Clinical Study
`
` Oncology 2013;85:208–215
` DOI: 10.1159/000354085
`
` Received: June 21, 2013
` Accepted: June 22, 2013
` Published online: September 24, 2013
`
` Larotaxel with Cisplatin in the First-Line Treatment
`of Locally Advanced/Metastatic Urothelial Tract or
`Bladder Cancer: A Randomized, Active-Controlled,
`Phase III Trial (CILAB)
`
` Cora N. Sternberg   a Iwona A. Skoneczna   b Daniel Castellano   c Christine Theodore   e
`Normand Blais   h Eric Voog   f Joaquim Bellmunt   d Frank Peters   i
`Solenn Le-Guennec   g Linda Cerbone   a Marie-Laure Risse   g Jean-Pascal Machiels   j
`
` a   Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome , Italy; b   Department of Urology, Maria
`Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw , Poland; c   Medical Oncology Department,
`University Hospital 12 de Octubre, Madrid , and d   Oncology Department, University Hospital del Mar, Institut Municipal
`d’Investigació Mèdica, Barcelona , Spain; e   Department of Medicine, Hôpital Foch, Suresnes , f   Centre Jean Bernard,
`Clinique V Hugo, Le Mans , and g   Sanofi, Paris , France; h   Department of Medicine, Hôpital Notre-Dame du Centre
`Hospitalier de l’Université de Montréal, Montreal , Canada; i   Internal Medicine, Orbis Medical Centre, Sittard ,
`The Netherlands; j   Cancer Center, Service d’Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de
`Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Brussels , Belgium
`
`
`
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`development of larotaxel (n = 337 randomized). The larotax-
`el dose was reduced to 40 mg/m 2 and cisplatin to 60 mg/m 2
`following a data monitoring committee safety review of the
`first 97 patients. At the time of analysis, the median OS was
`13.7 months [95% confidence interval (CI) 11.2–17.1] with
`larotaxel/cisplatin and 14.3 months (95% CI 10.5 to not
`reached) with gemcitabine/cisplatin [hazard ratio (HR) 1.21;
`95% CI 0.83–1.76; p = 0.33]. The median progression-free sur-
`vival (PFS) was 5.6 months (95% CI 4.1–6.2) with larotaxel/
`cisplatin and 7.6 months (95% CI 6.6–9.1) with gemcitabine/
`cisplatin (HR 1.67; 95% CI 1.24–2.25). More myelosuppres-
`sion was observed with gemcitabine/cisplatin. Conclusion:
`There was no difference in OS. Although the trial was closed
`prematurely, PFS appeared worse with larotaxel/cisplatin,
`suggesting that larotaxel/cisplatin does not improve out-
`comes versus cisplatin/gemcitabine.
` 2013 S. Karger AG, Basel
`
` ©
`
` Key Words
` Cisplatin · Larotaxel · Survival · Taxoids · Urologic
`neoplasms · XRP9881
`
` Abstract
` Background: This open-label, randomized phase III trial
`evaluated larotaxel/cisplatin versus gemcitabine/cisplatin as
`first-line treatment for locally advanced (T4b) or metastatic
`urothelial tract or bladder cancer. Methods: Patients were
`randomized to larotaxel 50 mg/m 2 with cisplatin 75 mg/m 2
`every 3 weeks (larotaxel/cisplatin) or gemcitabine 1,000
`mg/ m 2 on days 1, 8, and 15 with cisplatin 70 mg/m 2 on day
`1 every 4 weeks (gemcitabine/cisplatin). The primary end-
`point was overall survival (OS). Results: The trial was prema-
`turely closed following the sponsor’s decision to stop clinical
`
` © 2013 S. Karger AG, Basel
`0030–2414/13/0854–0208$38.00/0
`
`E-Mail karger@karger.com
` www.karger.com/ocl
`
` Cora N. Sternberg
` Department of Medical Oncology, San Camillo and Forlanini Hospitals
` Padiglione Flajani, 1st Floor, Circonvallazione Gianicolense 87
` IT–00152 Rome (Italy)
` E-Mail cstern   @   mclink.it
`
`002007002036
`
`AVENTIS EXHIBIT 2036
`Mylan v. Aventis, IPR2016-00712
`
`

`
` Introduction
`
` Patients and Methods
`
` Bladder cancer is the ninth most common cancer
`worldwide and affects three times more men than women
` [1] . At initial diagnosis, approximately 30% of patients
`present with locally invasive or metastatic disease. Stan-
`dard first-line treatment for nonresectable locally inva-
`sive or metastatic bladder cancer is combination chemo-
`therapy. The M-VAC (methotrexate/vinblastine/doxo-
`rubicin/cisplatin) regimen was associated with a survival
`advantage in the 1980s [2, 3] . More recently, gemcitabine/
`cisplatin demonstrated similar levels of activity in the
`metastatic setting, but with an improved safety profile
`versus M-VAC [4, 5] . Gemcitabine/cisplatin and M-VAC
`are currently the most common first-line chemotherapy
`regimens for locally invasive or metastatic bladder cancer
` [6–8] . However, overall survival (OS) remains poor (ap-
`proximately 12–15 months) [9] and new therapies are re-
`quired with improved efficacy and tolerability profiles.
