithbendamustineafter itsmarketlng approval111that
`.-Treandamay be reserved for prev1ouslytreatedpatients TheproposeddOSeandschedule
`in this appllcat1on18 supportedbythedoseand schedulestudied1ntrial 02CLLIII The
`study demgnallowed continuedtreatment until1ntolerabletox1c1ty, progresswnof disease,
`.- 0r.1nvest1gatordecision. The mediannumber of Cycles recelved1nbOthgroupswas six
`3 Thetyp1cal experlenceWithpurine analogs totreat CLL1s also with six courses -.
`-
`1
`
`i
`
`7.2.2 Explorations for Dose Response
`
`The Applicant did not perform a study comparing different doses of bendamustine. Therefore,
`and exploration for dose response could not be performed. Overall, the application submitted
`does contain adeczluate numbers of patients in the proposed population of CLL, at the proposed
`dose (100 mg/ m ), and schedule. Additionally, the patients in both treatment groups appear to
`have been exposed to similar doses and exposures of the respective agents.
`
`7.2.3 Special Animal and/or In Vitro Testing
`
`Reprotoxicity
`Development and reproductive toxicology studies were performed in mice and rats. These
`studies were non-GLP and are considered to be supportive, although reproductive toxicity is
`expected for any alkylating agent. Other nonclinical toxicology studies conducted with
`bendamustine were local tolerance studies in rabbits (GLP) and immunotoxicity studies in mice
`and human peripheral blood lymphocytes (non-GLP).
`
`QT Prolongation
`Safety pharmacology studies conducted with bendamustine included in Vitro evaluations of
`action potential duration using Beagle dog Purkinje fibers, an in Vitro assessment of hERG
`channel current, and an assessment of renal function in the Sprague-Dawley rat. The study to
`evaluate the effects of bendamustine on the action potential duration in dog Purkinje fibers and
`the study to assess potential effects on renal fimction in rats were conducted by \
`IN GLP). The study to assess bendamustine on hERG
`
`According to the Applicant:
`Beflddmuyime lad 120 efleci i/z Vii/'0 0/2 dog Pit/”mm? fléer arc/1'01:
`pate/21mlparame/e/o; i/zclzzm'flg amplitude, res/mgpate/71ml maximal
`
`76
`
`

`

`Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`
`Treanda (bendamustine)
`
`4120’ 467le pole/marl dam/[[072 fifldéf éotfl
`rate of depo/drl'Zd/z'o/I,
`120/7724] {60 ppm) and 1/014» {20 ppm] .s'lz'lrzz/la/z'wz rate; over a
`colzce/z/ra/z’o/z marge (f [f [0 2f ,ag/ml.
`[12 an 1'12 VIZ/’0 J/uafi/ to
`era/”ate [fie pate/zlzfi/ effect; of éefldamzutz'ize 0/2 flE/i’G céa/me/
`cur/em; a coflcefltrdtzbiz 0/2 ,ag/ml flaa’ 120 efflc/ 0/2 flEA’G cfla/me/
`cur/rem: Wflfle tartan/ratio}: 0/20 flg/ML 4724’ 200 ,a/I/ flaa’ a dare-
`depe/zde/z/ I'lzézb/tz'wz offlE/l’é' cfla/me/ Gil/7’67” raflgz'izgfl'om 20% [0
`6f%,
`raved/112642 Based 1400/1
`[fie rem/[23’ of flare 1'11 VIZ/0
`caraf’omyczz/ar
`54/641
`péarmaco/og/
`”yaks;
`éeim’amzm‘iize
`dem0”J/rd/€d a law dr/fiy/é/flage/zl'c rzirk at conce/z/ralz'o/zy Mal are
`eqw'm/eiz/ to, or J/Igfllljlgrea/er Mali [flare éez'lzg oéye/vea’1'12palm/713".
`
`Rev1ewerCOmmentsz. The non-cliniCaltestingofbendamuStine appears adequateto I
`explore potentlaladverse reaCtions. The reader1s referredto the PharmTox review for
`
`further detalls ofthe non-cllnlcaltesting forbendamustlne
`
`H
`
`7.2.4 Routine Clinical Testing
`
`Rewewer Comment: The clinicalevaluations of.trialpart1c1pantswere adequate to assess
`expected and unexpectedadverse reactionsin the CLL populat1on
`'
`-
`
`'
`
`7.2.5 Metabolic, Clearance, and Interaction Workup
`
`The reader is referred to Section 4.4 (Clinical Pharmacology). In vitro data suggest that plasma
`protein binding was approximately 95%, with albumin being the main binding protein at
`therapeutic plasma concentrations. In vitro data suggest that bendamustineIS not likely to
`displace or be displaced by other highly protein--bound drugs.
`
`Bendamustine is primarily metabolized by hydrolysis to the relatively inactive metabolites,
`monohydroxy bendamustine (HPl) and dihydroxy bendamustine (HP2). The active metabolites
`of bendamustine (.-hydroxybendamustine [M3] and N-des-methylbendamustine [M4]) are
`formed primarily via cytochrome (CYP) P450 system CYP1A2. However, both metabolites are
`present in low concentrations relative to the parent. In vitro data suggest that P-glycoprotein,
`BCRP, and/or other efflux transporters may have a role in bendamustine transport. Based on in
`vitro data, bendamustine is not likely to inhibit human CYP isoenzymes 1A2, 2C9/10, 2D6, 2E1,
`or 3A4/5. In addition, in vitro data indicate that bendamustine is not likely to induce substrates of
`CYP enzymes.
`
`77
`
`

