Original Study
`
`Analysis of Side Effect Profile of Alopecia, Nail
`Changes, Peripheral Neuropathy, and Dysgeusia
`in Prostate Cancer Patients Treated With
`
`Docetaxel and Cabazitaxel
`
`Aurelius Omlin,1 Oliver Sartor,2 Christian Rothe1'munclt,1 Richard Cathomas,3
`Johann S. De Bono,4 Liji Shen,5 Zhen Su,5 Silke Gillessenl
`
`Abstract
`
`Prospectively collected data on treatment-emergent adverse events (AEs} from 3 clinical trial databases
`['l'AX32T, VENICE, TROPICJ were analyzed for alopecia, nail changes, neuropathy, and dysgeusia. The fre-
`quency of new or worsening AEs for 1301 patients was significantly less for alopecia, nail changes, neuropathy,
`and dysgeusia for cabazitaxel compared with docetaxel. |nfon11ation on AE profile is important when dis-
`cussing treatment options with patients.
`Introduction: We hypothesized that the adverse event (AE} profile of cabazitaxel with regard to alopecia, nail changes,
`neuropathy. and dysgeusia differs from docetaxel. Materials and Methods: Prospectively collected data on
`treatment-emergent AEs (frequency and grade [G]) from clinical trial databases of docetaxel every 3 weeks (qaw) (in
`TAX32? and VENICE) and cabazitaxel q3w (in TROPIC) were analyzed. Flesults: The frequency of new or worsening
`AEs {all G and (33-4) for 1301 patients was significantly less for alopecia, nail changes, neuropathy, and dysgeusia for
`cabazitaxel compared with docetaxel. Conclusion: Treatment with cabazitaxel might cause less alopecia, nail
`changes, neuropathy, and dysgeusia compared with docetaxel.
`
`Clinical Genitourinary Cancer, Vol. I, No. I. I1 © 2015 Elsevier Inc. All rights reserved.
`Keywords: Adverse event, Cabazitaxel, Castratiorwesistarit prostate cancer, Clinical trial, Docetaxel
`
`Introduction
`
`First-line cheinotherapy with doeetasel and prednisone has been
`a standard treatment
`in metastatic castration-resistant prostate
`cancer (CRPC) since publication ofl pivotal phase Ill trials in 2004
`that demonstrated :1 significant survival l:nenefit."2 Docetaxel has a
`well known side eflect profile consisting ofueurropeuia (32% Grade
`[CI 3.34) and nonhenmtological toxicities including ztlopecia (65%),
`
`llxhntnnsspital St Callen, Department olitjncnlogy and Hent-urology. St Cullen,
`Switzerland
`£'l'ttlat1e ljttivetsity. Depurltttent of Medicine and Urology. New Orleatis. LA
`"Division ol'OntologyJ"l lcmatology. Kantonispital Grauhijnclcn. Chur, Switzerland
`"Prostate Cancer Targeted Therapies Group. Royal Mttrsden NHS Foundation Trust
`and Institute of Cancer Research.
`l(‘.R, Sutton. UK
`£’Sanol'i—Avt-ntls. B1'lt'.lgL‘V>"€lt'l_'l. Ni
`Suhnrittcd: Dec 2. 2014.‘ Revised: Jan 16. 3Ul 5: Accepted: Jan 373. 3Ul5
`
`.«’\dclIe.i.\i for correspondence: r\ureliu.i Omliu, Ml}. Ksntonsipiral St Callen, Depart-
`rnent ofoncology and Hematology. Rorschttcherstrasse 95. Cl‘l—9007 St Cullen.
`Switzerland
`E-mail contact: ttultliLls.tJt1rlii1E-“'kssg,.ch
`
`nail changes (30“/ti), sensory neuropathy (3l')"/tr), and change in taste
`(dysgeusia; 18%) according to the TAX327 data.‘ The SVUUG
`(Southwestern Oncology Group) 9916 trial of docetaxel with
`estramustine reported neurologic adverse events (AE5) at a fre-
`quency of 21%) (G3) and 2% ((34).)
