Treatment Of Metastatic Bladder Cancer at the Time Of Biochemical reLApse Following Radical Cystectomy (TOMBOLA)

• ClinicalTrials.gov Identifier: NCT04138628
• Recruitment Status: Recruiting
• First Posted: October 24, 2019
• Last Update Posted: August 8, 2022
• Sponsor: Jørgen Bjerggaard Jensen
• Collaborators: Aarhus University Hospital; Herlev Hospital; Rigshospitalet, Denmark; Odense University Hospital; Aalborg University Hospital
• Information provided by (Responsible Party): Jørgen Bjerggaard Jensen, Aarhus University Hospital

Tracking Information

• First Submitted Date: October 23, 2019
• First Posted Date: October 24, 2019
• Last Update Posted Date: August 8, 2022
• Actual Study Start Date: March 24, 2020
• Estimated Primary Completion Date: August 1, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 23, 2019)

Complete response (CR) after treatment with investigational agent initiated by ctDNA positive status after radical cystectomy (with or without concomitant visible metastases on CT). [ Time Frame: Time from treatment initiation with investigational agent until 12 months after initiation ]

CR in the current study is defined as ctDNA negative status combined with regular imaging (CT) after treatment. Thus, any metastasis visible on CT at the time of treatment initiation should undergo complete response. In Study Subjects without visible metastasis on CT at the time of treatment, initiation should result in unchanged status on CT. Data will be compared to available historical data on response to PD-1 / PD-L1 targeted agents.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 23, 2019)

• Duration of freedom from clinical relapse in Study Subjects showing decrease or stabilization of ctDNA level after treatment with investigational agent [ Time Frame: 12 months ]
  Time from initiation of therapy until response
• Overall survival after cystectomy in Study Subjects having biochemical relapse [ Time Frame: 5 years ]
  Percentage
• Cancer specific survival after cystectomy in Study Subjects having biochemical relapse [ Time Frame: 5 years ]
  Percentage
• Recurrence free survival after cystectomy in Study Subjects having biochemical relapse [ Time Frame: 5 years ]
  Percentage
• Cancer specific survival after cystectomy in Study Subjects having biochemical relapse stratified for potential predictive biomarkers for response to treatment [ Time Frame: 5 years ]
  Percentage
• Response rate to investigated agent stratified for PD-L1 expression and other predictive biomarkers like TMB, immune cell infiltration, tumor subtypes etc. [ Time Frame: 12 months ]
  Percentage
• Time to recurrence seen on imaging (symptomatic or asymptomatic) [ Time Frame: 5 years ]
  Percentage

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Treatment Of Metastatic Bladder Cancer at the Time Of Biochemical reLApse Following Radical Cystectomy
• Official Title: Treatment Of Metastatic Bladder Cancer at the Time Of Biochemical reLApse Following Radical Cystectomy

Brief Summary

Immunotherapy (checkpoint inhibitors) is approved as first and second line treatment to patients with metastatic bladder cancer. However, response rates are low and no biomarkers have yet shown strong predictive value for patient selection. Moreover, the term 'metastatic' is based on metastases visible on conventional CT scans and, thus, require a certain size of tumour load. Clinical trials are currently being conducted that investigate the use of adjuvant immunotherapy for this group of patients (treatment to all), which will result in massive over-treatment and huge costs to the healthcare system.

This project has the primary objective to identify new indications for initiating immunotherapy in patients with metastatic bladder cancer. Sensitive molecular techniques for detection of tumor DNA in the blood will be used to identify patients with early signs of metastatic disease. In addition, comprehensive biomarker analysis will be performed to identify predictors of treatment response.

Detailed Description

The study aim at investigate the response rate and oncological outcome of systemic immunotherapy (PDL-1 inhibitor; atezolizumab) administered early at the time of biochemical relapse (circulating tumor DNA (ctDNA) positive) in patients who have undergone radical cystectomy because of muscle invasive bladder cancer.

Biomarkers that predict response to systemic immunotherapy will be identified by comprehensive multi-omics analysis of primary tumors and metastatic lesions. Furthermore, we will determine if ctDNA levels during therapy can be used as a biomarker for early indication of therapy response.