`

`Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`
`Treanda‘ (bendamustine)
`
`There was no formal clinical pharmacology study conducted to specifically evaluate the effects
`of race, sex, or age on the pharmacokinetics of bendamustine. A cross-study comparison of the
`bendamustine exposures from study SDX-105-03 (7 Caucasians, 1 Other) and study 2006001 (6
`Japanese subjects) indicate that exposures in Japanese patients were slightly higher (20%) than
`those see in the Caucasian subjects. However, because of the limited number of patients, no
`conclusions can be drawn. More data are required to make definitive recommendations.
`
`7.2.6 Evaluation for Potential Adverse Reactions for Similar Drugs in Drug Class
`
`Class effects typically seen with alkylating agents include nausea, vomiting, and
`myelosuppression. These effects were properly evaluated in study 02CLLIII and were some of
`the most commonly seen toxicities.
`
`’Rev1ewer Comments The Applicant’s effortsto detect class-speelficadversereaCtions
`were adequate forthe indication sought. Pre-clinical testingindicated that bendathine _'
`*w1ll not likelylead to QTprolongatlon Thesponsorhas not conductedadequatecliniCal.
`analyses to assess thispetentialin humans per ICHguldelmes This evaluatlonshouldbe
`requested as a post-marketmg Commitment.
`
`'
`
`7.3.1 Deaths
`
`Thirty-four deaths occurred during the conduct of study 02CLLIII. An equal number (17) of
`deaths occurred in each treatment group. Seventy-one percent of deaths in both groups occurred
`more than 100 days after the last study drug dose. The most common attribution for death was
`progression of disease (41% of patients in each group). Four patients died during the treatment
`phase of the study or within 30 days of the last study drug dose, one patient in the bendamustine
`group (patient 10303) and three patients in the chlorambucil group (patients 10114, 10902, and
`20902). The Applicant provided the reported cause of death for these four patients. A review of
`the death narratives and eCRFs was undertaken to evaluate the attributions of these deaths. A
`
`description of the information reviewed about each event are provided below.
`
`Deaths Within 30 days of Last Study Drug Treatment
`The section below provides the verbatim patient narratives for deaths provided by the Applicant.
`
`Bendamustine Group
`
`Patient 10303: Patient was a 69-year-old, white man with symptomatic Binet stage B, chronic
`lymphocytic leukemia. Significant medical history included chronic obstructive pulmonary
`disease (COPD) and pleural effusion, which was reported as grade 3 at baseline. On Cycle 1,
`Day 1, the patient experienced an adverse event of grade 1 pleural effusion and a thoracocentesis
`
`78
`
`