`Although alopecia, nail cltanges, dysgeusia, and peripheral neu-
`ropathy are not lifeahreateniug and rarely severe in grading, they
`nevertheless represent :1 major burden to patients and potentially
`might leatl to dose reductions anti.-‘or early termination oftreatment.
`In a phase lll trial (TRQPIC) the novel tztxane E;:1lJ;1Iit2iXEl was
`shown to improve overall survival
`in the second—line setting of
`CRPC." The side effect profile of cahazitaxel is different to that of
`docetaxel, for example, with regard to neutropenia (TROPIC, GSM
`or 4: 82%; TAX327, 52%) and diarrhea (TROPIC, any G3: 47%;
`TAX327,
`32%). Recent publications on
`real—worlcl patient
`populations reported lower
`rates of ueutropeuia. G3/4 rate of
`cabazitaxel < 10%.
`likely because of patient selection and use
`015 growth factorsxéj Neither the phase lll trial pulzxlication nor
`the compassionate—u.~e: population publications provided detailed
`
`l558r?6i'3/5 ~ see lronlmutrer -:63 2l]l5 Elsevlet Int.
`hi1p:ffllx_dtli.atg_r’l D. l 016/i'.tlgt.2[ll 5.0] Dill
`
`llll
`
`lights reserved.
`
`Clinitul Genitourinary Cancer
`
`lulonlh 2015
`
`AVENTIS EXHIBIT 2220
`Mylan v. Aventis IPR2016-00712
`
`

`
`Side Effect Profile of Docetaxel and Cabazitaxel
`
`reports on the incidence or severity of alopecia, nail changes, and
`dysgeusia. New or worsening peripheral sensory or motor neurop-
`athy occurred in 14% (all grades) with cabazitaxel in the TROPIC
`trial, but only 1% had G3 toxicityum
`In clinical practice we noticed seemingly reduced non-
`hematological
`side effects of alopecia, nail changes, peripheral
`neuropathy, and dysgeusia. in patients during second—line eahazitaxel
`treatment. We hypothesized that the frequency of bothersome and
`visiblefstigmatizing nonhernatological side effects including alope-
`cia, nail changes, dysgeusia, and peripheral neuropathy might be less
`with cabazitaxel than with docetaxel.
`
`Materialfi and hnethOdS
`
`in the
`The database of the patients treated with cabazitaxel
`TROPIC trial, with docetaxel
`in the TAX327 trial, and with
`
`reviewed
`the VENICE trial was
`docetaxel monotherapy in
`retrospectively, The TROPIC trial was a randomized phase 11]
`study for patients with CRPC and disease progression after
`previous docetaxel chemotherapy. Patients were randomized to
`cabazitaxel 25 mgfmz every 3 weeks (q3w) for a maximum of
`10 cycles or
`to mitoxa.ntrone.'l A total of 755 patients were
`included; 371 patients received cabazitaxel and were available for
`analysis. The TAX327 trial compared docetaxel (75 mgfmz q3w
`or 30 mga"m2 for 5 of 6 weeks) with mitoxantrone as first—line
`treatment
`in CRPC.' Three hundred
`thirty—two patients
`received docetaxel q3w and were reviewed For this analysis. The
`VENICE trial included 1224 patients with CRPC who received
`docetaxel q3w or docetaxel with aflibercept. Five hundred ninety-
`eight patients who received docetaxel monotherapy were included
`
`in this analysis." All patients included in the 3 trials had provided
`written informed consent and the trials were approved by the
`local ethics committees.