` The taxanes docetaxel and paclitaxel are among the
`most active and most widely used cytotoxic drugs. Phase
`II trials of patients with advanced bladder cancer treated
`with the combination of a taxane and cisplatin have re-
`ported response rates (RRs) of 52–70%, times to progres-
`sion of 5–7 months, and OS of 8–14 months, with a safe-
`ty profile consistent with that reported in patients with
`other solid tumors [10–14] . However, a phase III trial
`conducted by the Hellenic Cooperative Oncology Group
`found that docetaxel in combination with cisplatin was
`less effective than M-VAC (both regimens given with
`prophylactic granulocyte colony-stimulating factor) in
`terms of RR, progression-free survival (PFS), and OS
` [15] .
` Larotaxel (XRP9881) is a next-generation semisyn-
`thetic taxane that has a similar mode of action to docetax-
`el and paclitaxel, with evidence of several possible advan-
`tages including activity in taxane-resistant tumor cells
`and the ability to cross the blood-brain barrier [16, 17] .
`Preliminary clinical data in metastatic breast cancer and
`non-small cell lung cancer suggested activity and an ac-
`ceptable safety profile [18, 19] . Furthermore, preclinical
`and early clinical data suggested synergy between laro-
`taxel and cisplatin [19, 20] .
` The aim of this phase III study (CILAB: cisplatin +
`larotaxel in first-line treatment of locally advanced/meta-
`static urothelial tract or bladder cancer; clinicaltrials.gov
`identifier NCT00625664) was to evaluate larotaxel plus
`cisplatin compared with gemcitabine plus cisplatin in
`terms of OS as first-line treatment for advanced urothe-
`lial tract or bladder cancer.
`
` Previously untreated patients ≥ 18 years old with histologically/
`cytologically confirmed transitional cell carcinoma of the urothe-
`lial tract or bladder that was locally advanced (T4b) or metastatic
`(lymph node or visceral) were eligible. Additional inclusion crite-
`ria were an Eastern Cooperative Oncology Group (ECOG) perfor-
`mance status (PS) of 0–2, and no prior palliative chemotherapy.
`Exclusion criteria included disease localized only to the radiation
`fields without radiologically confirmed disease progression within
`the radiation fields after completion of prior radiotherapy; treat-
`ment with neoadjuvant chemotherapy if <6 months had passed
`between the end of therapy and relapse; prior radiotherapy within
`6 weeks of enrolment; surgery within 3 weeks of randomization;
`pathologically node positive with no residual disease after surgery;
`inadequate bone marrow function (absolute neutrophil count
`<1.5 × 10 9 /l, platelet count <75 × 10 9 /l, or hemoglobin <9.0 g/dl)
`and liver function [alkaline phosphatase (AP) >5.0 × ULN or as-
`partate transaminase (AST)/alanine transaminase (ALT) >1.5 or
`2.5 × ULN if AP is >2.5 or 1.5 × ULN, respectively; or total biliru-
`bin >1.0× the ULN]; history or new evidence of brain metastases
`or leptomeningeal disease, and pregnancy or lactation.
