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Phase II trial of sequential gemcitabine Phase II trial of sequential gemcitabine and carboplatin followed by paclitaxel and carboplatin followed by paclitaxel

as first-line treatment of advanced as first-line treatment of advanced urothelial carcinomaurothelial carcinoma

Presented by Celine BOUTROSPresented by Celine BOUTROS

Hotel-Dieu de FranceHotel-Dieu de France

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BackgroundBackground

• Bladder cancer is the 4Bladder cancer is the 4thth cancer in men, the 9 cancer in men, the 9thth in women in women

• 69,000 new cases diagnosed in the US in 200869,000 new cases diagnosed in the US in 2008

• Transitional Cell Carcinoma (TCC): most frequent histological subtypeTransitional Cell Carcinoma (TCC): most frequent histological subtype

• The standard first-line regimen in advanced TCC:The standard first-line regimen in advanced TCC:

- 1989-2000: Methotrexate, Vinblastine, Doxorubicin, Cisplatin (MVAC)- 1989-2000: Methotrexate, Vinblastine, Doxorubicin, Cisplatin (MVAC)11

- > 2000: Gemcitabine plus Cisplatin- > 2000: Gemcitabine plus Cisplatin22 : similar activity, less toxicity : similar activity, less toxicity

1 Sternberg CN et al. Cancer 1989;64:2448-2458.2 Von der Maase H et al. J Clin Oncol 2000;18:3068-3077.

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Objectives of the studyObjectives of the study

• Explore the activity of Explore the activity of Gemcitabine plus Carboplatin Gemcitabine plus Carboplatin (GC) followed sequentially with (GC) followed sequentially with Paclitaxel in advanced TCC Paclitaxel in advanced TCC

Secondary Secondary objectiveobjective

Secondary Secondary objectiveobjective • Assess the toxicity profile of the Assess the toxicity profile of the

regimenregimen

Primary objectivePrimary objectivePrimary objectivePrimary objective

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Materials and MethodsMaterials and Methodseligibilityeligibility

Eligibility Criteria:Eligibility Criteria:

• At least one dimensionally measurable diseaseAt least one dimensionally measurable disease• Locally advanced or metastatic diseaseLocally advanced or metastatic disease• Histological infiltrative urothelial cancerHistological infiltrative urothelial cancer• No prior chemotherapy No prior chemotherapy unless given in more than one year free-unless given in more than one year free-intervalinterval• No prior radiation therapyNo prior radiation therapy• Performance status (PS) ≤ 2Performance status (PS) ≤ 2• Adequate blood counts and chemistriesAdequate blood counts and chemistries• Normal organ functionNormal organ function

Eligibility Criteria:Eligibility Criteria:

• At least one dimensionally measurable diseaseAt least one dimensionally measurable disease• Locally advanced or metastatic diseaseLocally advanced or metastatic disease• Histological infiltrative urothelial cancerHistological infiltrative urothelial cancer• No prior chemotherapy No prior chemotherapy unless given in more than one year free-unless given in more than one year free-intervalinterval• No prior radiation therapyNo prior radiation therapy• Performance status (PS) ≤ 2Performance status (PS) ≤ 2• Adequate blood counts and chemistriesAdequate blood counts and chemistries• Normal organ functionNormal organ function

Single-Arm, Multicenter, Phase II trial , from September 2004 to September 2007

Single-Arm, Multicenter, Phase II trial , from September 2004 to September 2007

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Materials and MethodsMaterials and Methodstreatmenttreatment scheduleschedule

Evaluation(RECIST)Evaluation(RECIST)

Gemcitabine Gemcitabine 800mg/m800mg/m2 2 (D1, D8) (D1, D8)

++Carboplatin AUC 2Carboplatin AUC 2

(D1, D8)(D1, D8)

Every 3 weeks for Every 3 weeks for 4 cycles4 cycles

Gemcitabine Gemcitabine 800mg/m800mg/m2 2 (D1, D8) (D1, D8)

++Carboplatin AUC 2Carboplatin AUC 2

(D1, D8)(D1, D8)

Every 3 weeks for Every 3 weeks for 4 cycles4 cycles

Paclitaxel Paclitaxel 60 mg/m60 mg/m22

weekly for 12 weekly for 12 weeksweeks

Paclitaxel Paclitaxel 60 mg/m60 mg/m22

weekly for 12 weekly for 12 weeksweeks

Evaluation(RECIST)Evaluation(RECIST)

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ResultsResultsPatient CharacteristicsPatient Characteristics

nn %%

Mean age (years)Mean age (years) 6868

Male / FemaleMale / Female 22 / 5 22 / 5 81/1881/18

ECOG PS ≤ 2ECOG PS ≤ 2 27 27 100100

Prior radical cystectomyPrior radical cystectomy 12 12 4444

Prior chemotherapyPrior chemotherapy 0 0 00

Distant metastasesDistant metastases 11 11 4040

Locoregional disease with only Locoregional disease with only positive lymph nodes positive lymph nodes 16 16 6060

Patients included Patients included 2727

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ResultsResultsDrug deliveryDrug delivery

GC sequenceGC sequencePaclitaxel Paclitaxel sequencesequence

Mean number of Mean number of cycles administeredcycles administered 3.53.5 77

Number of patients Number of patients removedremoved

-- progressionprogression

- personal request- personal request

77

66

11

66

00

66

Dose reduction for Dose reduction for myelosuppressionmyelosuppression 22 22

Assessment of drug delivery for GC and Paclitaxel Assessment of drug delivery for GC and Paclitaxel sequencessequences

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ResultsResultsTreatment efficacyTreatment efficacy

GC sequenceGC sequence End of therapyEnd of therapy

Overall response rateOverall response rateCRCRPRPR

41% 41% (1)(1)

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1010

43% 43% (2)(2)

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SD SD 33 44

PDPD 1111 44

Response Assessment to GC and Paclitaxel Response Assessment to GC and Paclitaxel sequences sequences

(1) 8 responses of 11 achieved in locally advanced TCC without distant metastases(2) Responses achieved in locally advanced TCC without distant metastases (same patients)

ResultsResultsfollow-upfollow-up

• Median response duration: 6 monthsMedian response duration: 6 months

• Median follow-up: 7 monthsMedian follow-up: 7 months

- 21 patients died- 21 patients died

- 6 remained alive ---> 2 CR- 6 remained alive ---> 2 CR

---> 1 PR---> 1 PR

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ResultsResultstreatment-relatedtreatment-related toxicities (grade 3/4)toxicities (grade 3/4)

GC sequenceGC sequence End of treatmentEnd of treatment

NeutropeniaNeutropenia 22 00

AnemiaAnemia 33 11

ThrombocytopeniaThrombocytopenia 22 00

Nausea/emesisNausea/emesis 11 00

DiarrheaDiarrhea 00 11

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ResultsResultsMyelosuppression-related complicationsMyelosuppression-related complications

GC sequenceGC sequence End of treatmentEnd of treatment

Febrile neutropeniaFebrile neutropenia 11 0

Platelet transfusionPlatelet transfusion 11 0

RBC transfusionRBC transfusion 1111 0

Bleeding episodesBleeding episodes 00 0

ConclusionConclusion

• Well tolerated regimenWell tolerated regimen

• ORR is in agreement with the results of ORR is in agreement with the results of previous regimensprevious regimens

• Limited number of patientsLimited number of patients

• Relatively short follow-up (7 months)Relatively short follow-up (7 months)

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