`
`Adverse events were coded according to Medical Dictionary for
`Regulatory Activities 12.0 for all 3 studies. The AES of alopecia, nail
`changes. sensory neuropathy, and taste changes were selected by the
`authors and grouped for the analysis. For cabazitaxel pretreatment
`2'-\_Es were also recorded. A_Es were graded according to the National
`Cancer Institute Common Terminology Criteria for Adverse Events
`(NCI CTCAE) version 3. In TAX327 NCI CTCAE version 2 was
`
`used.”' Neutropenia rates were calculated based on the scheduled
`laboratory tests in the protocol. Statistical comparisons of the
`incidence of designated AES was performed using ‘X2 tests between
`docetaxel q3w in the combined groups in TAX327 and VENICE
`studies and the cabazitaxel group in the TROPIC study. The odds
`ratio and the 95% confidence interval of these AEs were estimated.
`
`Results
`
`The cumulative frequency ofAEs (all grades and Grades 3-4) for
`the total -of 1301 patients is summarized in Table l. Significant
`differences between docetaxel (combined TAX327 and VENICE)
`
`and cabaziraxel were found for the frequency of all grades of
`the following selected AEs: alopecia (P < .0001), nail changes
`(P { .0001), neuropathy (P ‘C .0001), and dysgeusia (P = .0003).
`The frequencies of severe Alis (Grades 54) were not significantly
`different between the 2 treatment groups. For cabazitaxel,
`the
`recorded rates of pre-existing AEs were evaluated. For the alopecia,
`nail changes, and dysgeusia,
`the rate of all pre-existing AEs
`(all grade) were < 5% and only reached 19.7% for neuropathy.
`
`Table 1
`
`Percentage of Patients who Had New or Worsening AEs
`
`GAB
`TBIDPIG, n = 3?‘!
`
`P [Bomb DOG us. GAB)
`Odds Ilatlo {95% Cl}
`
`% All Grades
`Comb: 52.2
`T: 55.4
`V: 44.3
`
`Comb: 2?’
`T: 29.8
`V: 25.5
`
`Comb: 40.3
`T: 37.7
`V: 42.5
`
`Comb: 19.5
`T: 18.4
`V: 20.1
`
`C0mb: 34
`T: 41
`V: 31
`
`NA
`
`Grouped AE Term
`Alopeela
`
`Hall changes
`
`neuropathy
`
`Dysgeusia
`
`Heulmpenia
`
`Febrile Neulropenia
`
`Dealh '|\li1lIin 30 Days 01
`Last Dose of chemotlierapy
`
`% All Grades
`10.0
`
`% Grades 3-4
`NA
`
`< .0001
`9.34 {6.34—14.2}
`
`<.0001
`10.2 {5.?8—18.3)
`
`<.0001
`1.79 {1.38—2.33)
`
`.0003
`1.95 (1.35-2.80}
`
`<.0001
`0035 (0023-0055)
`
`.0041
`0.43 (0.20-0.30)
`
`.3201
`0. 74 (0.41-1.34}
`
`Abbreviations: AE = adverse event; GAB = cabazilairel; Comb = combined; DOC = dooelzaxel; T = TAX32? l11'a| database; V = VENICE trial database.
`
`2
`
`tlinitul Genilourinury Canter Morllh 2015
`
`

`
`The percentage of patients with pre-existing AES (all grades!3_> G3)
`for patients in the TROPIC study were 4.9a"0 for alopecia, =i.8i"0 for
`nail changes,
`l9.71'{l.3 for neuropathy, and 0.8.30 For dysgeusia,
`respectively. The frequency of neutropenia (calculated based on the
`scheduled laboratory tests in the protocol, not From the reported
`AEs), Febrile neutropenia, and death within 30 days oi: last dose of
`chemotherapy For the docetaxel arms of TAX327 and VENICE and
`for TROPIC are summarized in Table 1.
