Carboplatin and Gemcitabine Hydrochloride With or Without Vandetanib as First-Line Therapy in Treating Patients With Locally Advanced or Metastatic Urinary Tract Cancer

Sponsor

Cardiff University (Other)

Overall Status

Completed

CT.gov ID

NCT01191892

Collaborator

(none)

Enrollment

Locations

Arms

75.2

Duration (Months)

3.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as carboplatin and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vandetanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It is not yet known whether giving carboplatin and gemcitabine hydrochloride is more effective with or without vandetanib as first-line therapy in treating urinary tract cancer.

PURPOSE: This randomized phase II trial is studying giving carboplatin together with gemcitabine hydrochloride and to see how well it works when given with or without vandetanib as first-line therapy in treating patients with locally advanced or metastatic urinary tract cancer.

Condition or Disease	Intervention/Treatment	Phase
Bladder Cancer Transitional Cell Cancer of the Renal Pelvis and Ureter Ureter Cancer Urethral Cancer	Drug: carboplatin Drug: gemcitabine hydrochloride Drug: vandetanib Drug: Placebo	Phase 2

Detailed Description

OBJECTIVES:

Primary

To determine the antitumor activity (as measured by progression-free survival) of carboplatin and gemcitabine hydrochloride with versus without vandetanib as first-line treatment in patients with locally advanced or metastatic urothelial cell cancer who are not suitable to receive cisplatin.

Secondary

To determine the safety, feasibility, and tolerability of these regimens in these patients.
To determine the objective response rate.
To determine the overall survival of patients treated with these regimens
To assess the change of size of measurable lesions at 9 weeks of study therapy.

OUTLINE: This is a multicenter study. Patients are stratified according to relevant factors. Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive carboplatin IV over 30 minutes on day 1, gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, and an oral placebo once daily on days 1-21. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
Arm II: Patient receive carboplatin and gemcitabine hydrochloride as in arm I. Patients also receive oral vandetanib once daily on days 1-21. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

Blood and urine samples may be collected for laboratory analysis at baseline and after completion of study.

After completion of study treatment, patients are followed up at weeks 18, 26, 39, and 52.

Peer Reviewed and Funded or Endorsed by Cancer Research UK.

Study Design

Study Type:

Interventional

Actual Enrollment :

82 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Randomized Phase II Trial of Carboplatin and Gemcitabine +/- Vandetanib in First Line Treatment of Advanced Urothelial Cell Cancer in Patients Who Are Not Suitable to Receive Cisplatin

Study Start Date :

Jun 1, 2010

Actual Primary Completion Date :

Dec 1, 2015

Actual Study Completion Date :

Sep 5, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Carboplatin, Gemcitabine and Placebo	Drug: carboplatin Drug: gemcitabine hydrochloride Drug: Placebo Placebo of vandetanib tablet
Experimental: vandetanib Carboplatin, Gemcitabine and vandetanib	Drug: carboplatin Drug: gemcitabine hydrochloride Drug: vandetanib

Arm

Intervention/Treatment

Placebo Comparator: Placebo

Carboplatin, Gemcitabine and Placebo

Drug: carboplatin

Drug: gemcitabine hydrochloride

Drug: Placebo

Placebo of vandetanib tablet

Experimental: vandetanib

Carboplatin, Gemcitabine and vandetanib

Drug: carboplatin

Drug: gemcitabine hydrochloride

Drug: vandetanib

Outcome Measures

Primary Outcome Measures

Progression Free Survival [1 year]
Time to event PFS, follow-up to 1 year

Secondary Outcome Measures

Tolerability and feasibility [1 year]
Rate of randomisation and safety profile of randomised patients
Objective response rate as assessed by RECIST criteria [Up to 1 year]
Proportion of patients responding to treatment
Overall survival [2 years]
Patients will be followed up until death by using NHS flagging service.
Change in size of measurable lesions 9 weeks after start of chemotherapy [9 weeks]
Toxicity during and after treatment as assessed by NCI CTCAE v 4.0 [1 year]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed transitional cell carcinoma (pure or mixed histology) of the urothelium (upper or lower urinary tract)
Cancers with other pathologies are permitted provided the dominant morphology is transitional cell carcinoma
Radiologically measurable disease according to RECIST v 1.1 criteria
Locally advanced and/or metastatic disease not amenable to curative treatment with surgery or radiotherapy
Patient not suitable for cisplatin therapy, meeting 1 or more of the following criteria:
More than 75 years of age
ECOG performance status > 2
Creatinine clearance < 30 mL/min
Clinically significant ischemic heart disease (myocardial infarction or unstable angina more than 3 but less than 12 months prior to date of randomization, symptomatic angina, or NYHA class I within 3 months prior to date of randomization)
Prior intolerance of cisplatin
Any other factor that, in the opinion of the investigator, indicates that cisplatin is not suitable for the patient (e.g., unilateral hearing loss)