`

`Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`Treanda (bendamustine)
`
`procedure was performed the same day. On day 15, the pleural effusion was reported as a serious
`adverse event of grade 3 severity. In addition, on day 15, he experienced non-serious adverse
`reactions of grade 3 respiratory failure, dyspnea, and hypoxia, and results of an
`electrocardiogram noted a grade 2 supraventricular arrhythmia. The pleural effiision, respiratory
`failure, dyspnea, and hypoxia all required hospitalization, and the patient was treated with
`corticosteroids for systemic use and oxygen. On day 18, cefipime was added to the patient’s
`treatment regimen and all of the events continued. Subsequently, on day 19, the pleural effusion,
`respiratory failure, dyspnea, and hypoxia all increased in severity to grade 4, and a second
`thoracocentesis was performed. On day 20 (19 days after last dose of study drug), the patient
`died due to pleural effusion, respiratory failure, dyspnea, and hypoxia as a consequence of
`underlying COPD. All of the events reported for this patient were considered unrelated to study
`drug treatment by the investigator.
`
`Adverse Reaction(s) Leading to Death: Pleural effiision, respiratory failure-dyspnea, hypoxia
`
`Chlorambucil Group
`
`Patient 10114: Patient was a 47-year-old, white woman with symptomatic Binet stage C,
`chronic lymphocytic leukemia. On Cycle 1, Day 22, the patient had an adverse reaction of grade
`2 neutropenia (absolute neutrophil count [ANC]: 1.485 x 109/L), which was considered possibly
`related to study drug treatment by the investigator and continued. On day 27, she experienced
`grade 3 cough and grade 4 pyrexia (reported as non-serious adverse reactions) and was
`diagnosed with a serious adverse reaction of grade 4 bacterial pneumonia the same day. In
`addition, on day 27, the patient also experienced a non-serious adverse reaction of grade 3 rash.
`The patient was hospitalized due to the bacterial pneumonia, cough, pyrexia, and rash, and she
`was treated with cefiriaxone sodium, amikacin sulfate, ciprofloxacin, human albumin, digoxin,
`oxygen, and meropenem for the bacterial pneumonia. On day 29 (14 days after last dose of study
`drug), the patient died due to massive bacterial pneumonia, as a result of treatment for chronic
`lymphocytic leukemia. The bacterial pneumonia and rash were considered possibly related to
`study drug treatment by the investigator and the cough and pyrexia were considered unrelated to
`study drug treatment.
`
`Adverse Reaction(s) Leading to Death: Neutropenia,’ pneumonia bacterial, cough, pyrexia, rash
`
`Patient 10902: Patient was a 67-year—old, white woman with asymptomatic Binet stage B,
`chronic lymphocytic leukemia. Significant medical history included heart failure and right plural
`effusion. On day 76, she experienced a serious adverse reaction of grade 1 hemorrhage, which
`resulted in hospitalization; also on day 76, she had non-serious adverse reactions of grade 4
`thrombocytopenia (platelets: 90 x 109/L), grade 2 blood lactate dehydrogenase increased (LDH:
`1054 u/L), and grade 3 hyperbilirubinemia (bilirubin: 87.1 umol/L). The patient was treated with
`hydrocortisone and methylprednisolone for the thrombocytopenia, and received platelets. The
`hemorrhage was considered possibly related; the thrombocytopenia was considered unrelated;
`and the elevated LDH and hyperbilirubinemia were considered unlikely related to study drug
`treatment by the investigator. On day 81, the severity of the hemorrhage increased to grade 3;
`
`79
`
`

`

`Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`
`Treanda (bendamustine)
`
`and the severity of the elevated LDH decreased to grade 1; the severity of the hyperbilirubinemia
`decreased to grade 2; and the thrombocytopenia was ongoing. That same day (day 81), the
`patient also had a grade 2 adverse reaction of anemia, which was ongoing and considered
`unrelated to study drug treatment by the investigator. On day 84, the severity of the hemorrhage
`increased to grade 4, and the patient subsequently died on day 88 (17 days after last dose of
`study drug) due to the hemorrhage. The grade 4 hemorrhage was considered possibly related to
`study drug treatment by the investigator.
`
`Adverse Reaction(s) Leading to Death: Hemorrhage
`
`Patient 20902: Patient was a 63-year-old, white man with asymptomatic Binet stage C, chronic
`lymphocytic leukemia. Significant medical history included diabetes mellitus, myocardial
`ischemia, pneumonitis related to tumor infiltration, and heart failure. Prior to the study and
`concomitantly, the patient took allopurinol for prevention of hyperuricemia, furosemide and
`metildigoxin for heart failure, and isosorbide dinitrate for chronic cardiac ischemia. On day 29,
`the patient had nonserious adverse reactions of grade 3 anemia (hemoglobin: 77 g/L) and grade 2
`respiratory tract infection. The patient received red blood cells for the anemia, and midecamycin,
`ciprofloxacin, and ambroxol hydrochloride for the respiratory tract infection. On day 35, the
`patient experienced the serious adverse reaction of grade 3 cardiac failure, which resulted in
`hospitalization and for which the patient continued concomitant treatment with furosemide and
`metildigoxin. In addition, on day 35, the patient experienced the non-serious adverse reaction of
`grade 3 dyspnea, for which he was treated with concentrated oxygen and methylprednisolone.
`The respiratory tract infection was noted as having resolved on day 36 and the anemia, dyspnea,
`and cardiac failure continued until the patient’s death on day 37 (8 days afier last dose of study
`drug), which was due to all 4 of these events. With the exception of respiratory tract infection,
`which was considered unlikely related to study drug treatment by the investigator, all of these
`events were considered unrelated to study drug treatment.
`
`Adverse Reaction(s) Leading to Death: Anemia, respiratory tract infection, dyspnea, cardiac
`failure
`
`Neither narratives nor case report forms were provided for patients who died more than 30 days
`after study drug treatment. Therefore, the data on attribution of death could not be confirmed. In
`the bendamustine group, 2 (possibly 3) patients died from cardiac causes (10401, 20204, and
`23601). None of these three patients had any baseline medical conditions recorded in the
`medical history datasets that might increase the risk of such events. However, the concomitant
`medication datasets contained some medications used that could potentially be related to a
`history of cardiac disease. Patient 10401 was receiving amiodarone at baseline for a history of
`supraventricular arrhythmia. Patient 20204 was taking nifedipine for arterial hypertension at
`baseline and while on study. Patient 23601 was not recorded as taking any baseline medications
`that could be linked to cardiac death. The attribution cannot be clearly made to bendamustine
`because the patients were at increased risk of such events due to age (6th decade of life) and the
`lack of a close temporal relationship between bendamustine and the fatal event.
`
`80
`
`

