CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`
`
`APPLICATION NUMBER:
`201023
`201023
`
`
`PHARMACOLOGY REVIEW(S)
`PHARMACOLOGY REVIEW! S!
`
`
`
`
`
`
`
`
`
`

`

`MEMORANDUM
`
`
`Jevtana (Cabazitaxel)
`
`Date: June 14, 2010
`File for NDA 201023
`To:
`From: John K. Leighton, PhD, DABT
`
`Associate Director for Pharmacology/Toxicology
`
`Office of Oncology Drug Products
`
`
` I
`
` have examined pharmacology/toxicology supporting review and labeling provided by
`Drs. Khasar and Helms and supervisory memorandum provided by Dr. Verbois. I concur
`with their conclusions that Jevtana may be approved for the proposed indication and that
`no additional pharmacology/toxicology studies are needed.
`
`

`

`Application
`Type/Number
`--------------------
`NDA-201023
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`SANOFI AVENTIS
`SPA
`
`------------------------------------------
`CABAZITAXEL (XRP6258)
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOHN K LEIGHTON
`06/14/2010
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`
`
`
`
`201,023
`Application number:
`0000
`Supporting document/s:
`December 18, 2009
`Applicant’s letter date:
`03/31/2010
`CDER stamp date:
`Cabazitaxel (XRP6258)
`Product:
`Metastatic prostate cancer
`Indication:
`Sanofi Aventis SPA
`Applicant:
`Division of Drug Oncology Products
`Review Division:
`Reviewer: Whitney S. Helms, Ph.D.
`Hans Rosenfeldt, Ph.D. acting for
`Supervisor/Team Leader:
`S. Leigh Verbois, Ph.D.
`Robert L. Justice, M.D., M.S.
`Christy L. Cottrell
`
`Division Director:
`Project Manager:
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 201023 are owned by Sanofi Aventis or are data
`for which Sanofi Aventis has obtained a written right of reference.
`Any information or data necessary for approval of NDA 201023 that Sanofi
`Aventis 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 Sanofi Aventis 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 201023.
`
`6 pages of Pharmacology has been withheld in
`full immediately following this page as B4 CCI/
`TS
`
`

`

`Application
`Type/Number
`--------------------
`NDA-201023
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`SANOFI AVENTIS
`SPA
`
`------------------------------------------
`CABAZITAXEL (XRP6258)
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WHITNEY S HELMS
`06/14/2010
`
`HANS M ROSENFELDT
`06/14/2010
`
`

`

`
`
`MEMORANDUM
`
`
`
`
`
`
`Date: June 3, 2010
`From: S. Leigh Verbois, Ph.D.
`
`Supervisory Pharmacologist
`
`Division of Drug Oncology Products
`File for NDA #201,023
`To:
`
`Cabazitaxel (JEVTANA)
`Re: Approvability of Pharmacology and Toxicology
`
`
`Non-clinical studies that investigated the pharmacology and toxicology of cabazitaxel
`provided to support NDA 201,023 for the treatment of patients with metastatic prostate
`cancer were reviewed in detail by Whitney S. Helms, Ph.D., and G. Sachia Khasar, Ph.D.
`The supporting information included studies of intravenously administered cabazitaxel
`that investigated the drug’s pharmacology, pharmacokinetics and ADME, safety
`pharmacology, general toxicology (rat and dog), genetic toxicity (in vivo and in vitro),
`and reproductive toxicity in both rats and rabbits. The studies cited in the review consist
`primarily of original research conducted by the applicant.
`
`The pharmacology studies submitted to the NDA demonstrate that cabazitaxel is a taxane
`which binds tubulin, promotes microtubule polymerization and prevents disassembly.
`Based on this, the pharmacological classification of cabazitaxel is a microtubule
`inhibitor, like other taxanes which have similar mechanisms of action. Drug induced
`toxicity, including gastrointestinal toxicity, bone marrow toxicity, and neuronal toxicity
`were observed non-clinically. These findings are not unexpected and were well
`characterized.
`
`Cabazitaxel increased micronuclei in rats, and increased numerical aberrations with or
`without metabolic activation in an in vitro test in human lymphocytes. No induction of
`structural aberrations was observed in human lymphocytes. Additionally cabazitaxel was
`negative in the Ames test. The positive in vivo genotoxicity findings are consistent with
`the pharmacological activity of the compound (inhibition of tubulin depolymerization).
`
`Like other taxanes, cabazitaxel is a highly toxic to the developing embryo or fetus
`causing embryolethality, pre and post implantation loss, fetal death and decreased fetal
`weight at a doses approximately 0.02-0.06 times the Cmax in cancer patients at the
`recommended human dose of 25 mg/m2. Teratogenesis was not detected however minor
`variations, (i.e. delays in skeletal ossifications) at doses 0.02x the maximum
`recommended human dose were observed. In the rabbit study abject maternal toxicity
`without fetal or embryonic toxicity was observed. Although these studies utilized doses
`that there far below the clinical dose maternal toxicity or development toxicity was
`observed in each study. Because the potential benefit from the use of the JEVTANA in
`pregnant women in this patient population may outweigh the potential risk to the
`developing fetus, Pregnancy Category D is recommended for this patient population.
`
`

