Lapatinib, Cisplatin, Gemcitabine as First-Line Therapy in Treating Patients With Locally Advanced or Metastatic Urothelial Cancer

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC (Other)

Overall Status

Completed

CT.gov ID

NCT00623064

Collaborator

(none)

Enrollment

Location

Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cisplatin, and gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving lapatinib together with combination chemotherapy may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of lapatinib when given together with cisplatin and gemcitabine as first-line therapy in treating patients with locally advanced or metastatic urothelial cancer.

Condition or Disease	Intervention/Treatment	Phase
Bladder Cancer Transitional Cell Cancer of the Renal Pelvis and Ureter	Drug: cisplatin Drug: gemcitabine hydrochloride Drug: lapatinib ditosylate Other: pharmacological study	Phase 1

Detailed Description

OBJECTIVES:

Primary

Determine the maximum tolerated dose and recommended doses of lapatinib ditosylate when administered with gemcitabine hydrochloride and cisplatin, and determine on the basis of acute dose-limiting toxicity in course 1 in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract.

Secondary

To determine any relationship between drug exposure and adverse events in these patients.
To assess the antitumor activity in these patients.

OUTLINE: This is a multicenter, dose-escalation study of lapatinib ditosylate.

Lapatinib ditosylate, cisplatin, and gemcitabine hydrochloride: Patients receive oral lapatinib ditosylate once daily on days 1-28, cisplatin IV on day 2, and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity until the recommended dose of lapatinib ditosylate is determined.
Lapatinib ditosylate, cisplatin, gemcitabine hydrochloride: Subsequently enrolled patients receive oral lapatinib ditosylate (beginning at one dose level below the recommended dose determined in the previous combination) once daily on days 1-21, cisplatin IV on day 1, gemcitabine hydrochloride IV over 30 minutes. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

All patients undergo blood sample collection periodically for pharmacokinetic analysis.

After completion of study treatment, patients are followed weekly.

Study Design

Study Type:

Interventional

Actual Enrollment :

18 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Study of Cisplatin, Gemcitabine and Lapatinib as First Line Treatment in Advanced/Metastatic Urothelial Cancer

Study Start Date :

Nov 1, 2007

Actual Primary Completion Date :

Jun 1, 2012

Actual Study Completion Date :

Aug 1, 2012

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose of lapatinib ditosylate in combination with cisplatin/gemcitabine hydrochloride and cisplatin/gemcitabine hydrochloride based on the documentation of the acute dose-limiting toxicity in course 1 []

Secondary Outcome Measures

Pharmacokinetic profile of lapatinib ditosylate in combination with cisplatin/gemcitabine hydrochloride and cisplatin/gemcitabine hydrochloride []
Antitumor activity according to RECIST []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically proven transitional cell carcinoma of the urothelial tract
Metastatic or locally advanced disease
Measurable disease according to RECIST
Involvement of at least one target not in previously irradiated fields
Overexpressing HER1 and/or HER2 receptors (HER2 3+ by IHC OR HER2 FISH or CISH positive)
No clinical signs of CNS involvement

PATIENT CHARACTERISTICS:

WHO performance status 0-1
ANC ≥ 1,500/mm³
Thrombocytes > 100,000/mm³
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST/ALT ≤ 3 times ULN
Creatinine clearance ≥ 60 mL/min
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective double-barrier contraception during and for 3 months after completion of study treatment
Cardiac ejection fraction normal
Normal 12 lead ECG
No serious cardiac illness or medical condition within the past 6 months including, but not limited to, any of the following:
Documented congestive heart failure
High-risk uncontrolled arrhythmias
Angina pectoris requiring antianginal medication
Clinically significant valvular heart disease
Evidence of transmural infarction on ECG
Poorly controlled hypertension (e.g., systolic blood pressure [BP] > 180 mm Hg or diastolic BP > 100 mm Hg)
No peripheral neuropathy > grade 1
Able to swallow and retain oral medication
No other malignancy within the past 3 years except basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
No active or uncontrolled infections, serious illnesses, malabsorption syndrome or medical conditions, hepatitis, HIV, and/or cirrhosis
No psychological, familial, sociological, or geographical condition potentially hampering study protocol compliance or follow-up schedule
No current active hepatic or biliary disease (with the exception of Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver metastases or stable chronic liver disease)

PRIOR CONCURRENT THERAPY:

Recovered from any effects of surgery
Intravesicle therapy for superficial disease allowed
Prior neoadjuvant or adjuvant chemotherapy allowed
Must have a minimum interval of six months between the completion of neoadjuvant or adjuvant chemotherapy and the diagnosis of metastatic disease
No prior chemotherapy for metastatic disease
No radiotherapy within the past 4 weeks
No drugs and herbal inducers or inhibitors of CYP3A4 (e.g., bergamottin or glabridin) within 10 days prior to study treatment and while receiving lapatinib ditosylate therapy
No other concurrent anticancer therapy or investigational agents
No other concurrent anticancer agents
No concurrent treatment with other investigational therapy for other diseases or conditions
No concurrent prophylactic antibiotics
No concurrent prophylactic filgrastim (G-CSF)
At least 14 days since prior and no concurrent herbal or dietary supplements
No concurrent consumption of grapefruit juice