`
`Discussion
`
`The retrospective analysis of prospectively collected data of the 4
`nonhematological side effects alopecia, nail changes, peripheral
`neuropathy, and dysgeusia confirms the clinical
`impression that
`these side eFFects are considerably less common during treatment
`with cabazitaxel compared with docetaxel. Although some degree of
`dysgeusia and peripheral neuropathy is seen during cabazitaxel
`treatment, notably alopecia and nail changes are relatively rare.
`A total of 4 retrospective analyses including 533 patients have
`reported on the efficacy and safety of C3l):lZl[3_Xt':l in the context
`of expanded-access programs (EAPs).'l'? All of‘ these reports show
`significantly lower
`rates
`of‘ C334 neutropenia ranging from
`only 4% to 44%, compared with 82% in the TROPIC trial,
`resulting in reduced rates of Febrile neutropenia. Moreover,
`the
`rate of severe diarrhea was also much reduced. Although increased
`use of granulocyte—colony stirnulating Factor might be responsible
`For
`the improved neutropenia rate,
`the reduction in diarrhea
`might be the result of patient selection and proactive treatment,
`or Alis might be captured distinctly in these settings. Only 1 of
`the EAP reports mentions the 4 AEs assessed in our analysis,
`and stated that no 2 G3 alopecia, nail changes, or peripheral
`neuropathy were Found.x Interestingly, a phase I trial that eval-
`uated cabazitaxel in different solid tumors in 21 patients reported
`no occurrence of alopecia or nail changes. However, 24% of
`predominantly G1 peripheral neuropathy was noted, confirming
`our results.”
`
`An important question is. whether the distinct toxicity profile of
`C:ll)31.lt£l.XIIl results in an improved quality of life (QoL). Unfortu-
`nately, neither the TROPIC trial nor any of the EAP studies have
`specifically assessed QoL in a systematic manner. Furthermore, the
`improved side effect profile and presumably better tolerability of
`cabazitaitel compared with I.'l0CCTa.i(Cl might result in the adminis-
`tration of prolonged treatment with cabazitaxel. The TROPIC trial
`protocol restricted treatment to 10 cycles of cabazitaxel, and the
`same nile was applied in the F.APs. albeit, the median number of
`cabazitaxel cycles was only 6 in the TROPIC trial. The main rea-
`sons for discontinuation of cabazitaxel were disease progression
`(48%) and Alis (18%), and these rates might be explained in part
`because they were conducted in the second-line setting. A first-line
`phase III trial comparing docetaxel and cabazitaxel (FIRSTANA)
`has fully accrued and its results might shed a new light on the
`question of QOL and duration of treatment For cabazitaxel
`compared with docetaxel. It has to be acknowledged that dysgeusia,
`alopecia, neuropathy, and nail changes are not captured specifically
`in Frequently used Qol. questionnaires like Functional Assessment
`of Cancer Therapy—Prostate (FACT—P). We also note that in the
`ChernoHormonal Therapy Versus Androgen Ablation Randomized
`Trial for Extensive Disease in Prostate Cancer (Cl-IAARTEDJ trial,
`
`Aurelius Omlin et al
`
`with upfront use of the docetaxel being tested in hormone-sensitive
`metastatic disease, more patients received cabazitaxel as first-line
`chemotherapy in the castration—resistant state in the early doce—
`taxel arm compared with patients from the androgen deprivation
`therapy—alone arm.” The observation of lower rates of neuropathy
`with cabazitaxel compared with docetaxel was mentioned in a
`recent update of the TROPIC Study.8 in the literature, several
`mechanisms of taxane—induced neuropathy have been described and
`involve disruption of axonal
`transport, mitochondrial damage,
`increased ion channel activity, and neuronal
`injury and inflam-
`mation. D The difference in the AE profile of cabazitaxel might be
`because of its pharmacokinetic properties. The standard dose of