`

`Numerous issues chemistry and manufacturing issues were identified during the review
`of JEVTANA which impacted the pharmacology and toxicology review of JEVTANA.
`These are discussed in detail in the primary review and include the potential propensity of
`the drug product to form a precipitate, and impurity and residual solvent qualification.
`The sponsor has adequately qualified impurites either through non-clinical studies or
`through provided information. With regard to precipitate formation, although the lung is
`the most sensitive organ for precipitate induced toxicity and wheezing was noted in the
`rat in chronic study, precipitate was not noted in the study and nor was there
`histopathological evidence of pulmonary toxicity associated with wheezing. Although
`this is a theorectical concern there is not data to indicate that precipition occurred in the
`drug product in non-clinical studies.
`
`
`Recommendations: I concur with Drs. Helms’s and Khasar’s conclusion that
`pharmacology and toxicology data support the approval of NDA 201,023 for JEVTANA.
`There are no outstanding nonclinical issues related to the approval of JEVTANA for the
`proposed indication.
`
`
`

`

`Application
`Type/Number
`--------------------
`NDA-201023
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`SANOFI AVENTIS
`SPA
`
`------------------------------------------
`CABAZITAXEL (XRP6258)
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SANDI L VERBOIS
`06/03/2010
`
`

`

`NDA # 201,023 Sachia Khasar, Ph.D., Whitney S. Helms, Ph.D
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`
`
`
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`Applicant:
`Review Division:
`Reviewer:
`
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`
`201,023
`0000
`December 18, 2009
`03/31/2010
`Cabazitaxel (XRP6258)
`Metastatic prostate cancer
`Sanofi Aventis SPA
`Division of Drug Oncology Products
`G. Sachia Khasar, Ph.D.
`Whitney S. Helms, Ph.D.
`S. Leigh Verbois, Ph.D.
`Robert L. Justice, M.D., M.S.
`Christy L. Cottrell
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 201023 are owned by Sanofi Aventis or are data for
`which Sanofi Aventis has obtained a written right of reference.
`Any information or data necessary for approval of NDA 201023 that Sanofi Aventis 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 Sanofi Aventis 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 201023.
`
`

`

`NDA # 201,023 Sachia Khasar, Ph.D., Whitney S. Helms, Ph.D
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES................................................ 1
`
`TABLE OF CONTENTS
`
`PUBLIC HEALTH SERVICE........................................................................................... 1
`
`FOOD AND DRUG ADMINISTRATION.......................................................................... 1
`
`CENTER FOR DRUG EVALUATION AND RESEARCH ............................................... 1
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION ....................... 1
`
`DISCLAIMER.................................................................................................................. 1
`
`TABLE OF CONTENTS.................................................................................................. 2
`
`TABLE OF TABLES....................................................................................................... 4
`
`TABLE OF FIGURES ..................................................................................................... 7
`
`1 EXECUTIVE SUMMARY ......................................................................................... 8
`1.1 RECOMMENDATIONS............................................................................................ 8
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 8
`2 DRUG INFORMATION .......................................................................................... 12
`
`2.1 DRUG................................................................................................................. 12
`
`2.3 CLINICAL FORMULATION ............................................................................... 12
`
`2.4
`
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN.................... 13
`
`2.5 REGULATORY BACKGROUND ....................................................................... 13
`
`3 STUDIES SUBMITTED.......................................................................................... 13
`
`3.1
`
`STUDIES REVIEWED........................................................................................ 13
`
`REVIEWED UNDER IND 56,999 .................................................................................. 17
`
`3.2
`
`3.3
`
`STUDIES NOT REVIEWED ............................................................................... 18
`
`PREVIOUS REVIEWS REFERENCED.............................................................. 19
`
`4 PHARMACOLOGY................................................................................................ 20
`
` 2
`
`

