CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`NDA 22-249
`
`PHARMACOLOGY REVIEWg S!
`
`

`

`Tertiary Pharmacology Review
`
`By:
`
`Paul C. Brown, Ph.D.
`0ND 10
`NDA: 22—249
`
`Submission date: 9/19/07
`Drug: Bendamustine hydrochloride
`Sponsor: Cephalon, Inc.
`Indication: Chronic Lymphocytic Leukemia (CLL)
`Reviewing Division: Division of Drug Oncology Products
`
`'
`
`-
`Comments:
`I concur with the Division pharm/tox recommendation that the non-clinical studies
`submitted to this NDA provide sufficient information to support the use of Treanda ®
`(bendamustine hydrochloride) for the treatment of patients with chronic lymphocytic
`leukemia (CLL).
`.
`
`This alkylating agent exhibited the expected toxicity for this class of compound. As
`expected, bendamustine is mutagenic, carcinogenic, and teratogenic like other nitrogen
`mustard alkylating drugs.
`
`The sponsor proposed a pregnancy labeling category of D and the Division agreed with
`this category although some changes in specific wording describing the relevant studies
`were suggested by the pharm/tox reviewer. I concur with the pregnancy category of D
`and with the description of the findings in labeling.
`
`

`

`43
`
`This is a represen
`' this page is the m
`
`tation of an electronic record that was signe
`anifestation of the electronic signature.
`------------—-----------------------------------------------------------------—-------"---
`
`Paul Brown
`
`3/7/2008 11:17:23 AM
`PHARMACOLOGI ST
`
`

`

` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER:
`SERIAL NUMBER:
`
`DATE RECEIVED BY CENTER:
`
`PRODUCT:
`
`INTENDED CLINICAL POPULATION:
`
`SPONSOR:
`
`DOCUMENTS REVIEWED:
`
`REVIEW DIVISION:
`
`PHARM/TOX REVIEWER:
`
`PHARM/TOX SUPERVISOR:
`
`DIVISION DIRECTOR:
`
`PROJECT MANAGER:
`
`22-249
`
`002
`
`09/19/2007
`
`Treanda® (bendamustine hydrochloride)
`
`Chronic Lymphocytic Leukemia (CLL)
`
`Cephalon, Inc.
`
`Electronic submission
`
`Division of Drug Oncology Products
`
`(HFD—150)
`
`M. Anwar Goheer, Ph.D.
`
`John K. Leighton, Ph.D., D.A.B.T.
`
`Robert Justice, M.D., M.S.
`
`Dorothy W. Pease /Capt. Frank H. Cross Jr.
`
`Date of review submission to Division File System (DFS):
`
`March 11, 2008
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`22-249
`
`2. 6
`
`PHARMA COLOGY/TOXICOLOGY RE VIE W
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY
`
`NDA number:
`Review number:
`Sequence number/date/type of submission:
`Information to sponsor:
`Sponsor and/or agent:
`
`Manufacturer for drug substance:
`
`22—249
`2 (labeling review)
`001 / 09-19-2007 / NDA
`Yes (X) No ( )
`Cephalon, Inc.
`41 Moores Road, Frazer, PA 19355
`I‘
`/
`
`/
`
`/
`
`Reviewer name:
`Division name:
`HFD #:
`Review completion date:
`
`Drug:
`
`M. Anwar Goheer, Ph.D.
`Division of Drug Oncology Products
`150
`March 11, 2008
`
`Trade name:
`
`Generic name:
`
`Treanda (proposed),
`Cytostasan® (Germany) and Ribomustine® (Germany)
`N/A
`
`Code name:
`
`Chemical name:
`
`BMl, CEP-18083, ID00039, ID00275, ID08736, IMET3393,
`M000275, M000039, M008736, SDX-IOS, and ZIMET3393
`Bendamustine hydrochloride.
`1H-Benzimidazole-Z-butanoic acid, 5-[bis(2-
`chloroethy1)amino]- l-methyl- mondhydrochloride, or
`2-Benzimidazole butyric acid, 5--[bis(2-chloroethyl)amino]— 1-
`methyl-, monohydrochloride.
`CAS registry number:
`3543-75-7
`Molecular formula/molecular weight:
`C16H21C12N302.HC1 /
`’5 and 394.7 (hydrochloride)
`
`Structure:
`
`hemlmldazule- ring:
`purine analog?