`
` Study Design
` This was a prospective, multicenter, multinational, open-label,
`randomized (1: 1) phase III study. The primary efficacy endpoint
`was OS (defined as the time between the date of randomization and
`the date of death due to any cause). In the absence of confirmation
`of death, survival time was censored at the last date the patient was
`known to have been alive or the study cutoff date, whichever oc-
`curred first. Secondary efficacy endpoints included PFS and over-
`all RR.
` This study was conducted in accordance with the principles of
`the Declaration of Helsinki and the International Conference on
`Harmonization Good Clinical Practice guidelines. The study pro-
`tocol and consent form were approved by the local ethics commit-
`tee or institutional review board of each center. All patients pro-
`vided written informed consent before enrolment.
`
` Treatments and Assessments
` Patients were randomized (1: 1) to treatment with larotaxel 50
`mg/m 2 in combination with cisplatin 75 mg/m 2 every 3 weeks
`(larotaxel/cisplatin arm) or to gemcitabine 1,000 mg/m 2 on
`days 1, 8, and 15 in combination with cisplatin 70 mg/m 2 on day
`1 every 4 weeks (gemcitabine/cisplatin arm). Randomization was
`performed using balanced blocks via an interactive voice re-
`sponse system, with disease stage (locally advanced vs. metastat-
`ic), ECOG PS (0 or 1 vs. 2), and region as stratification factors.
`An ad hoc data monitoring committee (DMC) meeting was held
`on March 4, 2009, to review data from the first 97 patients treat-
`ed because 4 deaths (1 sudden death, 1 cardiac arrest, 1 septic
`shock, and 1 convulsion) had been reported during the study
`treatment in 13 patients enrolled in India. At the time of the
`meeting, a total of 12 deaths had occurred during the study treat-
`ment among the 138 patients enrolled in 18 countries. The DMC
`observed more deaths during the treatment period in the laro-
`taxel/cisplatin arm (n = 9) compared with the gemcitabine/cis-
`platin arm (n = 3) and recommended continuation of the study
`with two protocol modifications: exclusion of patients with
`ECOG PS 2 at study entry (deletion of the stratification factor)
`
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`209
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` Larotaxel with Cisplatin for Bladder
`Cancer
`
`Oncology 2013;85:208–215
`DOI: 10.1159/000354085
`
`

`
`Table 1. Demographics and baseline characteristics of all random-
`ized patients (ITT population)
`
`Larotaxel +
`cisplatin
`(n = 166)
`
`Gemcitabine +
`cisplatin
`(n = 171)
`
`64.0
`42–82
`139 (84)
`
`71 (45)
`81 (51)
`6 (4)
`
`124 (75)
`42 (25)
`
`9.8
`0.1–190.5
`
`162 (98)
`4 (2)
`
`15 (9)
`151 (91)
`
`117 (70)
`61 (37)
`43 (26)
`30 (18)
`30 (18)
`22 (13)
`
`Median age, years
`Range
`Males, n
`ECOG performance statusa, n
`0
`1
`2b
`Primary site, n
`Bladder
`Urothelial tract
`Median time from first diagnosis
`to randomization, months
`Range
`Histologic type, n
`Transitional cell
`Otherc
`Extent of disease at study entryd, n
`Locally advanced
`Metastatic
`Organs involvede, n
`Lymph nodes
`Lungs
`Bladder
`Bone
`Liver
`Muscle/soft tissue
`Number of organs involvedf
`55 (33)
`1
`71 (43)
`2
`40 (24)
`≥3
`Patients with measurable disease, n 148 (89)
`Prior chemotherapyg, n
`Adjuvant
`Neoadjuvant
`Prior surgery, n
`Prior radiotherapy, n
`
`31 (19)
`8 (5)
`148 (89)
`16 (10)
`
`64.0
`35–85
`138 (81)
`
`70 (44)
`83 (52)
`7 (4)
`
`131 (77)
`40 (23)
`
`9.1
`0.4–196.5
`
`170 (99)
`1 (0.6)
`
`18 (11)
`151 (89)
`
`130 (76)
`48 (28)
`48 (28)
`47 (27)
`35 (20)
`23 (13)
`
`49 (29)
`65 (38)
`56 (33)
`161 (94)
`
`29 (17)
`7 (4)
`151 (88)
`18 (11)
`
`and a reduction of the doses in the experimental arm for all new
`and ongoing patients (larotaxel from 50 to 40 mg/m 2 and cispla-
`tin from 75 to 60 mg/m 2 every 3 weeks).