`

`Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`
`Treanda (bendamustine)
`
`Threepatients (10102, 11001, & 20701) died of cerebrovascular events which are also increased
`in this age group. None of these three patients had any baseline medical conditions recorded that
`might increase the risk of such events. However, patient 11001 was recorded as taking
`nifedipine for arterial hypertension before the study began. Neither patient 10102 or 20701 were
`recorded as having used any medication at baseline that would indicate and increased risk of
`cerebrovascular events. The lack of temporal relationship to the study drug and the event makes
`an attribution to bendamustine less likely.
`
`_
`,
`.
`I'Rev1ewerSummary ofFatalEventsWithin30 DaysofTreatment
`'
`. Threepatientsdied within 30 days ofstudy drugin the chlorammieiltreatmentgroupas '
`comparedto 1inthe bendamustine group. Theonly patient in-the bendamustine treatment
`group to die.Within30 days oftreatment appearedto diefrom abaseline (non-cancer) medical
`condition The narrative-indicates thatthe patient wasmedically decompensatmg secondary
`to his baseline grade 3 pleuraleffusionson the first dayOftreatment. It15probablethatthis ,
`patient should haVe beenexcludedfiom trialeligibilitydue to an unstable medical condition
`Thisdeath1s notlikelytoberelatedto bendamustine therapy
`'
`>
`
`2
`
`.
`
`'
`
`7.3.2 Nonfatal Serious Adverse Reactions
`
`Severe (Grade 3-4) Adverse Reactions
`Eighty-eight (58%) patients in the bendamustine treatment group and 44 (31%) patients in the
`chlorambucil treatment group reported at least one grade 3 or 4 adverse reaction. Both grade 3
`and 4 adverse reactions occurred more frequently in the bendamustine treatment group than in
`the chlorambucil treatment group. Grade 3 events were reported in 33% of the bendamustine
`patients as compared to 22% in the chlorambucil patients. Grade 4 events were reported in 25%
`of patients in the bendamustine group as compared to 8% of patients in the chlorambucil group.
`The most common severe adverse reactions in the bendamustine treatment group by System
`Organ Class in the bendamustine treatment group were blood and lymphatic system disorders
`(41%), infections and infestations (7%), general disorders and administrative site conditions
`(5%), and vascular disorders (5%).
`
`Grade 3/ 4 hematologic adverse reactions with a frequency greater than 10% in the bendamustine
`treatment group were neutropenia (24%), leukopenia (15%), and thrombocytopenia (13%).
`Grade 3/4 non-hematologic adverse reactions were reported by 52 (34%) patients in the
`bendamustine treatment group and 25 (17%) patients in the chlorambucil treatment group. Grade
`3/ 4 non-hematologic adverse reactions with a frequency greater than 1% in the bendamustine
`treatment group were pyrexia (4%), pneumonia (3%), rash (3%), hypertension (3%),
`hypertensive crisis (2%), hyperuricemia (2%), and infection (2%). Five patients (3%) in the
`bendamustine treatment group experienced febrile neutropenia compared with none in the
`chlorambucil group. Neutropenic infection occurred in 10 bendamustine patients compared with
`1 in the chlorambucil group. There were 2 events of grade 3 sepsis, both in patients in the
`bendamustine treatment group. Both patients recovered. Grade 3/4 hematologic adverse reactions
`
`81
`
`