`
`water-soluble
`
`aikane carboxylic acid:
`
`4 - {5 - [Bis (2-chioroethyl} amino} ‘1‘-
`methyl-2-benzim‘idazoiyi'} bqtyric acid
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`22-249
`
`Relevant INDs/NDAs/DMFS:
`Drug class:
`Intended clinical population:
`Clinical formulation:
`
`IND 67,554
`Cytotoxic alkylating agent
`Chronic Lymphocytic Leukemia (CLL)
`Lyophilized powder for injection (100 mg/vial)
`
`Composition of drug product
`
` Component Reference to Standard Function Amount per Vial
`
`
`
`
`
`
`
`Bendamustiuc BC!
`
`In house standard
`
`Active Ingredient
`
`Mannitol
`
`USP
`
`_/———»
`
`100 mg
`
`170 mg
`
`
`/——-
`
`(Excerpted from the sponsor’s submission)
`
`Route of administration:
`
`Intravenous infusion over 30 minutes
`
`Treanda® is indicated for the treatment of patients with chronic
`Proposed Use:
`lymphocytic leukemia (CLL). The recommended dose is 100 mg/m2 administered as an
`intravenous infusion over 30 minutes on days 1 and 2 of a 28 days cycle, up to 6 cycles.
`
`Disclaimer: Tabular and graphical information are constructed by the reviewer unless
`cited otherwise.
`
`This NDA was submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and
`Cosmetic Act, for Treanda (bendamustine hydrochloride).
`.
`
`Data reliance 2 Except as specifically identified below, all data and information
`discussed below and necessary for approval of NDA 22-249 are owned by Cephalon Inc.
`or are data for which Cephalon has obtained a written right of reference. Any
`information or data necessary for approval of NDA 22-249 that Cephalon does not own
`or have a written right to reference constitutes one of the following: (I) published
`literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as
`described in the drug’s approved labeling. Any data or information described or
`referenced below from a previously approved application that Cephalon does not own (or
`from FDA reviews or summaries of a previously approved application) is for descriptive
`purposes only and is not relied upon for approval of NDA 22-249.
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`22-249
`
`The following recommendations to the sponsor’s proposed labeling are given. The
`Sponsor’s proposed wording is followed by the recommendation with the rationale for
`the recommended changes.
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`

`

`Reviewer:
`
`Anwar Goheer, PhD.
`
`NDA No.
`
`22-249
`
`
`
`15 REFERECES
`
`1. Clinical reference.
`
`2. Preventing occupational exposures to Antineoplastic and Other Hazardous Drugs
`in Health Care Settings. NIOSH Alert 2004-165.
`
`3 OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling
`Occupational Exposure to Hazardous Drugs. OSHA, 1999.
`http://wwwosha.gov/dts/osta/otm/otm vi/otm vi 2.html
`
`4 American Society of Health-System Pharmacists. ASHP Guidelines on Handling
`Hazardous Drugs. Am J Health—Syst Pharm. 2006; 63:1172-1193.
`
`5 Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and
`biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh,
`PA: Oncology Nursing Society.
`
`10
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Anwar Goheer
`
`3/11/2008 03:25:05 PM
`PHARMACOLOGIST
`
`John Leighton
`3/11/2008 03:50:24 PM
`PHARMACOLOGIST
`
`

`

`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`
`22-249
`
`001
`
`DATE RECEIVED BY CENTER:
`
`09/19/2007
`
`PRODUCT:
`
`Treanda® (bendamustine hydrochloride)
`
`INTENDED CLINICAL POPULATION:
`
`Chronic Lymphocytic Leukemia (CLL)
`
`SPONSOR:
`
`DOCUMENTS REVIEWED:
`
`Cephalon, Inc.
`
`Electronic submission
`
`REVIEW DIVISION:
`
`Division of Drug Oncology Products
`
`(HFD-ISO)
`
`PHARM/TOX REVIEWER:
`
`M. Anwar Goheer, Ph.D.
`
`PHARM/TOX SUPERVISOR:
`
`John K. Leighton, Ph.D., D.A.B.T.
`
`DIVISION DIRECTOR:
`
`~
`
`Robert Justice, M.D., M,S.