`

`NDA # 201,023 Sachia Khasar, Ph.D., Whitney S. Helms, Ph.D
`
`PRIMARY PHARMACOLOGY................................................................................. 20
`4.1
`SECONDARY PHARMACOLOGY............................................................................ 32
`4.2
`SAFETY PHARMACOLOGY................................................................................... 33
`4.3
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 54
`5.1
`PK/ADME........................................................................................................ 54
`ABSORPTION ............................................................................................................... 54
`DISTRIBUTION .............................................................................................................. 56
`METABOLISM ............................................................................................................... 59
`EXCRETION.................................................................................................................. 67
`6 GENERAL TOXICOLOGY..................................................................................... 69
`6.1
`SINGLE-DOSE TOXICITY..................................................................................... 69
`6.2 REPEAT-DOSE TOXICITY.................................................................................... 69
`7 GENETIC TOXICOLOGY ...................................................................................... 96
`7.1
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES)....................... 96
`7.2
`IN VITRO CHROMOSOMAL ABERRATION ASSAYS IN MAMMALIAN CELLS .................. 99
`7.3
`IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY)................ 107
`7.4 OTHER GENETIC TOXICITY STUDIES.................................................................. 110
`8 CARCINOGENICITY ........................................................................................... 115
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .............................. 115
`9.1
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT............................................. 115
`EMBRYONIC FETAL DEVELOPMENT .............................................................................. 124
`11
`INTEGRATED SUMMARY AND SAFETY EVALUATION............................... 144
`
`PHARMACOLOGY..................................................................................................... 144
`
`SAFETY PHARMACOLOGY...................................................................................... 146
`
`TOXICOLOGY ............................................................................................................ 148
`
`REPRODUCTIVE TOXICTY ....................................................................................... 149
`
`GENETIC TOXICITY................................................................................................... 152
`
`IMPURITIES................................................................................................................ 152
`
`APPENDIX/ATTACHMENTS........................................................................... 162
`
`12
`
`
` 3
`
`

`

`NDA # 201,023 Sachia Khasar, Ph.D., Whitney S. Helms, Ph.D
`
`Table of Tables
`Table 1: Cabazitaxel In Vitro Inhibition of Tumor Cell Lines......................................... 21
`Table 2: Cabazitaxel In Vitro Inhibition of Chemoresistant Cell Lines .......................... 23
`Table 3: Inhibition of P388 by Cabazitaxel and Its Metabolites ..................................... 24
`Table 4: In Vivo Tumor Effects ...................................................................................... 25
`Table 5: In Vivo Effects on Human Tumor Models ........................................................ 26
`Table 6: Effects on Subcutaneous or Intracranially Implanted Tumors ........................ 30
`Table 7: Affinities of RPR 116258 for the 25 Binding Sites Studied ............................. 33
`Table 8: RPR 116258 Effects on Rat Activity ............................................................... 36
`Table 9: Anticonvulsant Test........................................................................................ 38
`Table 10: Proconvulsant Test....................................................................................... 38
`Table 11: Effects on Sleep Time .................................................................................. 40
`Table 12: Tail Latency/Nociception Effects .................................................................. 41
`Table 13: hERG Assay Inhibition .................................................................................. 42
`Table 14: In Vitro Effects on Action Potential ................................................................ 43
`Table 15: In Vitro Effects on Action Potential-Difference from Pre-treatment Control .. 43
`Table 16: Effects on Respiration Rate.......................................................................... 48
`Table 17: Effects on Renal Function ............................................................................ 50
`Table 18: Effects on Spasmogen Response ................................................................ 52
`Table 19: Effects on GI Movement............................................................................... 54
`Table 20: Sampling schema.......................................................................................... 55
`Table 21: Cabazitaxel plasma concentrations............................................................... 55
`Table 22: Plasma PK parameters of cabazitaxel in male rats ....................................... 55
`Table 23: Mean percentage of in vitro bound and free.................................................. 56
`Table 24: Dosing protocol ............................................................................................. 57
`Table 25: Cmax and AUC ............................................................................................. 57
`Table 26: Placental Transfer ......................................................................................... 59
`Table 27: Microsome P450 Content............................................................................. 60
`Table 28: AUC values of cabazitaxel and metabolites .................................................. 62
`Table 29: Plasma .......................................................................................................... 63
`Table 30: Rat, Dog and Human Comparison of in vivo Metabolc Profile in Excreta..... 63
`Table 31: XRP6258 and its metabolites in liver and lungs ............................................ 64
`Table 32: Radioactivity elimination in male and female rats.......................................... 67
`Table 33: Cabazitaxel in Rat Breast Milk...................................................................... 69
`Table 34: Mortality......................................................................................................... 71
`Table 35: Clinical signs ................................................................................................. 72
`Table 36: Hematology ................................................................................................... 75
`Table 37: Clinical chemistry .......................................................................................... 76
`Table 38: Urinalysis....................................................................................................... 77
`Table 39: Gross pathology ............................................................................................ 78
`Table 40: Organ Weights ............................................................................................. 78
`Table 41: Histological findings....................................................................................... 79
`Table 42: cabazitaxel toxicokinetics in male and female SD rats.................................. 83
`Table 43: Clinical Signs................................................................................................. 85
`Table 44: Heart rate and QTcv...................................................................................... 88
`
` 4
`
`

