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

• ClinicalTrials.gov Identifier: NCT03379909
• Recruitment Status: Recruiting
• First Posted: December 20, 2017
• Last Update Posted: January 19, 2021
• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Radboud University; Jeroen Bosch Ziekenhuis; Sint Franciscus Gasthuis
• Information provided by (Responsible Party): J.W. Wilmink, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Tracking Information

• First Submitted Date: December 16, 2017
• First Posted Date: December 20, 2017
• Last Update Posted Date: January 19, 2021
• Actual Study Start Date: September 1, 2019
• Estimated Primary Completion Date: January 1, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 29, 2018)

Overall response [ Time Frame: 3 months ]

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.

Original Primary Outcome Measures (submitted: December 16, 2017)

Overall response [ Time Frame: 8 weeks ]

The primary outcome is the objective response rate (partial responses + complete responses) after 8 weeks 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.

Current Secondary Outcome Measures (submitted: March 29, 2018)

• Time to recurrence [ Time Frame: 5 years ]
  The duration of the time to recurrence of NMIBC after stopping metformin treatment. Patients will be followed for a maximum duration of 5 years.
• Toxicity [ Time Frame: 3 months ]
  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.
• Partial response [ Time Frame: 3 months. ]
  At least 30% reduction in the longest diameter of the marker lesion.

Original Secondary Outcome Measures (submitted: December 16, 2017)

• Time to recurrence [ Time Frame: 5 years ]
  • The duration of the time to recurrence of NMIBC after stopping metformin treatment. Patients will be followed for a maximum duration of 5 years.
• Toxicity [ Time Frame: 8 weeks ]
  • 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase II Study of Oral Metformin for Intravesical Treatment of Non-muscle-invasive Bladder Cancer
• Official Title: Phase II Study of Oral Metformin for Intravesical Treatment of Non-muscle-invasive Bladder Cancer
• Brief Summary: 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 marker tumour deliberately left following transurethral resection of multiple, papillary NMIBC tumours.
• 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 marker tumour deliberately left following transurethral resection of multiple, papillary NMIBC tumours. All patients will receive metformin orally at doses up to 1500 mg twice daily. Metformin treatment will start within 2 weeks following transurethral resection, in which all but the marker lesion will be resected. After 3 months of metformin treatment, the effect of metformin on the marker lesion is evaluated by cystoscopy and biopsy under anaesthesia. Residual tumour, if present at this evaluation, will be resected. In case of complete disappearance of the marker lesion the former tumour area will be biopsied.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Superficial Bladder Cancer
• Bladder Cancer

Intervention

Drug: Metformin

Metformin orally at doses up to 1500 mg twice daily for 3 months.

Study Arms

Experimental: Treatment arm

Metformin orally at doses up to 1500 mg twice daily for 3 months.

Intervention: Drug: Metformin

• Publications *: Molenaar RJ, van Hattum JW, Brummelhuis IS, Oddens JR, Savci-Heijink CD, Boevé 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 16, 2017): 49
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 1, 2025
• Estimated Primary Completion Date: January 1, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 2 lesions but no more than 10.
• The resected lesions must contain detrusor muscle to confirm a Ta/T1 disease.
• All visible lesions must be completely removed by transurethral resection at entry to the study, except for an untouched marker lesion measuring 0.5-1.0 cm in its greatest dimension.
• 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 >60 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT03379909
• Other Study ID Numbers: Medonc-17-11
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: J.W. Wilmink, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Study Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Collaborators

• Radboud University
• Jeroen Bosch Ziekenhuis
• Sint Franciscus Gasthuis

• Investigators: Not Provided
• PRS Account: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Verification Date: January 2021