`
`PROJECT MANAGER:
`
`Dorothy W. Pease
`
`Date of review submission to Division File System (DFS):
`
`February 27, 2008
`
`

`

`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW
`
`3
`7
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY....................................A............................... 7
`
`2.6.2 PHARMACOLOGY ....................................................................................................... 13
`2.6.2.1
`Brief summary ....................................................................................................................... 13
`2.6.2.2
`Primary pharmacodynamics .................................................................................................. 14
`2.6.2.3
`Secondary pharmacodynamics .............................................................................................. 34
`2.6.2.4
`Safety pharmacology ............................................................................................................. 37
`2.6.2.5
`Pharmacodynamic drug interactions ..................................................................................... 43
`
`2.6.3 PHARMACOLOGY TABULATED SUMMARY....................................................... 44
`
`2.6.4 PHARMACOKINETICS/TOXICOKINETICS .......................................................... 44
`2.6.4.1
`Brief summary ....................................................................................................................... 45
`2.6.4.2
`Methods of Analysis.............................................................................................................. 46
`2.6.4.3
`Absorption ............................................................................................................................. 47
`2.6.4.4
`Distribution ........................................................................................................................... 49
`2.6.4.5
`Metabolism ............................................................................................................................. 56
`2.6.4.6
`Excretion ............................................................................................................................... 67
`2.6.4.7
`Pharmacokinetic drug interactions ............................................................................... 64
`
`Other Pharmacokinetic Studies ................................................... 69
`2.6.4.8
`2.6.4.9
`Discussion and Conclusions .................................................................................................. 69
`2.6.4.10
`Tables and figures to include comparative TK summary ...................................................... 70
`
`2.6.5 PHARMACOKINETICS TABULATED SUMIVIARY ............................................... 70
`
`2.6.6 TOXICOLOGY......................................................... 70
`2.6.6.1
`Overall toxicology summary ................................................................................................. 71
`2.6.6.2
`Single-dose toxicity ............................................................................................................... 73
`2.6.6.3
`Repeat-dose toxicity .............................................................................................................. 75
`2.6.6.4
`Genetic toxicology ......................................; ....................................................................... 100
`2.6.6.5
`Carcinogenicity ................................................................................................................... 110
`2.6.6.6
`Reproductive and developmental toxicology ...................................................................... 113
`2.6.6.7
`Local tolerance.................................................................................................................... 124
`2.6.6.8
`Special toxicology studies ................................................................................................... 126
`2.6.6.9
`Discussion and Conclusions ................................................................................................ 128
`2.6.6.10
`Tables and Figures .............................................................................................................. 129
`
`2.6.7 TOXICOLOGY TABULATED SUMMARY ...... ..................................................... 129
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS ............................................. 130
`
`APPENDIX/ATTACHMENTS ............................................................................................... 130
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`22-249
`
`EXECUTIVE SUMMARY
`
`1.
`
`Recommendations
`
`The non-clinical studies submitted to
`A. Recommendation on approvability:
`this NDA provide sufficient information to support the use of Treanda ®
`(bendamustine hydrochloride) for the treatment of patients with chronic
`lymphocytic leukemia (CLL).
`B. Recommendation for nonclinical studies:
`studies are required.
`.
`C. Recommendations on labeling: A separate review will be conducted.
`
`No additional non-clinical
`
`11.
`
`Summary of nonclinical findings
`
`Bendamustine hydrochloride
`Brief overview of nonclinical findings:
`A.
`[Treanda®, Cytostasan® (Germany), and Ribomustine® (Germany)] belongs to
`bifianctional nitrogen mustards. Nitrogen mustard and its derivatives are alkylating drugs
`which dissociate into electrophilic alkyl groups. These groups form covalent bonds with
`electron-rich nucleophilic moieties. The bifunctional covalent linkage produced can lead
`to cell death via several pathways. The precise mechanism of action of bendamustine has
`not been fiilly characterized.
`
`The cytotoxic activity of bendamustine, bendamustine impurities,
`Pharmacology:
`and bendamustine degradationproducts had been studied in human tumor cell lines. The
`antineoplastic activity of bendamustine was tested in vivo in xenograft models.
`In both in
`viva and in vitro tests, bendamustine showed cell cycle effects analogous to other
`alkylating drugs including cyclophosphamide and chlorambucil.