` Tumor assessments, involving abdominal, pelvic, and chest
`CT, or MRI scans, and other exams as clinically indicated, were
`performed at baseline and every 8 weeks. Assessment of respons-
`es  was based on Response Evaluation Criteria in Solid Tumors
`(RECIST). Assessments were repeated to confirm a partial or com-
`plete response (at least 4 weeks after the initial documentation of
`the response) and at the end of the study treatment.
` Patients were treated until RECIST-defined disease progres-
`sion, unacceptable toxicity, or patient refusal of further study treat-
`ment. Safety was assessed by adverse-event (AE) reporting, physi-
`cal examination, and laboratory analysis. AEs and laboratory data
`were graded according to the National Cancer Institute Common
`Terminology Criteria for Adverse Events (version 3.0).
`
` Statistical Analysis
` Assuming the median OS in the control arm (gemcitabine/cis-
`platin) was 14 months, a total of 511 deaths was needed to detect
`with 90% power a 25% reduction in the hazard ratio (HR) (i.e. me-
`dian survival time of 18.7 months) in the larotaxel/cisplatin arm
`relative to the control arm using a two-sided log-rank test at a sig-
`nificance level of 0.05. Based on an anticipated accrual period of
`30 months followed by a 7-month follow-up after randomization
`of the last patient, approximately 900 patients (450 in each arm)
`were required to achieve the targeted number of events. The
`planned cut-off for efficacy endpoints was when 511 deaths had
`occurred. An interim futility analysis was planned after 200 PFS
`events had occurred, and the trial was to be stopped if the condi-
`tional power was <40% based on the original hypothesis (HR ≥ 1.05
`in favor of the gemcitabine/cisplatin arm).
` The intention-to-treat (ITT) population included all random-
`ized patients and was the primary analysis population for OS and
`PFS. Tumor response was assessed in the evaluable patient popula-
`tion, which consisted of all randomized and treated patients with
`measurable disease at study entry, without major protocol devia-
`tions, and who could be evaluated for response. The safety popula-
`tion included all patients who received at least one dose of the
`study drug.
` The primary analysis of OS and PFS was the comparison be-
`tween treatment groups using a log-rank test stratified by extent of
`disease (locally advanced or metastatic) as declared at randomiza-
`tion. HRs and corresponding confidence intervals (CIs) were esti-
`mated using a Cox proportional hazards model stratified for the
`same factor. Kaplan-Meier estimates of survival were provided.
`The overall RR was summarized using descriptive statistics and
`95% CIs.
`
` Results
`
` This trial was prematurely discontinued before the
`planned interim analysis after the sponsor’s decision to
`stop clinical development of larotaxel. This decision was
`based on the lack of larotaxel efficacy versus comparators
`in previous randomized studies (one in pancreatic can-
`cer and two in breast cancer) and the DMC recommen-
`
` Figures in parentheses are percents.
`a n = 158 for larotaxel + cisplatin; n = 160 for gemcitabine +
`cisplatin.
`b Enrolled before the DMC recommendation (March 4, 2009)
`to exclude patients with an ECOG PS of 2.
`c Transitional cell and adenocarcinoma, signet-ring cell adeno-
`carcinoma, urothelial carcinoma with squamous metaplasia, uro-
`thelial carcinoma, and papillary urothelial carcinoma.
`d n = 169 for gemcitabine + cisplatin.
`e Organs with an incidence >10%.
`f n = 170 for gemcitabine + cisplatin.
`g n = 38 for larotaxel + cisplatin; n = 34 for gemcitabine + cis-
`platin.
`
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`Oncology 2013;85:208–215
`DOI: 10.1159/000354085
`
` Sternberg    et al.
`
`

`
`dation to reduce the dose of larotaxel and cisplatin in the
`current study, in part due to the incidence of toxicity
`(mainly infections). For these two reasons it was deemed
`unlikely that the trial would meet its primary efficacy
`endpoint of a 25% reduction in the HR for OS. Patients
`on treatment at the time of study discontinuation and
`deriving benefit could continue treatment. The cutoff
`date for analysis of the primary endpoint was February
`11, 2010.
