Phase II Study of Oral Metformin for Intravesical Treatment of Non-muscle-invasive Bladder Cancer (TROJAN)

A multi-center, open-label, phase II clinical study of metformin in up to evaluable 49 patients with low-grade NMIBC with the aim to determine the overall response to administration of oral metformin for 3 months in a index papillary NMIBC tumour.

Study Overview

• Status: Recruiting
• Conditions: Bladder Cancer; Superficial Bladder Cancer
• Intervention / Treatment: Drug: Metformin

Detailed Description

A multi-center, open-label, phase II clinical study of metformin in up to 49 patients with low-grade NMIBC with the aim to determine the overall response to administration of oral metformin for 3 months in a index tumour (0.5-1 cm) selected ane measured during cystoscopy. All patients will receive metformin orally at doses up to 1500 mg twice daily. Metformin treatment will start directly after informed consent is obtained. After 3 months of metformin treatment, the effect of metformin on the index lesion is evaluated by performing a transurethral resection of the bladder tumour under anaesthesia. Residual tumour, if present at this evaluation, will be resected. In case of complete disappearance of the index lesion the former tumour area will be biopsied.

• Study Type: Interventional
• Enrollment (Estimated): 49
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: M. J. Remmelink, MD; Phone Number: 0204441376; Email: m.j.remmelink@amsterdamumc.nl
• Study Contact Backup: Name: J. W. Wilmink, MD, PhD; Phone Number: 0205665983; Email: j.w.wilmink@amsterdamumc.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Recruiting
    • Academic Medical Center
    • Principal Investigator: J. W. Wilmink, MD, PhD
    • Contact: J. W. Wilmink, MD, PhD; Phone Number: 31 20 5665955; Email: j.w.wilmink@amsterdamumc.nl
    • Contact: J. R. Oddens, MD, PhD; Email: j.r.oddens@amsterdamumc.nl
    • Principal Investigator: J. R. Oddens, MD, PhD
  • Gelderland
    • Nijmegen, Gelderland, Netherlands
      • Not yet recruiting
      • Radboudumc
      • Contact: A. G. van der Heijden, MD, PhD; Email: toine.vanderheijden@radboudumc.nl
      • Principal Investigator: A. G. van der Heijden, MD PhD
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands
      • Not yet recruiting
      • Sint Franciscus Gasthuis
      • Contact: ER Boeve, MD PhD
      • Principal Investigator: ER Boeve, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age > 18 years.
• Patients with primary or recurrent suspectedTa or T1, G1 or G2 (low grade) urothelial carcinoma of the bladder with no suspicion of carcinoma in situ.
• Patients must have at least 1 lesion but no more than 5.
• There must be one index lesion measuring between 0.5 and 1.0 cm in its greatest dimension.
• Bimanual examination immediately following cystoscopyshould be carried out and no mass should be felt.
• Adequate renal function (eGFR >50 ml/min/1.73m2 according to CKD-EPI). (47)
• 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 with positive cytology (suspected for high-grade urothelial carcinoma, TPS 4 or TPS 5) or suspected grade 3 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment arm; Metformin orally at doses up to 1500 mg twice daily for 3 months.	Drug: Metformin; Metformin orally at doses up to 1500 mg twice daily for 3 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response	The primary outcome is the objective response rate (complete responses) 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 for marker lesion removal.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to recurrence	The duration of the time to recurrence of NMIBC after stopping metformin treatment. Patients will be followed for a maximum duration of 5 years.	5 years
Partial response	At least 30% reduction in the longest diameter of the marker lesion.	3 months.
Toxicity of metformin treatment	The number of grade 1-4 and grade 5 (fatal) NCI Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE) events during treatment with metformin. All patients will be evaluable for toxicity from the time of their first treatment with metformin.	3 months

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Radboud University Medical Center

Publications and helpful links

General Publications

• Molenaar RJ, van Hattum JW, Brummelhuis IS, Oddens JR, Savci-Heijink CD, Boeve ER, van der Meer SA, Witjes JF, Pollak MN, de Reijke TM, Wilmink JW. Study protocol of a phase II clinical trial of oral metformin for the intravesical treatment of non-muscle invasive bladder cancer. BMC Cancer. 2019 Nov 21;19(1):1133. doi: 10.1186/s12885-019-6346-1.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2019
• Primary Completion (Estimated): July 31, 2024
• Study Completion (Estimated): October 1, 2029

Study Registration Dates

• First Submitted: December 16, 2017
• First Submitted That Met QC Criteria: December 16, 2017
• First Posted (Actual): December 20, 2017

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 19, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: metformin; marker lesion
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Urinary Bladder Neoplasms; Non-Muscle Invasive Bladder Neoplasms; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: Medonc-17-11

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No