`
`During safety pharmacology testing, bendamustine at 20
`Safety pharmacology:
`and 25 mg/kg affected the urine output, urinary electrolyte (kaliuretic and natriuretic) and
`glomerular filtration rate (creatinine clearance) in Sprague Dawley rats, suggesting
`dysfilnction of glomerular filtration. Histopathology lesions in the kidney were also
`found in the pivotal rat and dog studies described below. Bendamustine hydrochloride
`perfused at concentrations of 1.5 and 7.5 ug/mL in isolated canine Purkinje fibers had no
`statistically significant effect on action potential parameters. Bendamustine at 20 uM and
`200 uM significantly inhibited the hERG tail current amplitude and caused a significant
`deceleration of the tail current decay time constant in HEK 293 cells stably expressing
`the potassium channel. No effects on hERG channel were seen at 2 uM. The clinical
`significant of these findings are not clear. However, cardiotoxicity was also noted upon
`histopathological evaluation in the rat and dog pivotal toxicity studies. Heart failure was
`also noted in the clinical trials. This finding may translate into adverse effects that need
`to be fully explored in future clinical trials. A QT evaluation in patients is planned as
`part of post-marketing (phase 4 commitments).
`
`Pharmacokinetics: Bendamustine was metabolized by both dog and human
`microsomes mainly by Phase 1 metabolism to produce an oxidative metabolite and an N-
`desmethyl metabolite. These processes appeared to be CYP1A2 mediated. Two active
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`22-249
`
`circulating metabolites in human and dog liver preparations were y—hydroxybendamustine
`(M3) and N—desmethylbendamustine (M4). The highest tissue levels of bendamustine
`were'in the kidney and liver. The mass balance study in rats showed that significant
`radioactivity was recovered in both feces (~50%) and urine (~3 7%). The majority of
`radioactivity was eliminated rapidly and remained constant from 1 hour to 24 hours.
`
`During traditional toxicity assessment, the acute (single dose)
`Toxicology:
`toxicity studies were conducted in mice and rats to determine the lethal doses using
`various routes and are reported in the literature (non-GLP). Bendamustine at 80, or 160
`mg/kg/day by stomach tube for 28 consecutive days produced 50% mortalities in rats.
`Body weight gain and food consumption decreased in a dose dependent manner. Total
`white blood count and lymphocytes partly recovered in the surviving animals during the
`recovery phase. There was a dose dependent atrophy of the thymus and inhibition of
`bone marrow hematopoiesis. Bendamustine at 40 and 60 mg/kg by stomach tube for 90
`consecutive days produced 70% and 100% mortalities in Wistar rats, respectively,
`between week 7 and 14. Prior to death, respiration was impaired and the abdomen of the
`animals was extremely swollen. White blood cells and lymphocytes were decreased in
`bendamustine animals. Histopathologically, lymph nodes, spleen and thymus were
`atrophic.
`
`Pivotal repeat dose toxicity studies of 15—weeks intermittent dosing were conducted in
`Sprague-Dawley rats and beagle dogs (GLP). Male and female ‘" JD (SD) rats
`(20/sex/group) were dosed bendamustine at 5, 10, or 15 mg/kg/day via 30 minute
`intravenous infusion once daily for 3 consecutive days in each of five dose cycles. Each
`dose cycle consisted of 21 days (3 dose days followed by 18 non-dose days). Mortalities
`(28) occurred in control and test animals throughout the study. Swollen ventral
`abdomens were observed in control and treated animals. This may be due to infiision
`apparatus and decreased white blood c'ounts observed in the bendamustine treated groups.
`Hematological evaluations showed a dose-related decrease in white blood cell and
`absolute lymphocyte counts. Treatment related microscopic changes were in the kidney
`(tubular degeneration] necrosis), heart (cardiomyopathy, focal/multifocal, in male
`animals only), and bone marrow hyperplasia (femur and sternum). As pointed out in the
`Pharmacokinetic section, the kidney had high levels of bendamustine and was a
`significant route of excretion. Bone marrow hyperplasia was not dose-related (4 animals
`given 5 mg/kg/dose, 1 female given 10 mg/kg/dose, and 1 male given 15 mg/kg/day). All
`animals with bone marrow hyperplasia died at unscheduled intervals and absence of it in
`surviving animals suggests that the findings were not test article related or that the timing
`of the observation was not optimal. The plasma concentrations of bendamustine and both
`metabolites (M3 & M4) were dose-related over the dose range evaluated. Systemic
`exposure to bendamustine did not appear to differ consistently with respect to the sex of
`the animal or the day of dosing. The apparent t1/2 values ranged from 0.14 to 0.36 hr.
`Concentrations of M3 and M4 were typically below the limit of quantitation by 2 and 1
`hour, respectively, after the start of the infusion.