`

`NDA # 201,023 Sachia Khasar, Ph.D., Whitney S. Helms, Ph.D
`
`Table 45: Hematology ................................................................................................... 89
`Table 46: Clinical Chemistry.......................................................................................... 90
`Table 47: Urinalysis....................................................................................................... 90
`Table 48: Gross Pathology............................................................................................ 91
`Table 49: Organ weight................................................................................................. 91
`Table 50: Histological findings....................................................................................... 92
`Table 51: Results of assay of lymphocytes from a female donor (20 h)...................... 102
`Table 52: Results of assay of lymphocytes from a male donor (20 h)......................... 104
`Table 53: Results of assay of lymphocytes from a male donor (44 h)......................... 105
`Table 54: In vitro chromosome abberation test ........................................................... 106
`Table 55: Experimental design.................................................................................... 108
`Table 56: Cytotoxicity and incidence of micronucleated PE........................................ 109
`Table 57: Historical controls ........................................................................................ 109
`Table 58: TA1535 and TA1537 ................................................................................... 112
`Table 59: TA98 and TA100 ......................................................................................... 113
`Table 60: TA102.......................................................................................................... 114
`Table 61: Historical controls ........................................................................................ 114
`Table 62: Male Fertility Mortality ................................................................................ 116
`Table 63: Clinical Signs.............................................................................................. 117
`Table 64: F1 Necropsy Results .................................................................................. 120
`Table 65: Fertility Parameters ..................................................................................... 120
`Table 66: Pregnancy Parameters............................................................................... 120
`Table 67: F1 Necropsy Results .................................................................................. 123
`Table 68: Fertility Parameters .................................................................................... 123
`Table 69: Pregnancy Parameters............................................................................... 123
`Table 70: Maternal Rat Mortality ................................................................................. 125
`Table 71: Maternal Rat Clincal Signs ......................................................................... 125
`Table 72: Rat Cesarean Section Data......................................................................... 127
`Table 73: F1 Birth Weight............................................................................................ 128
`Table 74: F1 Malformations/Variations....................................................................... 128
`Table 75: Rat Maternal Clinical Signs ......................................................................... 130
`Table 76: Hematology ................................................................................................ 132
`Table 77: Clinical Chemistry........................................................................................ 132
`Table 78: Cesarean Section Data ............................................................................... 133
`Table 79: Fetal Birth Weight........................................................................................ 133
`Table 80: Rabbit Cesarean Section Data.................................................................... 136
`Table 81: Rabbit Fetal Body Weight............................................................................ 136
`Table 82: Rabbit F1 Malformations/Variations ............................................................ 136
`Table 83: Rabbit Mortality .......................................................................................... 138
`Table 84: Rabbit Macroscopic Findings ..................................................................... 140
`Table 85: Rabbit Maternal Mortality............................................................................ 141
`Table 86: Rabbit Maternal Toxicokinetics................................................................... 143
`Table 87: Rabbit Maternal Hematology...................................................................... 143
`Table 88: Rabbit Maternal Clinical Chemistry ............................................................ 143
`Table 89: Rabbit Fertility Data..................................................................................... 144
`Table 90: Rabbit Cesarean Section Data................................................................... 144
`
` 5
`
`

`

`NDA # 201,023 Sachia Khasar, Ph.D., Whitney S. Helms, Ph.D
`
`Table 91: Safety Pharmacology Summary................................................................. 152
`Table 92: Reproductive Toxicology Summary............................................................. 156
`
`
` 6
`
`

