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Pilot Study of Lapatinib (Tyverb®) in Neoadjuvant Treatment for Patients With Locally Bladder Carcinoma Before Cystectomy

Phase 0
18 Years
Not Enrolling
Bladder Carcinoma, Infiltrative Bladder Carcinoma, Cystectomy

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Trial Information

Pilot Study of Lapatinib (Tyverb®) in Neoadjuvant Treatment for Patients With Locally Bladder Carcinoma Before Cystectomy

Patients with invasive bladder tumor , candidates for radical cystectomy. Patients will
receive Lapatinib during 3 weeks +/- 5 days, before cystectomy. A comparison of tissue from
the original biopsy and cystectomy after Lapatinib will allow this to occur.

TREATMENT AND STRATEGY Lapatinib in bladder carcinoma -Overall there are arguments for
considering that egf pathway is involved in bladder carcinoma and so far that drugs
inhibiting EGF pathway could have an impact for therapeutical endpoints.

Nevertheless it is unclear that from previous studies that adding egf inhibiting drug to
chemotherapy is clinically relevant, essentially by difficulties to measure a beneficial
endpoint while downstream EGF pathways have been modified by these drugs, as shown with
lapatinib (see 2.1.5).

Furthermore, there is no argument for initial selection of patients based on the initial
egfr and/or her 2 tumor profile, asking for more intense knowledge.

LAPATINIB TREATMENT Patients will receive lapatinib therapy at a daily standard dose of 1500

LAPATINIB TREATMENT DURATION Patients will then receive 3 weeks of lapatinib therapy +
possible 5 days. As the study is a non direct benefit study, the exposition to the drug is
proposed during the standard window of 3 to 4 weeks to organize a radical cystectomy in
patients with muscle invasive bladder carcinoma. In this study patients, the standard
procedure is not delayed for the purpose of the study.

The duration of exposition to lapatinib as to be long enough to have a continuous impact of
biological events to induce indeed inhibition of EGF pathway but also to impact on more
complex or more distal events as apoptosis and so to be able to measure it. This justifies a
3 weeks of treatment + possible up to 5 days more due to surgical organization procedures.

Surgery will take place on the last day of treatment, which is recommended due to the
half-life of lapatinib. Nevertheless for surgical purpose, the drug could be not given on
the day of surgery.

Inclusion Criteria:

- Patients must sign and date IRB/EC-approved informed consent,

- Age ≥ 18

- Patients must have a life expectancy of at least 6 months,

- Patients must have a Karnofsky performance status ≥ 80%,

- Clinical stage T2NxM0 to T4aNxM0 bladder cancer

- Muscle-invasive transitional cell carcinoma by histology (focal squamous and/or
adenocarcinoma differentiation defined as ≤ 10% of tumor volume allowed, sarcomatoid
and small-cell components not allowed)

- Considered to have a macroscopic residue in the bladder to allow comparison of tissue
samples at cystectomy to initial biopsies

- Candidates for radical cystectomy

- Patient with normal cardiac function, LVEF ≥ 50% measured by echocardiography or MUGA

- Able to swallow and retain oral medication

- A female is eligible to enter and participate in this study if she is of :
Non-child-bearing potential (i.e., a woman with functioning ovaries who have a
current documented tubal ligation or hysterectomy or a woman who is menopausal), or
Child-bearing potential (i.e. a woman with functioning ovaries and no documented
impairment of oviductal or uterine function that would cause sterility. This
category includes women with oligomenorrhoea (even severe), women who are
perimenopausal and young women who have begun to menstruate), who have a negative
serum pregnancy test at screening, and agree to one of the following consistent and
correct use of one acceptable methods of birth control : Any intrauterine device
(IUD) with a documented failure rate of less than 1% per year, or combined oral

- care must be taken to avoid pregnancy in partners of male patients.

- Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other study procedures.

- Affiliated or profit patient of a social security system

Exclusion Criteria:

- Prior pelvic radiation or neoadjuvant chemotherapy.

- Pregnancy or breastfeeding.

- Other severe acute or chronic medical or psychiatric condition that would impart, in
the judgment of the investigator, excess risk associated with study participation or
study drug administration, or which, in the judgment of the investigator, would make
the patient inappropriate for entry into this study.

- Patients with significantly reduced LVEF or LVEF < 50%.

- Patient with any of the following liver abnormal laboratory test :

- Serum bilirubin > 1,5 x upper limit of normal (ULN) (in case of Gilbert syndrome, a
higher serum total bilirubin (< 2 ULN) is allowed

- Alanine amino transferase (ALAT) or aspartate amino transferase (ASAT) > 2,5 ULN

- Platelets <100 x 109/L, hemoglobin < 9 g/dl, absolute neutrophil count (ANC) <1.5 x

- Have current active hepatic or biliary disease (with exception of patients with
Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver
disease per investigator assessment)

- Serum creatinine > 1.5 x ULN.

- Previous therapy targeting EGFR or HER-2.

- Predominantly non transitional cell histology.

- Diagnosis of any second malignancy within the last 3 years, except basal cell
carcinoma, squamous cell skin cancer, or in situ carcinoma of the cervix uteri that
has been adequately treated with no evidence of recurrent disease for 12 months.

- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
major resection of the stomach or bowel, that could affect absorption of lapatinib.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to lapatinib

- Uncontrolled inter-current illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, that would limit compliance with study requirements.

- History of uncontrolled or symptomatic angina

- History of arrhythmias requiring medications, or clinically significant, with the
exception of asymptomatic atrial fibrillation requiring anticoagulation

- Myocardial infarction < 6 months from study entry

- Uncontrolled or symptomatic congestive heart failure

- Ejection fraction below the institutional normal limit

- Any other cardiac condition, which in the opinion of the treating physician, would
make this protocol unreasonably hazardous for the patient

- Use of an investigational agent within 30 days or 5 half-lives, whichever is the
longer, preceding the first dose of investigational product.

- Concurrent treatment with an investigational agent

- Concurrent treatment with cytotoxic chemotherapy, immunotherapy, biologic therapy,
hormonal therapy or curative radiotherapy for locally advanced or metastatic TCC of
the urothelial tract.

- Concomitant requirement for medication classified as CYP3A4 inducers or inhibitors.

- Patient under safeguard of justice

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label

Outcome Measure:

Effect on egf pathway at a molecular level of 3 weeks treatment by lapatinib.

Outcome Description:

The primary objective of the study is to evaluate the effect at a molecular level, of 3 weeks of neoadjuvant lapatinib, in locally advanced muscle-invasive transitional cell carcinoma of the bladder. A comparison of tissue from the original biopsy and cystectomy after lapatinib will allow this to occur. This effect will be evaluated by studying proliferation and apoptotic markers as well as the phosphorylation of proteins which are components of the egf signalling pathway.

Outcome Time Frame:

At surgery (day 21-27)

Safety Issue:


Principal Investigator

Geneviève CHENE, Pr

Investigator Role:

Study Chair

Investigator Affiliation:

USMR Bordeaux


France: Ministry of Health

Study ID:

CHUBX 2009/04



Start Date:

January 2011

Completion Date:

October 2011

Related Keywords:

  • Bladder Carcinoma
  • Infiltrative Bladder Carcinoma
  • Cystectomy
  • Phase 0
  • Bladder carcinoma
  • egf pathway
  • infiltrative bladder carcinoma
  • cystectomy
  • Urinary Bladder Neoplasms
  • Carcinoma