`
` Patients
` Between February 2008 and February 2010, three
`hundred thirty-seven patients were randomized; 137
`were enrolled before the DMC recommendation/proto-
`col amendment to reduce the larotaxel/cisplatin dose.
`Demographics and characteristics of the patients were
`balanced between the two treatment arms ( table 1 ).
` At the time of this analysis, 82% of all patients in the
`trial had discontinued treatment, 30% of whom stopped
`owing to disease progression and 28% because of an AE
`( table 2 ). The median number of treatment cycles admin-
`istered was 5 in the larotaxel/cisplatin arm and 4 in the
`gemcitabine/cisplatin arm, corresponding to median
`treatment exposures of 15 and 16 weeks, respectively ( ta-
`ble 3 ). The relative dose intensity was lower in the gem-
`citabine/cisplatin arm owing to gemcitabine dose omis-
`sions on day 1 (2 patients), day 8 (57 patients), and day 15
`(107 patients).
`
` Analysis of Survival and Response
` The analysis of OS (primary endpoint) was based on a
`total of 107 deaths (56 in the larotaxel/cisplatin arm and
`51 in the gemcitabine/cisplatin arm). There was no sig-
`nificant difference in OS between the two arms. The me-
`dian OS was 13.7 months (95% CI 11.2–17.1) in the laro-
`taxel/cisplatin arm and 14.3 months (95% CI 10.5 to not
`reached) in the gemcitabine/cisplatin arm ( fig. 1 a). The
`HR for larotaxel/cisplatin versus gemcitabine/cisplatin
`was 1.21 (95% CI 0.83–1.76; p = 0.33).
` The analysis of PFS was based on a total of 184 events
`(101 in the larotaxel/cisplatin arm and 83 in the gem-
`citabine/cisplatin arm). PFS appeared better in the gem-
`citabine/cisplatin arm, with a median PFS of 7.6 months
`(95% CI 6.6–9.1) versus 5.6 months (95% CI 4.1–6.2) in
`the larotaxel/cisplatin arm ( fig. 1 b; HR 1.67; 95% CI 1.24–
`2.25). Similar results for OS and PFS were observed for
`the 137 patients randomized before the protocol amend-
`ment.
` Tumor response was evaluable in 193 patients (57%)
`(90 in the larotaxel/cisplatin arm and 103 in the gem-
`
`Table 2. Disposition of patients (ITT population)
`
`Patients, n
`
`Larotaxel +
`cisplatin
`(n = 166)
`
`Gemcitabine +
`cisplatin
`(n = 171)
`
`Patients off treatment
`AEs
`Disease progression
`Poor compliance
`Lost to follow-up
`Othera
`Ongoing treatment
`Randomized and not treated
`
`139 (84)
`45 (27)
`56 (34)
`1 (0.6)
`0 (0.0)
`37 (22)
`23 (14)
`4 (2)
`
`139 (81)
`50 (29)
`46 (27)
`2 (1)
`0 (0.0)
`41 (24)
`27 (16)
`5 (3)
`
` Figures in parentheses are percents.
`a The main reason was patient and/or investigator decision: 31
`patients in the larotaxel + cisplatin arm and 32 patients in the gem-
`citabine + cisplatin arm.
`
`Table 3. Study drug exposure in the safety population
`
`Drug
`
`Cycles
`administered, n
`
`Duration of
`exposure, weeks
`
`Relative dose
`intensity, %
`
`Larotaxel
`Gemcitabine
`Cisplatin
`+ larotaxel
`+ gemcitabine
`
`5.0 (1.0–18.0)
`4.0 (1.0–18.0)
`
`15.3 (3.0–55.0)
`16.4 (4.0–76.7)
`
`97.5 (1.8–126.8)
`75.9 (31.5–105.6)
`
`5.0 (1.0–17.0)
`4.0 (1.0–18.0)
`
`15.0 (3.0–53.0)
`16.2 (4.0–76.7)
`
`96.5 (52.4–129.3)
`96.8 (49.5–107.5)
`
` Data are presented as medians (range).