`

`NDA # 201,023 Sachia Khasar, Ph.D., Whitney S. Helms, Ph.D
`
`Table of Figures
`
`Figure 1: Response of SC GXF-209 Gastric Tumor to Treatment with Docetaxel or
`RPR 116258A ............................................................................................................... 27
`Figure 2: Time for Mean Tumor Weight to Reach 1000 mg ......................................... 29
`Figure 3: Beagle Dog Arterial Blood Pressure.............................................................. 45
`Figure 4: Beagle Dog Heart Rate, RR, QTc ................................................................. 46
`Figure 5: Beagle Dog Cardiac Output/Stroke Volume/Respiration Rate ...................... 47
`Figure 6 : Structure of Radiolabelled Cabazitaxel ........................................................ 60
`Figure 7: Proposed in vitro metabolic pathway in liver microsomes .............................. 61
`Figure 8: Proposed metabolic pathway ......................................................................... 65
`Figure 9: Western blots of CYP 2B1/2 and CYP3A...................................................... 66
`Figure 10: Male and Female rat weights ....................................................................... 73
`Figure 11: Male and Female Rat Food Consumption.................................................... 74
`Figure 12: Male and Female body weights.................................................................... 86
`Figure 13: Male and Female food consumption ............................................................ 87
`Figure 14: Cmax............................................................................................................ 94
`Figure 15: AUC ............................................................................................................. 95
`Figure 16: Male and Female Body Weights ............................................................... 118
`Figure 17: Male Food Consumption-Precohabitation ................................................. 119
`Figure 18: Female Body Weight................................................................................. 122
`Figure 19: Female Food Consumption....................................................................... 122
`Figure 20: Female Body Weight................................................................................. 126
`Figure 21: Female Food Consumption....................................................................... 127
`Figure 22: Maternal Body Weight................................................................................ 131
`Figure 23: Maternal Food Consumption...................................................................... 131
`Figure 24: Maternal Rat Toxicokinetics ....................................................................... 132
`Figure 25: Female Body Weight.................................................................................. 135
`Figure 26: Female Food Consumption....................................................................... 135
`Figure 27: Rabbit Body Weight .................................................................................. 139
`Figure 28: Rabbit Food Consumption......................................................................... 139
`Figure 29: Rabbit Maternal Body Weight..................................................................... 142
`Figure 30: Rabbit Maternal Food Consumption.......................................................... 142
`
`
` 7
`
`

`

`NDA # 201,023 Sachia Khasar, Ph.D., Whitney S. Helms, Ph.D
`
`1
`
`Executive Summary
`
`1.1 Recommendations
`
`1.1.1 Approvability
`
`Recommended for approval. The non-clinical studies with cabazitaxel support the safety
`of its use in hormone refractory metastatic prostate cancer.
`
`1.1.2 Additional Non Clinical Recommendations
`
`None
`
`
`1.1.3 Labeling
`
`See labeling for recommendations. Separate labeling review will be provided.
`
`
`1.2 Brief Discussion of Nonclinical Findings
`
`Cabazitaxel is a microtubule inhibitor derived from the taxane, docetaxel. Like
`other taxanes, cabazitaxel acts by binding tubulin and promoting microtubule
`polymerization and preventing disassembly. In in vitro assays, the effects of cabazitaxel
`on microtubule assembly and stabilization were comparable to the effects docetaxel and
`more pronounced than the effects of paclitaxel at similar concentrations. Cabazitaxel
`also showed in vitro activity against a panel of tumor cell lines that were paclitaxel or
`docetaxel resistant with IC50s that were as much as 10-fold lower than those of
`docetaxel. A panel of murine and human tumor cell lines with resistance to other
`cytotoxic agents also had some sensitivity to cabazitaxel at physiologically relevant
`concentrations.
`
`In vivo studies were conducted to examine the potential activity of cabazitaxel
`against a variety of tumor types in tumor implant models. Treatment with cabazitaxel
`led to delayed tumor progression compared to untreated controls in nude mice
`implanted with several different human gastric, prostate, colon, lung, pancreatic, kidney,
`and head and neck tumors. With 4/9 lines tested in this model (including a colon, a
`head and neck, a pancreatic, and a prostate line) tumor free survival was recorded.
`When treatment with cabazitaxel was compared directly to treatment with docetaxel in
`these lines, cabazitaxel had similar or improved activity. In a human docetaxel-resistant
`breast tumor model, cabazitaxel treatment o