`
`Bendamustine hydrochloride was administered to beagle dogs (3/sex/group) at dosage
`levels of 1.65, 3.3 or 6.6 mg/kg/day by 30 minute daily intravenous infusion over 4
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`22-249
`
`consecutive days for a total of three treatment cycles. Each cycle was followed by a 31
`days recovery period. Three high dose animals (2 males & 1 female) showed
`deterioration of health and were killed on humane grounds during the recovery phase of
`the second treatment. Remaining high dose animals were killed on day 29 of this period.
`Brown/yellow liquid vomitus was noted in treated animals. Body weight loss and
`reduction in food consumption were noted in both sexes in a dose—related manner. Heart
`rates were reduced during cycle 2 at 6.6 mg/kg/day (2 males & 1 female, 3/6 animals).
`Myocardial interstitial inflammation, left atrioventricular valve hemorrhage and
`leukocytosis were observed in high dose animals. Reduction in WBC counts and
`lymphocytes were observed in a dose-related manner. Bone marrow suppression
`(decreased myeloid cells) was observed in animals sacrificed on humane grounds.
`Lymphoid tissues of high dose animals showed marked or severe changes indicating
`immunosuppression. Bendamustine also affected testes (seminiferous tubular atrophy),
`and resulted in mucosal congestion and hemorrhage in the intestines. Systemic exposure
`was demonstrated at all three dose levels and was dose proportional in cycle 3.
`
`Genetic toxicology: Bendamustine induced mutation in Ames test with or without
`metabolic activation. In the in vitro chromosome aberration assay using human
`lymphocytes, bendamustine produced chromosome aberrations in the presence and
`absence of metabolic activation. Bendamustine also induced a significant increase in the
`incidence of micronucleated polychromatic erythrocytes in male and female rats.
`Hydroxy bendamustine (M3) in the presence and absence of metabolic activation also
`induced structural chromosomal aberration in human lymphocytes in vitro. Therefore,
`bendamustine is a genotoxic alkylating agent.
`
`Although study design in the published paper (Arch
`Carcinogenicity:
`Geschwulstforsch 1974; 43(1):l6-21) was not adequate to fiilly assess the carcinogenic
`potential of bendamustine, intraperitoneal injections of bendamustine for four days
`produced peritoneal sarcoma in mice. Oral administration for four days induced
`mammary carcinoma and pulmonary adenomas in mice. Pulmonary adenoma showed
`signs of malignancy accompanied by pleural rupture dedifferentiation. The evaluations
`of carcinogenic potentials for oncology drugs are usually not required.
`
`Embryo-fetal developmental studies
`Developmental and reproductive toxicity:
`were not conducted by the sponsor. Published non-GLP studies referenced by the
`sponsor have not been adequately conducted to fully evaluate the developmental toxicity
`of bendamustine. During embryo-fetal developmental toxicity study, intraperitoneal
`administration of bendamustine produced embryotoxic and teratogenic effects in mice.
`Malformations observed included exencephaly, cleft palates, and dwarfism (decreased
`body weights). Bendamustine (ip administration) also caused external (bent/circinate
`tail) and internal (hydronephrosis and hydrocephalus) malformation in Wistar rats. These
`developmental findings clearly demonstrate bendamustine as a nitrogen mustard
`alkylating agent.
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`22—249
`
`Perivenous injection of bendamustine at a concentration of 0.6 or
`Local tolerance:
`1.0 mg/ml or intra-arterial injection at a concentration of 0.2 or 0.6 mg/mL produced
`local irritation at the injection sites in the ear of New Zealand White rabbits.
`
`Bendamustine is a bifunctional nitrogen mustard
`Pharmacologic activity:
`B.
`derivative. Nitrogen mustard and its derivatives are alkylating agents which dissociate
`into electrophilic alkyl groups. These groups form covalent bonds with electron-rich
`nucleophilic moieties. This bifunctional covalent linkage produced can lead to cell death
`via several pathways. The exact mechanism of action of bendamustine remains
`unknown.
`
`Reduction in WBC
`Nonclinical safety issues relevant to clinical use:
`C.
`and lymphocytes were observed in a dose related manner during pivotal repeat dose ‘
`toxicity studies in rats and dogs. Treatment related microscopic changes were seen in
`kidneys (tubular degeneration/necrosis) in both species. Cardiomyopathy
`(focal/multifocal) was observed in male rats only. Heart rates of dogs at 6.6 mg/kg/day
`were reduced during cycle 2 (2 males & 1 female, 3/6 animals). A vigilant monitoring of
`QT prolongation is warranted until more clinical experience is gained; a clinical study is
`planned as a part of post-marketing. Bendamustine is mutagenic, carcinogenic, and
`teratogenic like other nitrogen mustard alkylating drugs.