`
`citabine/cisplatin arm). The tumor RR was 31% (95% CI
`22–41) in the larotaxel/cisplatin arm and 43% (95% CI
`33–52) in the gemcitabine/cisplatin arm ( table 4 ).
`
` Safety
` The rates of AEs were comparable in the two arms
`(98% for larotaxel/cisplatin and 99% for gemcitabine/
`cisplatin). A higher proportion of patients in the gem-
`citabine/cisplatin arm reported AEs grade ≥ 3 (77 vs. 57%
`for larotaxel/cisplatin). Similar proportions of patients
`in both groups reported serious AEs (40 and 39% of pa-
`tients in the larotaxel/cisplatin and gemcitabine/cispla-
`tin arms, respectively). Table 5 details the AEs in both
`treatment groups. The most frequent nonhematologic
`AE in both arms was fatigue; diarrhea was more frequent
`with larotaxel/cisplatin than with gemcitabine/cisplatin.
`More grade 3/4 hematologic abnormalities (neutrope-
`nia, thrombocytopenia, and anemia) were reported in
`
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`211
`
` Larotaxel with Cisplatin for Bladder
`Cancer
`
`Oncology 2013;85:208–215
`DOI: 10.1159/000354085
`
`

`
`24
`
`00
`
`GC
`LC
`
`21
`
`11
`
`GC
`LC
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`OS
`
`18
`
`54
`
`9
`
`12
`Time (months)
`
`58
`52
`
`28
`31
`
`15
`
`13
`14
`
`0
`
`a
`Patients at risk (n)
`GC
`171
`LC
`166
`
`3
`
`123
`117
`
`6
`
`92
`77
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`PFS
`
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`21
`
`24
`
`18
`
`02
`
`15
`
`22
`
`9
`
`12
`Time (months)
`
`32
`15
`
`11
`5
`
`0
`
`b
`Patients at risk (n)
`GC
`171
`LC
`166
`
`3
`
`103
`92
`
`6
`
`65
`43
`
` Fig. 1. Kaplan-Meier curves of OS ( a ) and
`PFS ( b ). GC = Gemcitabine/cisplatin; LC =
`larotaxel/cisplatin.
`
`the gemcitabine/cisplatin arm. This was observed both
`before and after the dose reduction in the larotaxel/cis-
`platin arm ( table 6 ). A total of 6 patients (3.7%) (3/68 and
`3/94 pre- and postamendment, respectively) in the laro-
`taxel/cisplatin arm and 10 (6.0%) patients (5/66 and
`
`5/100 pre- and postamendment, respectively) in the
`gemcitabine/cisplatin arm experienced neutropenic
`complications (febrile neutropenia or neutropenic in-
`fection, any grade). There was more sensory neuropathy
`(all grades) in the larotaxel/cisplatin arm (23%) com-
`
`212
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`Oncology 2013;85:208–215
`DOI: 10.1159/000354085
`
` Sternberg    et al.
`
`

`
`Table 4. Tumor responses in evaluable patients
`
`Response
`
`Larotaxel + cisplatin (n = 90)
`
`Gemcitabine + cisplatin (n = 103)
`
`Best overall response, n
`CR
`PR
`Stable disease
`Progressive disease
`Overall response rate (CR + PR), n
`95% CI
`
`2 (2)
`26 (29)
`41 (46)
`21 (23)
`28 (31)
`22–41
`
`2 (2)
`42 (41)
`45 (44)
`14 (14)
`44 (43)
`33–52
`
` Figures in parentheses are percents. The evaluable population for tumor response consisted of all randomized
`and treated patients with measurable disease at study entry, without major protocol deviation and evaluable for
`response. CR = Complete response; PR = partial response.
`
`pared with the gemcitabine/cisplatin arm (14%); grade
`3/4 sensory neuropathy occurred in 3% of patients on
`larotaxel/cisplatin and in 0.6% of patients on gem-
`citabine/cisplatin. More alopecia was observed in the
`larotaxel/cisplatin arm. A total of 14 (8.6%) and 12 pa-
`tients (7.2%) died during the study treatment in the laro-
`taxel/cisplatin and gemcitabine/cisplatin arms, respec-
`tively, including 8 (4.9%) and 2 (1.2%) due to AEs. Be-
`fore the protocol amendment, 10 patients died in the
`larotaxel/cisplatin arm and 7 patients died in the gem-
`citabine/cisplatin arm; the corresponding numbers of
`deaths in each arm after the amendment were 4 and 5,
`respectively.