PATIENT CHARACTERISTICS:

See Disease Characteristics
ECOG performance status 0-2
Serum bilirubin ≤ 1.5 times upper limit of normal (ULN)
Creatinine clearance ≥ 30 mL/min
Potassium ≥ 4.0 mmol/L OR below the CTCAE grade 1 upper limit
Magnesium normal OR below the CTCAE grade 1 upper limit
Serum calcium ≤ 2.9 mmol/L (If serum calcium is < lower limit of normal [LLN], then adjusted serum calcium must be ≥ LLN)
ALT/AST ≤ 2.5 times ULN
Alkaline phosphatase ≤ 2.5 times ULN (< 5 times ULN if judged by the investigator to be related to liver metastases)
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective barrier-method contraception during and for 3 months (women) or 2 months (men) after completion of study therapy
No evidence of severe or uncontrolled systemic disease or any concurrent condition that, in the investigator's opinion, makes it undesirable for the patient to participate in the trial or that would jeopardize compliance with the protocol
No significant risk of cardiac complications, defined as any of the following:
Clinically significant cardiovascular event (e.g., myocardial infarction, superior vena cava syndrome [SVC], NYHA classification of heart disease ≥ class II within 3 months prior to entry, or presence of cardiac disease that, in the opinion of the investigator, significantly increases the risk of ventricular arrhythmia)
History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia
Atrial fibrillation, controlled on medication, is not exclusionary
No QTc prolongation with other medications that requires discontinuation of that medication
No congenital long QT syndrome or first-degree relative with unexplained sudden death under 40 years of age
No QTc that is immeasurable or ≥ 480 msec on screening ECG
If a patient has a QTc interval ≥ 480 msec on screening ECG, the ECG screen may be repeated twice (at least 24 hours apart) and the average QTc from the three screening ECGs must be < 480 msec in order for the patient to be eligible for the study
Patients who are receiving a drug that has a risk of Torsades de Pointes are excluded if QTc is ≥ 460 msec
No presence of left bundle branch block
No hypertension not controlled by medical therapy (systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg)
No currently active diarrhea that, in the investigator's opinion, may affect the ability of the patient to either absorb vandetanib or to tolerate additional diarrhea episodes
No previous or current malignancies of other histology within the past 5 years except for carcinoma in situ of the cervix, adequately treated basal cell or squamous cell carcinoma of the skin, or prostate cancer

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
At least 2 weeks since prior and no concurrent known potent CYP3A4 inducers (e.g., barbiturates, rifampicin, rifabutin, phenytoin, carbamazepine, troglitazone, phenobarbital, or St. John wort) or medication that has known adverse interactions with vandetanib
Dexamethasone (or equivalent) allowed as a pre-medication for chemotherapy
At least 4 weeks since prior major surgery and complete surgical wound healing
At least 30 days since prior and no other concurrent investigational agents
No prior chemotherapy (unless delivered perioperatively and completed > 12 months prior to first presentation of recurrent disease)
No other concurrent anticancer drug

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beatson West of Scotland Cancer Centre	Glasgow	Scotland	United Kingdom	G12 0YN
2	Wales Cancer Trials Unit	Cardiff	Wales	United Kingdom	CF11 9LJ
3	Ayr Hospital	Ayr		United Kingdom	KA66DX
4	Royal Bournemouth General Hospital	Bournemouth		United Kingdom	BH7 7DW
5	Queens Hospital	Burton upon Trent		United Kingdom	DE13 0RB
6	Velindre Hospital	City And County Of Cardiff		United Kingdom	CF142TL
7	Western General Hospital	Edinburgh		United Kingdom	EH4 2XU
8	Calderdale Royal Infirmary	Halifax		United Kingdom	HX30PW
9	Huddersfield Royal Infirmary	Huddersfield		United Kingdom	HD3 3EA
10	The Royal Lancaster Infirmary	Lancaster		United Kingdom	LA1 4RP
11	St. James's University Hospital	Leeds		United Kingdom	LS9 7TF
12	The Royal Free Hospital	London		United Kingdom	NW3 2QG
13	St Marys Hospital	London		United Kingdom	W21NY
14	Charing Cross Hospital	London		United Kingdom	W68RF
15	Christie Hospital	Manchester		United Kingdom	M20 4BX
16	Mount Vernon Hospital	Northwood Middlesex		United Kingdom	HA6 2RN
17	Churchill Hospital	Oxford		United Kingdom	OX37LJ
18	Weston Park Hospital	Sheffield		United Kingdom	S102SJ
19	Southampton General Hospital	Southampton		United Kingdom	S016 6YD
20	Royal Surrey County Hospital	Surrey		United Kingdom	GU27XX
21	The Royal Marsden Hospital	Surrey		United Kingdom	KT2 7QB