The primary objective is to determine the complete response rate to administration of oral metformin Secondary objectives are: to determine the partial response rate, the overall safety of metformin, the quality of life during metformin treatment…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome is the complete response rate (complete responses) of the
index lesion after 3 months of treatment with metformin. Evaluable patients are
those who have received at least 500 mg metformin twice daily for one week and
who undergo a cystoscopy and biopsy under anaesthesia for tumour removal.
The response rate calculation is as follows:
- Complete response: complete disappearance of the index lesion, the absence of
new tumours at other sites and a negative bladder washout;
- No response: persistence of the index lesion or the appearance of new lesions
with stage T1 or less;
- Progressive disease: a tumour with stage T2 or greater in the index lesion or
at another site.
The assessment of tumour lesions is generally considered to be relatively
insensitive to inter- and intraobserver heterogeneity, especially because these
studies typically have a binary endpoint (either complete response or no
response/progressive disease). However, in order to pursue the most unbiased
and reproducible analysis possible, cystoscopic images of the index lesions
before and after metformin treatment will be recorded and independently scored
by two experts. This will be independent urologists that are blinded to the
timing of the image acquisition (pre- or post-treatment). Differences in
opinion will be discussed and, if necessary, solved by a third independent
urologist.
Secondary outcome
- partial response rate: the percentage of patients that, after 3 months of
treatment with metformin, have at least a 30% decrease of the sum of the
longest perpendicular diameter of the index lesion or complete disappearance of
the index lesion, the absence of new tumours at other sites but a positive
bladder washout. This is a secondary outcome as the photographical measurement
and post-hoc assessment of index lesions is not standardized and measuring
these lesions using the span of the biopsy device at the cystoscopy and the
span of the cutting loop at the TURB for reference may introduce errors. The
blinded panel of independent urologists (discussed above) will determine the
partial response rate using before-after cystoscopic images taken during
initial cystoscopy and TURB (see Figure 1);
- overall safety of metformin, as scored by CTCAE grading, will be evaluated
after a week and after every subsequent dose increase during a telephone
appointment and after 6 weeks during a visit at the outpatient clinic, and
after 3 months at the admittance for the transurethral resection or biopsy. At
6 weeks and 3 months blood analysis for serum creatinine will be performed as
well. All patients will be evaluated for toxicity from the time of their first
treatment with metformin. The duration of the time to recurrence after marker
lesion resection, as observed by a cystoscopy every 3 to 12 months (depending
on the prognostic risk group) as part of standard NMIBC patient follow-up.
Patients will be followed for a maximum duration of 5 years. The time to
recurrence will be compared between patients that have continued metformin
treatment after the study period (and correlated to their total metformin
treatment duration) and patients that have stopped using metformin after the
primary study duration in a non-blinded (and non-randomized) fashion.
- Patient reported outcomes using SF-36 and EORTC QLQ-NMIBC24 questionnaires;
before metformin treatment, after 6 weeks and after 3 months.
Background summary
Non-muscle-invasive bladder cancer (NMIBC) is the most common neoplasm of the
urinary tract, with ~3,700 new cases and a prevalence of ~32,000 patients in
the Netherlands in 2016. Despite current treatments such as transurethral
resection and intravesical treatment with Bacillus Calmette-Guerin (BCG) or
mitomycin C, it is associated with high risk of recurrence and/or progression.
The need for life-long invasive surveillance and treatment puts NMIBC among the
most expensive cancers to treat on a per-patient basis and it represents a
major public health challenge. Moreover, BCG is poorly available, which further
complicates NMIBC treatment. Therefore, the development of a safe, low-cost,
and orally active drug for preventing and treating recurrence and progression
of NMIBC is a priority in urologic oncology. Metformin is a widely used, cheap
and safe drug that is first-in-line for the treatment of type 2 diabetes
mellitus (T2DM). Substantial laboratory evidence supports the hypothesis that
metformin has antineoplastic activity in bladder cancer. Moreover,
epidemiologic studies have suggested that metformin reduces the occurrence and
recurrences of NMIBC in patients with T2DM, as compared with T2DM patients not
treated with metformin. While there are many ongoing trials of metformin for
various indications in oncology, metformin has not been able to improve patient
survival so far. One explanation could be that metformin fails to accumulate to
a sufficient concentration in tissues to exert sufficient antineoplastic
effects. In support of this, many in vitro studies show direct
antiproliferative actions of metformin at millimolar concentrations, but with
conventional oral doses of metformin, the serum concentrations are in the
micromolar range. A recent study in a transgenic model of NMIBC, mice treated
with metformin demonstrated a ~240-fold higher drug concentration in urine
compared to serum, resulting in improved survival, reduced urinary tract
obstruction and reduced bladder weight. In humans, metformin is also excreted
unchanged in the urine, where concentrations are >100-fold higher than in the
serum. Thus, from a pharmacokinetic perspective, NMIBC is particularly
interesting for clinical trials to evaluate metformin as an antineoplastic
agent.