`docetaxel (75 mglmzl results in greater tissue exposure compared
`with the standard dose of cabazitaxel (25 mga"m2).H Furthermore,
`preclinical data show that cabazitaxel has a rapid intracellular up-
`take (approximately IO tirnes Faster) compared with docetaxel
`possibly because of its highly lipophilic structure, which could
`explain the lower
`rate of neuropathy.1:"]° Interestingly,
`for
`the
`albumin-bound paclitaxel (nab-paclitaitel), cellular uptake was also
`shown to be more efficient and rapid.” In a large phase III clinical
`trial in patients with non-small-cell lung cancer the combination
`of nab—paclitaxel with carboplatin compared with paclitaxel com—
`bined with carboplatin showed reduced rates of G3 sensory neu-
`ropathy (3% vs. 11%) for the nab—paclitaxel combination.” Our
`results have to be interpreted with caution because they have been
`collected retrospectively and compare first— and second—line treat-
`ments. Underrcporting in case of patients with a baseline medical
`history of the examined Alis cannot be ruled out. Moreover it is
`possible that patients with severe side efiects during first-line
`doceta:-tel
`treatment might not have been included in the
`TROPIC trial. Finally,
`it
`is important
`to note that
`the median
`number of cycles was 6 for cabazitaxel, but a median of 9.5 or 9
`cycles of docetaxel were applied in the TAX327 and VENICE
`trials, respectively. We have not attempted to correct these data as a
`Function of time of treatment.
`
`conclusion
`
`We provide evidence for a Clil'TCl‘E[lt side effect profile of the 2
`taxanes cabazita:-tel and docetaxel with possible lower
`rates of
`alopecia and nail cl1a.nges and reduced rates of dysgeusia and pe-
`ripheral neuropathy with treatment with cabazitaxel. These findings
`could have an influence on physician treatment decisions in patients
`with CRPC. The results of the ongoing phase III trial comparing
`docetaxel and cabazitaxel
`in the first-line setting {FIRSTANAJ
`are eagerly awaited and will provide a prospective head—to—head
`comparison oF the 2 drugs and will provide direct evidence For a
`significant difFerence in the side cfFect profile.
`
`Clinical Practice Points
`
`0 The AE profile oficabazitaxel with regard to regards to alopecia,
`nail changes, neuropathy, and dysgeusia has not been well
`described.
`
`0 The analysis of 3 clinical trial databases (docetaxel: TAX327,
`VENICE; cabazitaxel: TROPIC} revealed significant diFFer—
`ences For the Frequency oF treatment—emergent AF.s For alope—
`cia. nail changes. neuropathy, and dysgeusia in Favor of
`cabazitaxel.
`
`Elinitul Geniiuurinury Ennter
`
`lllliiiilli 2015
`
`

`
`Side Efl’ect Profile of Docetaxel and Cabazitaxel
`
`ARTICLE IN PRESS
`
`o This information might help in daily practice in discussions
`of treatment options for patients with advanced prostate
`cancer.
`
`0 The ongoing FIRSTANA trial that is comparing docetaxel with
`cabazitaxel in the first—line setting will provide l'i.l1‘tl'1El' informa-
`tion on the toxicity profile of both chernotherapies.
`
`Disclosure
`
`A.O.: advisory role for and travel support from Sanofi—Aventis,
`and an advisory role For Janssen, Astellas, Astrazeneea, Pfizer,
`and Bayer. 0.8. and J.S.D.B.: consultant and investigator for
`Sanofi-Aventis. L.S. and Z.S.: employees and stock holders of
`Sanofi-Aventis. S.G.: advisory roles fiat Bayer, Curevac, ]a.nssen,
`Millenium, Astellas, Sanofi-Aventis, Dendreon, and Orion, and
`
`Speakers bureau (uncompensated) for Amgen, Bayer, and Janssen.
`R.C.: advisory role for Sanofi—Aventis, Bayer, Astellas, and Janssen.
`C.R.: advisory role for Astellas, Pfizer and Honoratia from GSK,
`Novartis.
`
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`4
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`Clinitul Genitourinary {unter
`
`lil0ITlll 2015