`
`APPEARS THSS WAY
`0N ORlGlNAL
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`22-249
`
`2.6 PHARMACOLOGY/TOXICOLOGYREVIEW
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY
`
`NDA number:
`Review number:
`Sequence number/date/type of submission:
`Information to sponsor:
`Sponsor and/or agent:
`
`Manufacturer for drug substance:
`
`22-249
`1
`001 / 09-19-2007 / NDA
`Yes () No (X)
`Ccphalon, Inc.
`41 Moores Road, Frazer, PA 19355
`/
`/
`/
`./
`/
`/
`
`Reviewer name:
`Division name:
`HFD #:
`
`M. Anwar Goheer, Ph.D.
`Division of Drug Oncology Products
`150
`
`Review completion date:
`
`February 27, 2008
`
`Drug:
`
`Trade name:
`
`Generic name:
`
`Treanda (proposed),
`Cytostasan® (Germany) and Ribomustine® (Germany)
`N/A
`
`Code name:
`
`Chemical name:
`
`BMl, CEP-18083, ID00039, ID00275, ID08736, IMET3393,
`M000275, M000039, M008736, SDX-lOS, and ZIMET3393
`Bendamustine hydrochloride.
`1H—Benzimidazole—2-butanoic acid, 5-[bis(2-
`chloroethyl)amino]-1-methyl- monohydrochloride, or
`2-Benzimidazole butyric acid, 5-[bis(2-chloroethyl)amino]-1-
`methyl-, monohydrochloride.
`CAS registry number:
`3543-75-7
`Molecular formula/molecular weight:
`C16H21C12N302HC1 /
`
`' H
`V
`'
`. and 394.7 (hydrochloride)
`'
`
` benzimldazole ring:
`purine anaiog?
`________________
`
`Structure:
`
`a
`
`i I I I i i l
`
`
`
`.....L.
`
`,
`
`c):I3:9393;
`
`z\zN --‘.fl
`
`
`
`Nitrogen mustard:
`alkyiaflng agent
`
`w»»»
`
`9x)3?! ZI
`
`««(~«»~
`
`h-
`
`-.u_--.___.“_h_
`
`u-_--_.“.-_____
`
`alkane carboxyiic acid;
`water-soluble
`
`4 - {5 - [Bis (2~chioroethyl) amino] «1 »
`methyl-2~benzimidazoiyl} butyric acid
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`22-249
`
`Relevant INDs/NDAs/DMFS:
`Drug class:
`Intended clinical population:
`Clinical formulation:
`
`IND 67,554
`Cytotoxic alkylating agent
`Chronic Lymphocytic Leukemia (CLL)
`Lyophilized powder for injection (100 mg/vial)
`
`Composition of drug product
`—-———————————_______________________
`Component
`Reference to Standard
`Function
`Amount per Vial
`
`Bendamustine HCl
`Mannitol
`
`In house standard
`USP
`
`Active Ingredient
`‘M
`
`100 mg
`170 mg
`
`J _
`
`“MK.“DH.A . mum-“WWW
`¢-—-———‘—\
`
`(Excerpted from the sponsor’s submission)
`
`Route of administration:
`
`Intravenous ll‘lfilSIOIl over 30 minutes
`
`Treanda® is indicated for the treatment of patients with chronic
`Proposed Use:
`lymphocytic leukemia (CLL). The recommended dose is 100 mg/m2 administered as an
`intravenous infiJsion over 30 minutes on days 1 and 2 of a 28 days cycle, up to 6 cycles.
`
`Disclaimer: Tabular and graphical information are constructed by the reviewer unless
`cited otherwise.
`
`This NDA was submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and
`Cosmetic Act, for Treanda (bendamustine hydrochloride).
`
`Data reliance : Except as specifically identified below, all data and information
`discussed below and necessary for approval of NDA 22-249 are owned by Cephalon Inc.
`or are data for which Cephalon has obtained a written right of reference. Any
`information or data necessary for approval of NDA 22-249 that Cephalon does not own
`or have a written right to reference constitutes one of the following: (1) published
`literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as
`described in the drug’s approved labeling. Any data or information described or
`referenced below from a previously approved application that Cephalon does not own (or
`from FDA reviews or summaries of a previously approved application) is for descriptive
`purposes only and is not relied upon for approval of NDA 22-249.