Study objective
The primary objective is to determine the complete response rate to
administration of oral metformin
Secondary objectives are: to determine the partial response rate, the overall
safety of metformin, the quality of life during metformin treatment using
patient- reported outcomes and the time to recurrence after
Exploratory objectives: the investigation of tumour biology markers in biopsies
or tumour resection tissue taken, the pharmacokinetic analysis of metformin
levels in urine and serum, and (in case of promising results) a preliminary
economic evaluation to estimate potential cost savings that could be achieved
using metformin in NMIBC patients compared to standard adjuvant treatment.
Study design
This is a phase II clinical study of metformin administered in NMIBC. Patients
entering the study will have suspected Ta/T1, G1/G2 (low grade) tumours and
negative cytology.
Intervention
All patients will receive metformin orally in a starting dose of 500 mg once
daily, which is then stepwise increased to 1500 mg twice daily (doses above
1000 mg twice daily are restricted to patients with adequate renal function,
creatinine clearance >=60 mL/min). The stepwise dose increase mimics
conventional metformin dosing schemes in the treatment of diabetes mellitus
type 2 and is to reduce gastro-intestinal side effects.
Study burden and risks
Burden: 1 extra study visits, check-up visit at the outpatient clinic during
metformin treatment.
Risks:
- Related to side effects of metformin: metformin is generally considered to be
a safe drug with a relatively favorable safety profile.
De Boelelaan 1117
Amsterdam 1081 HV
NL
De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
Age > 18 years. Patients with primary or recurrent multiple histologically
confirmed Ta or T1 (non-muscle invasive), G1 or G2 (low grade) urothelial
carcinoma of the bladder with no evidence of carcinoma in situ. Patients must
have at least 1 lesion but no more than 5. Bimanual examination immediately
following transurethral resection under anaesthesia should be carried out and
no mass should be felt. Adequate renal function (creatinine <150 µmol/L and/or
an eGFR >>50 ml/L). Adequate liver function (bilirubin <1.5 times upper limit
of normal, ALAT or ASAT <2.5 the upper limit of normal). Eligible patients must
be fully informed of the investigational nature of the study and written signed
informed consent must be obtained prior to any study specific investigations.
Mentally, physically, and geographically able to undergo treatment and follow
up.
Exclusion criteria
Patients having muscle-invasive disease (stage T2 or greater) or CIS.
Patients with grade 3 (high-grade) tumours.
Patients with diabetes mellitus receiving metformin or having received
metformin in the past 6 months.
Patients who have received intravesical treatment (chemotherapy or
immunotherapy) within the last 3 months.
Patients that are currently receiving other anti-cancer therapy.
Patients with existing urinary tract infection or recurrent severe bacterial
cystitis.
Patients that need to be treated with a transurethral catheter.
Patients with urogenital tumours with histology other than urothelial carcinoma
(i.e. squamous cell or adenocarcinoma) or with urothelial carcinoma involving
the upper tract or the prostatic urethra.
Patients with a history of other primary malignancy (other than squamous or
basal cell skin cancers or cone biopsied CIS of the uterine cervix or prostate
carcinoma treated curatively with normal PSA values at inclusion) in the last
five years.
Patients with active, uncontrolled impairment of the renal, hepatobiliary,
cardiovascular, gastrointestinal, urogenital, neurologic or hematopoietic
systems that, in the opinion of the investigator, would predispose to the
development of complications from the administration of metformin.
Patients who are using loop diuretics, cimetidine, ranitidine, cetirizine,
trimethoprim, vandetanib, kinidine and/or HIV medication, for which no
reasonable alternative is available.
Women who are pregnant or lactating. Individuals of reproductive potential may
not participate unless agreeing to use an effective contraceptive method for
themselves and/or their sexual partner.
Patients with ECOG-WHO performance status of 3 or 4.
Patients with a known history of alcohol abuse.
Patients with a known hypersensitivity to metformin.
Patients who in the investigator's opinion, cannot comply with provisions of
the protocol or do not understand the nature of the study.
Design
Recruitment
Medical products/devices used
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-002883-41-NL |
| ClinicalTrials.gov | NCT03379909 |
| CCMO | NL62588.018.17 |
| OMON | NL-OMON25176 |