`

`Clinical Review
`
`.
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`
`Treanda (bendamustine)
`
`with a frequency greater than 5% in the chlorambucil treatment group were neutropenia (9%)
`and thrombocytopenia (8%) (Table 7-7).
`
`Table 7-7 Grade 3 and 4 Adverse Reactions Occurring in Either Treatment Group by System Organ Class,
`Preferred Term, and Severity (Treated Analysis Set; Applicant Table)
`
`Number 1%! of natients‘
`Bendamustine
`Chlorambucil
`gfi=153l
`1§=1432
`Grade
`Grade
`4
`4
`
`3 or 4
`
`3
`
`3
`
`3 or 4
`
`32 (22)
`
`12 (8)
`
`44 (31)
`
`20 (14)
`17 (12)
`5 (3)
`2(1)
`10 (7)
`0
`0
`0
`0
`2 (l)
`1 (<1)
`3 (2)
`0
`0
`0
`l (< 1)
`1 (<1)
`l (< 1)
`0
`0
`0
`0
`3 (2)
`0
`[(<1)
`0
`l (<1 l)
`l (< 1)
`2 (l)
`
`1 (<1)
`0
`1 (<1)
`2 (l)
`0
`0
`0
`2 l
`
`5 (3)
`9 (6)
`8 (6)
`0
`1 (<1)
`0
`O
`0
`O
`O
`0
`0
`O
`O
`O
`O
`0
`0
`0
`O
`0
`O
`0
`O
`0
`O
`O
`0
`1 (<1)
`
`1 (<1)
`O
`0
`0
`0
`0
`O
`0
`
`25 (17)
`26 (18)
`13 (9)
`2 (l)
`11 (8)
`0
`0
`O
`O
`2 (l)
`1 (<1)
`3 (2)
`0
`0
`0
`I (<1)
`1 (<1)
`1 (<1)
`0
`0
`0
`0
`3 (2)
`0
`1(<1)
`O
`1 (<1)
`1 (<1)
`3 (2)
`
`2 (1)
`0
`l (< l)
`2 (l)
`0
`0
`0
`2 1
`(continued)
`
`System organ class
`Preferred term
`Total number of patients with at least
`1 adverse event
`Total number of patients with at least
`1 nonhematologic adverse event
`Blood and lymphatic system disorders
`Neutropenia
`Leukopenia
`Thrombocytopenia
`Lyniphopenia
`Anemia
`Febrile neutropenia
`Hemolysis
`Granulocytopenia
`Hemolytic anemia
`Cardiac disorders
`Arrhythmia supraventricular
`Cardiovascular disorder
`Myocardial infarction
`Cardiac failure
`Extrasystoles
`Ventricular extrasystoles
`Ear and labyrinth disorders
`Vertigo
`Eye disorders
`Retinal detachment
`Gastrointestinal disorders
`Diarrhea
`-
`Nausea
`Vomiting
`Abdominal pain
`Palatal disorder
`General disorders and administration site
`conditions
`0
`6(4)
`Pyrexia
`O
`2 (1)
`Fatigue
`0
`0
`General physical health deterioration
`0
`2 (1)
`Hepatobiliary disorders
`0
`1 (<1)
`Cholestasis
`0
`1 (<1)
`Hepatotoxicity
`0
`1 (<1)
`'
`Janndice
`0
`0
`H erbilirubinemia
`Abbreviations and footnotes are provided on the last page of this table
`
`50 (33)
`
`38 (25)
`
`40 (26)
`36 (24)
`16 (10)
`20 (13)
`16 (10)
`10 (7)
`3 (2) '
`1 (<1)
`1 (<1)
`0
`0
`2 (1)
`1 (<1)
`1 (<1)
`0
`0
`0
`0
`1 (<1)
`1 (<1)
`1 (<1)
`I (<1)
`4 (3)
`2 (l)
`1(<1)
`1 (<1)
`0
`0
`7 (5)
`
`12 (8)
`27 (18)
`20 (13)
`3 (2)
`4 (3)
`O
`1 (<1)
`0
`0
`0
`O
`1 (<1)
`0
`0
`1 (<1)
`0
`0
`0
`0
`0
`0
`0
`0
`O
`0
`0
`O
`0
`0
`
`88 (58)
`
`52 (34)
`63 (41)
`36 (24)
`23 (15)
`20 (13)
`10 (7)
`4 (3)
`1 (<1)
`1 (<1)
`0
`O
`3 (2)
`1 (<1)
`1 (< 1)
`1 (<1)
`0
`0
`0
`1 (<1)
`1 (<1)
`1 (<1)
`1 (< l)
`4 (3)
`2 (l)
`v 1 (<1)
`1 (<1)
`0
`0
`7 (5)
`
`6 (4)
`2 (l)
`O
`2 (l)
`l (< l)
`l (< l)
`1 (<1)
`0
`
`Data in above table was confirmed by review of raw and derived datasets and CRFs.
`Table continues on next page.
`
`82
`
`