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`22-249
`
`Studies reviewed within this submission:
`
`4.2.1 Pharmacology
`
`4.2.1.1 Primary Pharmacodynamics
`
`4.2.1.1.1 Effect of Bendamustine on Different Human Tumour Cell Lines In vitro. Study
`0640. 00. C7. 04.
`'
`
`4.2. 1. 1. 5 Cell Cycle Alterations by Bendamustine1n Comparison with Other Cytotoxic
`Agents. Study 0640. 00. C7. 01.
`4.2.1. 1.6 The Efficacy of Bendamustlne1s Slightly Decreased by P-glycoprotein and
`MXR/BCRP Resistance Mechanisms. Study 0640.00.C7.02
`4.2.1.1.9 Bendamustine Hydrochloride and the Antitumor Drug Screen Program of the
`National Cancer Institutes (NCI). Study F-DE-NCI—2004.
`4.2.1.1.7 Analysis of the Cytotoxic Potential of Bendamustine Hydrochloride on Human
`Lymphocytes as Compared to its Degradation and By-Products. Study 744303.
`4.2.1.1.8 Analysis of the Cytotoxic Potential of Bendamustine Hydrochloride on Tumor
`Cell Lines as Compared to its Degradation Products. Study 754900.
`4.2.1.1.10 Analysis of the Cytotoxic Potential of Bendamustine Hydrochloride on Tumor
`Cell Lines as Compared to its Metabblite N—Desmethyl Bendamustine. Study
`789401
`
`4.2.1.1.11 Analysis of the Cytotoxic Potential of Bendamustine Hydrochloride on Tumor
`cell Lines as Compared to its Metabolite N—Desmethyl Bendamustine. Study
`789403.
`.
`
`4.2.1.1.2 Effect of Bendamustine Hydrochloride By-Products and -"
`—-\:/_‘
`, on Tumour Cell Growth. Study 0640.01 .C07.06.
`4.2.1.1.3 Efficacy of Bendamustine Hydrochloride on the Human Mammary Carcinoma
`MDA-MB 231 in the NMRI nu/nu Mouse after Intravenous Treatment. Study
`0640.00.C8.02.
`
`4.2.1.1.4 Efficacy of Bendamustine Hydrochloride on the Human Lung Carcinoma LX-l
`in the NMRI nu/nu Mouse after Intravenous Treatment. Study 0640.00.C08.01.
`4.2.1.1.13 Efficacy Dose Response for SDX-105 in a Xenograft Model of SUDHL-l in
`SCID Mice. Study T109.
`4.2.1.1.14 Efficacy of SDX-IOS and Rituxan in a Xenograft Model of Daudi in SCID
`Mice. Study T1 16.
`4211.15 Efficacy of SDX-105 and Rituxan in a Xenograft Model ofDaudi in SCID
`Mice. Study T124.
`4.2. 1.1.16 Dose Response of SDX- 105 and SDX- 1011n a Xenograft Model of Daudl1n
`.
`SCID Mice. Study T110.
`
`4.2.1.2 Secondary Pharmacodynamics
`
`4.2.1.2.1 Effect of Bendamustine Hydrochloride on Different Non-Malignant Cells of
`Mice and Humans in Comparison to Other Well—Known Cytostatic Drugs. Study
`0640.01.C07.07.
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`22—249
`
`4.2.1.2.2 Determination of the Cytotoxic Potential of SDX-105 in Cultured Human
`Hepatocytes after In vitro Exposure. Study DM-2005-002.
`4.2.1.1.12 Cytotoxicity Assay In vitro with BALB/C3T3 Cells: Neutral Red (NR) Test
`with Bendamustine Hydrochloride at Simultaneos Irradiation with Artificial
`Sunlight. Study 789402.
`
`4.2.1.3 Safety Pharmacology
`
`4.2.1.3.1 Evaluation of Effect on Urine Output, Urinary Electrolyte Balance and
`Glomerular Filtration Rate in the Rat with a Saline Overload Following Two
`Successive 30-Minute Intravenous Infusions. Study 20010337 PGR.
`4.2.1.3.2 Evaluation of Effect on Cardiac Action Potential in Isolated Canine Purkinje
`Fibers. Study 20010339 PECM.
`4.2.1 .3.3 Bendamustine Hydrochloride: Effects on HERG-l Tail Currents Recorded from
`Stably Transfected HEK 293 Cells. Study 853896.