`
` Discussion
`
` The phase III CILAB trial was designed to compare
`OS with larotaxel/cisplatin and gemcitabine/cisplatin
`as a first-line treatment for advanced urothelial tract or
`bladder cancer. The trial was prematurely discontin-
`ued  after 337 patients had been randomized (the
`planned enrolment was 900 patients) due to the spon-
`sor’s decision to halt clinical development of larotaxel.
`A futility analysis was not undertaken at the time the
`study was stopped. Nonetheless, data from the ITT pop-
`ulation suggested that treatment with larotaxel/cisplatin
`was associated with worse median PFS than gem-
`citabine/cisplatin. As the study was stopped approxi-
`mately 11 months after the protocol amendment reduc-
`ing the dose of larotaxel/cisplatin, the PFS data were
`mature mainly for patients recruited and randomized
`before the dose reduction; in general, follow-up times
`for patients randomized after the amendment would
`
`have been very short. PFS is therefore not likely to have
`been better than with the initial higher larotaxel/cispla-
`tin doses used.
` With regard to the safety profile of the two regimens,
`no striking differences were observed apart from more
`myelosuppression in the gemcitabine/cisplatin arm. The
`difference in hematologic toxicity between the study arms
`was observed both before and after the amendment to re-
`duce the larotaxel/cisplatin dose. After the dose reduc-
`tion, the number of on-treatment deaths was similar in
`the two arms.
` Since the development of the M-VAC regimen in the
`1980s, no chemotherapeutic regimen has been proven to
`significantly improve OS in patients with advanced blad-
`der cancer. The taxanes are active in bladder cancer and
`are often used in the second-line setting after cisplatin-
`based combination chemotherapy. Addition of paclitaxel
`to gemcitabine/cisplatin in a 3-drug regimen provided a
`higher RR and a 3.1-month survival benefit that did not
`reach statistical significance [21] .
` In conclusion, there was no difference in OS between
`the treatment groups (primary endpoint). Although the
`study was closed prematurely, PFS appeared to be worse
`in patients treated with larotaxel/cisplatin, suggesting
`that this regimen does not improve outcomes compared
`with cisplatin/gemcitabine. Improvements in survival
`for patients with advanced or metastatic urothelial can-
`cer await the development of novel chemotherapy regi-
`mens and/or the optimization of current regimens,
`through novel combinations and scheduling. Molecular
`profiling of bladder cancers has led to the testing of sev-
`eral agents that target specific markers of disease prog-
`nosis, with a number of these agents showing early
`promise.
`
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` Larotaxel with Cisplatin for Bladder
`Cancer
`
`Oncology 2013;85:208–215
`DOI: 10.1159/000354085
`
`

`
`Table 5. Treatment-emergent AEs occurring in ≥5% of patients in the safety population
`
`Grouped preferred term
`
`Larotaxel + cisplatin (n = 162)
`all g rades
`grade 3/4
`
`Gemcitabine + cisplatin (n = 166)
`all grades
`grade 3/4
`
`Any event
`Hematologica