`

`Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`
`Treanda (bendamustine)
`
`Continuation of Table 7.7
`
`System organ class
`Preferred term
`
`3
`
`Number (%) of patients‘
`Bendnmustine
`Chlorttmbucil
`(§==153)
`(N=143)
`Grade
`Grade
`4
`4
`
`3 or 4
`
`3
`
`3 or 4
`
`0
`0
`5 (3)
`0
`1 (<1)
`0
`o
`0
`0
`0
`1 (<1)
`1 (~11)
`1 (<1)
`1 (<1)
`6 (4)
`0
`0
`0
`0
`0
`2(1)
`1 (< 1)
`1 (<1)
`1 (<1)
`1 (<1)
`1 (<1)
`2 (1)
`0
`0
`0
`1 (<1)
`0
`1 (<1)
`0
`
`t)
`0
`1 (<1)
`0
`0
`0
`o
`0
`0
`0
`0
`0
`l (<- 1)
`0
`2 (1)
`0
`0
`t)
`0
`0
`0
`1 (<1)
`0
`0
`1 (<1)
`0
`0
`0
`0
`0
`0
`0
`0
`t]
`
`0
`t)
`0
`0
`0
`0
`
`0
`0
`2(1)
`0
`I (<1)
`1 <1)
`(continued)
`
`Immune system disorders
`Hypersensitivity
`Infectious and infestations
`Pneumonia
`infection
`Pseudomonal sepsis
`Sepsis
`Tracheobronchitis
`Upper respiratory tract infection
`Viral infection
`Hepatitis B
`Herpes zoster
`Pneumonia bacterial
`Respiratory tract infection
`Investigations
`Blood lactate dehydrogenase increased
`Blood alkaline phosphatase increased
`Blood bilirubin increased
`Blood creatinine increased
`Blood uric acid increased
`Gannna-glutamyl trattsfemse increased
`Hemoglobin decreased
`Alanine aminotransferase increased
`Aspartate aminotransferase increased
`Platelet count decreased
`Weight increased
`Metabolism and nutrition disorders
`Hyperuricemia
`Dehydration
`Hyperglycemia
`i-Iyperkalemia
`Hypokalemia
`Anorexia
`Neoplasms benign, malignant and
`unspecified (including cysts and polyps)
`1 (<1)
`1 (<1)
`Tumor lysis syndrome
`0
`1 (<1)
`Bronchial carcinoma
`0
`1 (<1)
`Nervous system disorders
`0
`l ('11)
`Paraplegia
`0
`0
`Facial palsy
`1)
`0
`Neuralgia
`Abbreviations and footnotes are provided on the last page of this table.
`
`_
`
`2 (l)
`2 (l)
`10(7)
`4 (3)
`3 (2)
`1 (<1)
`l
`(A—: I)
`1 (<1)
`1 (~-’ 1)
`I (<1)
`0
`0
`0
`0
`4 (5)
`2 (l)
`1 (<1)
`1 (<1)
`0
`0
`1 (<1)
`1 (<1)
`0
`0
`0
`0
`3 (2)
`0
`1 (<1)
`l («T 1)
`0
`l (”1.1)
`0
`Z (I)
`
`0
`0
`0
`0
`0
`0
`o
`0
`0
`0
`0
`0
`0
`0
`2 (l)
`0
`0
`0
`l (<I)
`i (<1)
`0
`0
`0
`0
`0
`o
`3(2)
`3 (2)
`0
`0
`1 (<1)
`0
`0
`1 (<1)
`
`2 (1)
`2 (1)
`10(7)
`4 (3)
`3 (2)
`1 (<1)
`i (<1)
`1 (<1)
`1 (<1)
`1 (<1)
`0
`0
`0
`0
`6 (4)
`2(1)
`1 (<1)
`1 (<1)
`l (<--l)
`1 (<1)
`1 (<1)
`l (f l)
`0
`l)
`0
`0
`6 (4)
`3 (2)
`1 (<1)
`1 (-~" 1)
`1 (<1)
`1 (<1)
`O
`3 (2)
`
`2 (l)
`1 (<1)
`1 (<1)
`1 ('11)
`0
`0
`
`0
`0
`4 (3)
`0
`1 (< 1)
`0
`0
`0
`0
`0
`I (4' 1)
`1 (< 1)
`0
`1 (<1)
`4 (3)
`0
`0
`0
`0
`0
`2 (I)
`0
`1 (<1)
`1 (<1)
`0
`t (<I)
`2 (1)
`0
`0
`0
`1 ('11)
`0
`1 (<1)
`0
`
`0
`0
`2 (l)
`O
`1 (<1)
`1
`<1 1)
`
`Data in above table was confirmed by review of raw and derived datasets and CRFs.
`Table continues on next page.
`
`83
`
`