`
`4.2.1.4 Pharmacodynamic Drug Interactions. N/A
`
`4.2.2 Pharmacokinetics
`
`4.2.2.1 Analytical Methods and Validation Reports
`
`4.2.2.1.] Validation of a High Performance Liquid Chromatographic Method for the
`Measurement of Bendamustine and Two Major Metabolites in Dog Plasma and
`Urine. Study KLG-09.
`4.2.2.1.2 Validation Report: Determination of Bendamustine M3 Metabolite, and M4
`Metabolite in K2EDTA rat plasma. Study DP-2007-030.
`
`4.2.2.2 Absorption
`
`4.2.2.2.1 Studies on the Pharrnacokinetics of Bendamustine [14C] in the Rat. Study DM-
`2006-012.
`
`4.2.2.3 Distribution
`
`4.2.2.3.1 Disposition of 14C-Bendamustin in Mice and Rats. Study DM-2007-001.
`4.2.2.3.2 The Tissue Distribution of Total Radioactivity in the Rat Following Intravenous
`Administration of [14C]-CEP—18083. Study DM-2005-006.
`4.2.2.3.3 The Tissue Distribution of Total Radioactivity in the Pigmented Rat Following
`Intravenous Administration of [14C]-CEP-18083.HCl (Quantitative Whole Body
`Autoradiography). Study Am 02 DM-2005-007.
`'
`4.2.2.3.4 Excretion and Distribution Studies of 14C—Bendamustin in the Dog. Study
`KLG-OS.
`
`10
`
`

`

`Reviewer:
`
`Anwar Goheer, Ph.D.
`
`NDA No.
`
`22-249
`
`4.2.2.4 Metabolism
`
`4.2.2.4.1 In vitro Evaluation of CEP—18083 (Bendamustine) as an Inducer 0f Cytochrome
`P450 Expression in Cultured Human Hepatocytes. Study DM-2005-004.
`4.2.2.4.2 In vitro Metabolism studies of l4C—Bendamustin. Study 99-37—KLG—01.
`4.2.2.4.4 In vitro Plasma Protein Binding Studies of Bendamustine. Study KLG-06.
`4.2.2.4.3 Metabolic Profile of [14C]-CEP—1 8083 (Bendamustine) in Rat Urine and Bile:
`Preliminary Structural Identification of Metabolites. Study DM-2006-002.
`
`4.2.2.5 Excretion
`
`4.2.2.5.] The Disposition of [14C]-CEP-18083 in the Rat Following Intravenous
`Administration. Study Am 01 DM-2005-005.pdf
`
`4.2.2.6 Pharmacokinetic Drug Interactions:
`
`N/A
`
`4.2.2.7 Other Pharmacokinetic Studies:
`
`N/A
`
`4.2.3 Toxicology
`
`4.2.3.1 Single Dose Toxicity Studies
`
`4.2.3.1.1 Bendamustine Single-Dose Toxicity Study in Mice and Rats. Haertl 1989.
`
`' 4.2.3.2 Repeat Dose Toxicity Studies
`
`4.2.3.2.1 5-Day Intermittent Intravenous Infusion Dose Range Finding Toxicity Study
`with CEP—18083 (Bendamustine) in Rats with a 16-Day Recovery Period. Study
`DS-2006—01 1.
`
`4.2.3.2.2 lS-Week Intermittent Intravenous Infusion Toxicity and Toxicokinetic Study
`with CEO-18083 (Bendamustine) in Rats with a 4-Week Recovery Period. Study
`DS-2006-010.
`
`4.2.3.2.5 Bendamustine One-Month Oral Toxicity Study in Rats. Horn et a] 1984.
`4.2.3.2.6 Bendamustine 3-M0nths Oral Toxicity Study in Rats. Janowski 1985
`4.2.3.2.3 Bendamustine Hydrochloride Maximum Tolerated Dose and Five Day Repeated
`Dose Study in Dogs by Intravenous Infusion. Study 0640.98.C2.01.
`4.2.3.2.4 Bendamustine Hydrochloride Toxicity to Dogs by Daily Intravenous Infusion
`Over a Minimum of Three 4-Day Cycles Each Followed by a Period Without
`Treatment of up to 31 Days. Study.0640.98.C2..02.
`
`4.2.3.3 Genotoxicity Studies
`
`4.2.3.3.1 Bendamustin