`Neutropenia
`Leukopenia
`Anemia
`Thrombocytopenia
`Nonhematologic
`Fatigue
`Nausea
`Diarrhea
`Vomiting
`Decreased appetite
`Constipation
`Sensory neuropathy
`Abdominal pain
`Alopecia
`Urinary tract infection
`Stomatitis/mucositis
`Dysgeusia
`Fever
`Weight loss
`Peripheral edema
`Decreased creatinine renal clearance
`Back pain
`Insomnia
`Increased blood creatinine
`Hypersensitivity
`Dyspepsia
`Headache
`Arthralgia
`Dizziness
`Dyspnea
`Hiccups
`Hematuria
`Pain in an extremity
`Anxiety
`Cough
`Deep vein thrombosis
`
`158 (98)
`
`101 (65)b
`117 (74)c
`156 (98)c
`69 (43)c
`
`104 (64)
`90 (56)
`74 (46)
`61 (38)
`51 (32)
`40 (25)
`37 (23)
`33 (20)
`33 (20)
`29 (18)
`22 (14)
`21 (13)
`19 (12)
`19 (12)
`18 (11)
`16 (10)
`14 (9)
`13 (8)
`12 (7)
`12 (7)
`11 (7)
`10 (6)
`9 (6)
`9 (6)
`9 (6)
`9 (6)
`8 (5)
`8 (5)
`6 (4)
`6 (4)
`5 (3)
`
`92 (57)
`
`55 (35)b
`26 (16)c
`12 (8)c
`3 (2)c
`
`22 (14)
`5 (3)
`20 (12)
`8 (5)
`6 (4)
`2 (1)
`5 (3)
`2 (1)
`0 (0)
`5 (3)
`1 (0.6)
`0 (0)
`0 (0)
`1 (0.6)
`1 (0.6)
`3 (2)
`2 (1)
`0 (0)
`0 (0)
`4 (2)
`0 (0)
`1 (0.6)
`2 (1)
`1 (0.6)
`2 (1)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`4 (2)
`
`164 (99)
`
`143 (86)
`155 (93)
`161 (97)
`153 (92)
`
`108 (65)
`84 (51)
`28 (17)
`48 (29)
`35 (21)
`46 (28)
`23 (14)
`19 (11)
`20 (12)
`26 (16)
`13 (8)
`14 (8)
`32 (19)
`12 (7)
`19 (11)
`8 (5)
`20 (12)
`14 (8)
`15 (9)
`0 (0)
`7 (4)
`14 (8)
`6 (4)
`13 (8)
`16 (10)
`8 (5)
`14 (8)
`11 (7)
`9 (5)
`14 (8)
`12 (7)
`
` Values are presented as numbers (%). a Laboratory evaluations. b n = 156. c n = 159.
`
`128 (77)
`
`100 (60)
`70 (42)
`36 (22)
`75 (45)
`
`23 (14)
`4 (2)
`2 (1)
`5 (3)
`0 (0)
`1 (0.6)
`1 (0.6)
`2 (1)
`0 (0)
`6 (4)
`1 (0.6)
`0 (0)
`1 (0.6)
`0 (0)
`1 (0.6)
`0 (0)
`3 (2)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`1 (0.6)
`2 (1)
`0 (0)
`1 (0.6)
`0 (0)
`0 (0)
`1 (0.6)
`0 (0)
`0 (0)
`5 (3)
`
`Table 6. Grade 3/4 hematologic AEs before and after protocol amendment
`
`Grouped preferred term
`
`Anemia
`Leukopenia
`Neutropenia
`Thrombocytopenia
`
`Preamendment
`larotaxel +
`cisplatin (n = 68)
`
`gemcitabine +
`cisplatin (n = 66)
`
` Postamendment
`lar otaxel +
`cisplatin (n = 94)
`
`gemcitabine +
`cisplatin (n = 100)
`
`1 (1.5)
`1 (1.5)
`12 (17.6)
`0 (0)
`
`5 (7.6)
`4 (6.1)
`28 (42.4)
`30 (45.5)
`
`1 (1.1)
`1 (1.1)
`5 (5.3)
`0 (0)
`
`6 (6.0)
`3 (3.0)
`34 (34.0)
`29 (29.0)
`
`Values are presented as numbers (%).
`
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`Oncology 2013;85:208–215
`DOI: 10.1159/000354085
`
` Sternberg    et al.
`
`

`
` Acknowledgments
`
` Disclosure Statement
`
` We thank the patients who participated in this trial and their
`families. We also acknowledge the contribution made by members
`of the independent DMC (Karim Fizazi, Robert Dreicer, and Jean-
`Marie Boher).
` This trial was sponsored by Sanofi. Medical writing support
`was provided by Adelphi Communications Ltd. and was support-
`ed by Sanofi.
`
` Dr. Machiels has received research grant funding from Sanofi.
`Dr. Le-Guennec and Dr. Risse are employees of Sanofi. All remain-
`ing authors declare no conflicts of interest.
`
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