`

`Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`'
`
`Treanda (bendamustine)
`
`Continuation of Table 7.7
`
`System organ class
`Preferred term
`
`3
`
`Number (%) of patients'
`Bendamustiue
`Chloranlbucil
`(i§=153)
`(5:143)
`Grade
`Grade
`4
`4
`
`3 or 4
`
`3
`
`3 or 4
`
`,
`
`2 (1)
`1 (<1)
`l («. l)
`l
`(<7 l)
`I (<1)
`
`I (<1)
`2 (1)
`
`1 (<1)
`1 (<1)
`0
`0
`0
`
`0
`2 (l)
`
`0
`l(<l)
`1 (~51)
`0
`1 (<1)
`l (‘11)
`1 (<1)
`D
`0
`0
`0
`0
`3(2)
`0
`2 (l)
`I (<1)
`0
`0
`
`3 (2)
`2(1)
`1 (<1)
`I (<1)
`1 (<1)
`
`1 (<1)
`4 (3)
`
`I («‘l)
`l(-'¢l)
`1 (<1)
`1 (<1)
`1 (<21)
`l ((1)
`1 (<1)
`7 (5)
`4 (3)
`i (<1)
`1 (<1)
`l («3.1)
`8 (5)
`4 (3)
`3 (2)
`1 (<1)
`0
`0
`
`Renal and urinary disorders
`Renal impaimtent
`Pollzdtinria
`Renal failure acute
`Reproductive system and breast
`disorders
`Epididpnitis
`Respiratory, thoracic and mediastinal
`disorders
`1 (<1)
`Cough
`0
`Dyspnca
`0
`Hypoxia
`1 (<1)
`Lung infiltration
`0
`Pleural effusion
`0
`Pulmonary embolism
`0
`Respiratory failure
`7 (5)
`Skin and subcutaneous tissue disorders
`4 (3)
`Rash
`l (q)
`Rush generalized
`1 (<1)
`Skin burning sensation
`1 (<1)
`Urticnria
`5 (3)
`Vascular disorders
`4 (3)
`Hypertension
`1 (<1)
`Hypertensive crisis
`0
`Circulatory collapse
`0
`Anerial occlusive disease
`0
`Hemorrhage
`SOURCE: Summary [5.30. Summary 15.25, and Listing 20.
`" If a patient reported an adverse event more than once. the greatest severity is presented for that adverse
`event.
`
`0
`0
`0
`0
`0
`
`0
`4 (3)
`
`I (<1)
`2(1)
`0
`0
`1 (<1)
`0
`0
`4 (3)
`3 (2)
`1 (<1)
`0
`0
`3 (2)
`2(1)
`0
`0
`1 (Cl)
`(l
`
`I)
`0
`0
`0
`0
`
`O
`1 (<1)
`
`0
`0
`0
`0 -
`0
`1 (<1)
`0
`0
`0
`0
`O
`D
`1 (<1)
`0
`0
`D
`0
`I (<1)
`
`0
`0
`0
`0
`0
`
`0
`5 (3)
`
`I (<1)
`2(1)
`0
`0
`I (<1)
`I (<1)
`0
`4 (3)
`3 (2)
`1 (<1)
`0
`0
`4 (3)
`2(1)
`D
`0
`l (i I)
`I (<1)
`
`-
`
`NOTE: Patients are cmmted only once in each preferred term category and only once in each system organ
`class category. at the greatest severity for each.
`
`Data in above table was confirmed by review of raw and derived datasets and CRFS.
`
`Serious Adverse Events
`
`Fifty-two serious adverse events (SAEs); were reported by 43 patients during the study;
`including those that led to death. Among these, 27 (18%) patients receiving bendamustine
`reported 32 SAEs and 16 (11%) patients receiving chlorambucil reported 20 SAEs.
`
`The most common SAE was infection with 7 (5%) patients treated with bendamustine and 6
`(4%) patients treated with chlorambucil reporting this SAE. SAEs occurring in 22 patients in the
`bendamustine group were pneumonia (3 patients), hypersensitivity (3 patients), anemia (2
`
`84
`
`

`

`Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`
`Treanda (bendamustine)
`
`patients), tumor lysis syndrome (2 patients), and vomiting (2 patients). The SAE occurring in 2
`or more patients receiving chlorambucil was herpes zoster (2 patients). All other SAEs in each
`group were reported in only one patient each. One patient in the chlorambucil group reported
`two occasions of hypersensitivity (Table 7-8).
`
`Table 7-8 Serious Adverse Reactions Occurring in Either Treatment Group by System Organ Class and
`Preferred Term (Treated Analysis Set; Applicant Table)
`
`Bendamustine
`Chlorambucll
`
`(N=153)
`Number
`(%) of
`System organ class
`patientsa
`Preferred term
`27 (18)
`Patients reporting at least 1 serious adverse event
`4 (3)
`Blood and lymphatic system disorders
`2 ( l)
`Anemia
`1 (<1)
`Anemia hemolytie autoimmune
`I («11)
`Hemolysis
`-
`1 (<1)
`Pancytopenia
`0
`Hcmolytic anemia
`1 (<1)
`Cardiac disorders
`1 (<11)
`Myocardial infarction
`0
`Cardiac failure
`1 (<1)
`Eye disorders
`1 (<2!)
`Retinal detachment
`2(1)
`Gastrointestinal disorders
`2 (l)
`Vomiting
`0
`_
`Abdominal pain
`2(1)
`General disorders and administration site conditions
`1 (<1)
`General physical health deterioration
`l (-‘-'l)
`Pyrexia
`1 (<1)
`Hepatobtllary disorders
`1 (<1)
`Gallbladder pain
`3 (2)
`Immune system disorders
`3 (2)
`l-lypersensilivity
`7 (5)
`Infections and infestations
`3 (2)
`Pneumonia
`1 (<1)
`Herpes zoster
`1 (ail)
`Infection
`1 (-:l)
`Respiratory tract infection
`1 (<1)
`Sepsis
`0
`Hepatitis B
`0
`Meningitis
`O
`Pneumonia bacterial
`0
`Uppcr respiratory tract infection
`0
`Injury, poisoning and procedural complications
`0
`Head injury
`1 (<1)
`Metabolism and nutrition disorders
`I (<1)
`Dehydration
`1 (<1)
`hrlusculoskeletal and connective tissue disorders
`i (<1)
`Sacral pain
`Abbreviations and footnotes are provided on the last page of this table.
`
`Number
`of events
`32
`5
`2
`1
`I
`l
`0
`1
`1
`0
`1
`I
`2
`2
`0
`2
`i
`l
`1
`I
`4
`4
`7
`3
`1
`l
`l
`1
`0
`0
`0
`0
`0
`0
`1
`I
`1
`1
`
`93:14.5)
`Number
`(%) of
`patients“
`16 (11)
`l (<l)
`0
`0
`0
`0
`l (<1)
`1 (<1)
`‘ 0
`i (<1)
`0
`0
`1 (<1)
`0
`I (<1)
`1 (<1)
`0
`I (<1)
`0
`0
`l (<l)
`l ('11)
`6 (4)
`0
`2 (l)
`0
`0
`0
`I (<1)
`I (it)
`1 (11)
`I (<1)
`1 (<1)
`i (<1)
`0
`0
`0
`0
`
`Number
`of events
`20
`l
`0
`0
`0
`0
`1
`1
`0
`‘1
`0
`O
`1
`0
`I
`1
`0
`I
`0
`0
`2
`2
`6
`l)
`2
`0
`0
`0
`I
`I
`l
`I
`1
`1
`0
`0
`0
`0
`(continued)
`
`85
`
`