The hypotheses is that 1) early initiation of immunotherapy in high-risk (ctDNA positive) patients will result in better response rates and improved survival compared to later treatment following conventional imaging diagnosis of metastasis, and 2) biomarkers for predicting response can be identified and used for tailoring treatment regimens in the future to patients at high risk and at high likelihood of response.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

Single country Investigator Initiated, Open-label, Single-arm, Non-randomized, Phase II study

Masking: None (Open Label)
Primary Purpose: Diagnostic

Condition

• Bladder Cancer
• Bladder Cancer, Metastatic

Intervention

Drug: Atezolizumab

The study drug will be given according to current recommendations as systemic treatment every third week for 12 months or until progression. Treatment will be initiated within 28 days of detection of ctDNA.

Study Arms

Experimental: ctDNA screening arm

Flat dose 1200 mg Atezolizumab every three weeks for up to 13 months

Intervention: Drug: Atezolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 23, 2019): 282
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: November 1, 2029
• Estimated Primary Completion Date: August 1, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• ≥18 years of age at the time of signing the Informed Consent Form
• For male study subjects: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm.
• Signed Informed Consent Form
• ECOG PS 0, 1 or 2
• Is, according to the Investigator's judgement, able to comply with the trial protocol
• Ability to understand the Participant Information Sheet orally and in writing
• Preoperative PET/CT of thorax, abdomen, and pelvis with no suspicion of organ metastases or lymph node metastasis* above the aortic bifuraction

• Study Subjects undergoing radical cystectomy due to histologically documented muscle invasive urothelial carcinoma (including subtypes) stage cT2-4a in the urinary bladder following NAC** in cisplatin-fit Study Subjects.

  • Study Subjects who have undergone down-staging chemotherapy because of lymph node metastasis with no organ metastases can be included if complete response regarding lymph nodes are identified on preoperative imaging.

    • NAC includes Study Subjects who have stopped after one course of chemotherapy because of side effects or local non-metastatic progression

Exclusion Criteria:

• Subjects undergoing non-radical cystectomy for palliative reasons
• Non-radical surgery estimated intraoperative
• Other histology of BC than urothelial carcinoma - mixed tumours with urothelial features are allowed
• Concomitant invasive cancer within 5 years other than non-melanoma skin cancer and prostate cancer without metastasis
• Known contraindication to immunotherapy
• A history of autoimmune disease. Study Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

• Study Subjects who meet any of the following criteria will be excluded from study entry:

  • History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
  • Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment
• HIV positive
• History of pneumonitis (History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Hepatitis B or hepatitis C infection
• Subjects who have received a live, attenuated vaccine within 28 days prior to enrolment

Sex/Gender

• Sexes Eligible for Study: All

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

Contacts

Contact: Jørgen B Jensen, MD, DMSc; +45 30915459; bjerggaard@skejby.rm.dk

Contact: Lars Dyrskjøt, Professor; +45 78455320; lars@clin.au.dk

• Listed Location Countries: Denmark

Administrative Information

• NCT Number: NCT04138628
• Other Study ID Numbers: DaBlaCa-14; 2019-001679-36 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

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

• Current Responsible Party: Jørgen Bjerggaard Jensen, Aarhus University Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Jørgen Bjerggaard Jensen
• Original Study Sponsor: Same as current

Collaborators

• Aarhus University Hospital
• Herlev Hospital
• Rigshospitalet, Denmark
• Odense University Hospital
• Aalborg University Hospital

Investigators

• Principal Investigator: Jørgen B Jensen, Professor; Dept. Of Urology, Aarhus University Hospital, Denmark
• Study Chair: Lars Dyrskjøt, Professor; Dept. Of Molecular Medicine (MOMA) Aarhus University Hospital, Denmark
• Principal Investigator: Mads Agerbæk, MD; Dept. Of Oncology, Aarhus University Hospital, Denmark
• Study Chair: Karin Birkenkamp-Demtröder, Ass. professor; Dept. Of Molecular Medicine (MOMA) Aarhus University Hospital, Denmark

• PRS Account: Aarhus University Hospital
• Verification Date: August 2022