`

`Clinical Review
`
`Qin Ryan, MD, PhD for efficacy review
`Virginia Kwitkowski, MS, RN, CRNP for safety review
`NDA 22249
`
`Treanda (bendamustine)
`
`Data in above table was confirmed by review of raw and derived datasets and CRFS.
`
`Continuation of Table 7.8
`Bendamusline
`(Thlorambucil
`
`System organ class
`Preferred term
`
`Neoplasms benign, malignant and unspecified
`(including cysts and polyps)
`Tumor lysis syndrome
`Nervous system disorders
`Paraplegia
`Neuralgia
`Reproductive system and breast disorders
`Epididymitis
`Respiratory, thoracic and mediustinnl disorders
`Lung infiltration
`Pleural effusion
`Epistaxis
`Laryngeal edema
`Pulmonary embolism
`Skin and subcutaneous [issue disorders
`Unicaria
`Vascular disorders
`Arterial occlusive disease
`Hemorrhage
`Phlebilis
`
`SOURCE: Summary 15.28. Ad lloc Summary I 1. Listing 2|.
`“ Patients may have reponed more than 1 adverse event.
`
`(N=153)
`Number
`
`(N=143)
`Number
`
`(%) of
`atients“
`
`Number
`of events
`
`(%) of
`atiean“
`
`Number
`of events
`
`2 (l)
`2 (l)
`1 (<1)
`1 (<1)
`0
`1 (<1)
`1 (<1)
`2 (l)
`1 (<1)
`l (<l)
`0
`0
`0
`1 (<1)
`1 (<1)
`0
`0
`0
`0
`
`2
`2
`1
`1
`0
`1
`I
`2
`1
`l
`0
`0
`0
`1
`I
`0
`0
`0
`0
`
`0
`0
`1 (<1)
`0
`l (<l)
`0
`0
`3 (2)
`0
`0
`1 (<1)
`1 (<1)
`1 (<1)
`0
`0
`3 (2)
`1 (<1)
`I (<11)
`I <1
`
`0
`()
`1
`0
`1
`0
`0
`3
`0
`0
`1
`1
`1
`0
`0
`3
`1
`1
`1
`
`Data in above table was confirmed by review of raw and derived datasets and CRFs.
`
`,
`I'Rev1ewer comments: The bendamustlne group experienced more serious andsevere .
`‘ (grade3&4) adverse events thanthe chlorambucil group;- The serious and severe (grade 3
`/& 4) adVerSe reactions seenWith bendamustlneare not unusual feracytotoxic agent in”this
`- patient population. ThereaCtiVons seencantypically be managed by an oncologist. Serious
`adverse reactiOns are not asClinically useful asSevere (grade 3 and 4) adVerse reaCtions
`becauseVSAEsinclude hespitalizations. SOme countriesadmitpatientsfor reasons that
`
`"Wouldnotresult111 VaU.S.admission; partly dueto the variatiOnsin healthcaresystems.
`
`7.3.3 Dropouts and/or Discontinuations
`
`Adverse reactions were the most frequent cause of study withdrawal. Twenty-two pati