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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04138628
Recruitment Status : Recruiting
First Posted : October 24, 2019
Last Update Posted : June 23, 2020
Aarhus University Hospital
Herlev Hospital
Rigshospitalet, Denmark
Odense University Hospital
Aalborg University Hospital
Information provided by (Responsible Party):
Jørgen Bjerggaard Jensen, Aarhus University Hospital

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.

Condition or disease Intervention/treatment Phase
Bladder Cancer Bladder Cancer, Metastatic Drug: Atezolizumab Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 282 participants
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
Official Title: Treatment Of Metastatic Bladder Cancer at the Time Of Biochemical reLApse Following Radical Cystectomy
Actual Study Start Date : March 24, 2020
Estimated Primary Completion Date : August 1, 2022
Estimated Study Completion Date : November 1, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arm Intervention/treatment
Experimental: ctDNA screening arm
Flat dose 1200 mg Atezolizumab every three weeks for up to 13 months
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.

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. 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

  2. Overall survival after cystectomy in Study Subjects having biochemical relapse [ Time Frame: 5 years ]

  3. Cancer specific survival after cystectomy in Study Subjects having biochemical relapse [ Time Frame: 5 years ]

  4. Recurrence free survival after cystectomy in Study Subjects having biochemical relapse [ Time Frame: 5 years ]

  5. Cancer specific survival after cystectomy in Study Subjects having biochemical relapse stratified for potential predictive biomarkers for response to treatment [ Time Frame: 5 years ]

  6. 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 ]

  7. Time to recurrence seen on imaging (symptomatic or asymptomatic) [ Time Frame: 5 years ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04138628

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Contact: Jørgen B Jensen, MD, DMSc +45 30915459
Contact: Lars Dyrskjøt, Professor +45 78455320

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Aalborg Universitetshospital Not yet recruiting
Aalborg, Denmark, 9100
Contact: Knud Fabrin, MD    +45 97663008      
Principal Investigator: Knud Fabrin, MD         
Principal Investigator: Andreas Carus, MD         
Aarhus University Hospital Recruiting
Aarhus, Denmark, 8200
Contact: Jørgen B Jensen, MD    +4530915682   
Principal Investigator: Mads Agerbæk, MD         
Principal Investigator: Jørgen B Jensen, MD         
Rigshospitalet Not yet recruiting
Copenhagen, Denmark, 2100
Contact: Ulla N Joensen, MD    +45 35452111      
Principal Investigator: Ulla N Joensen, MD         
Principal Investigator: Helle Pappot, MD         
Herlev Hospital Not yet recruiting
Herlev, Denmark, 2730
Contact: Gitte W Lam, MD    +45 38680140      
Principal Investigator: Line H Dohn, MD         
Principal Investigator: Gitte W Lam, MD         
Odense Universitetshospital Not yet recruiting
Odense, Denmark, 5000
Contact: Thor K Jensen, MD    +45 65414400      
Principal Investigator: Thor K Jensen, MD         
Principal Investigator: Niels V Jensen, MD         
Sponsors and Collaborators
Jørgen Bjerggaard Jensen
Aarhus University Hospital
Herlev Hospital
Rigshospitalet, Denmark
Odense University Hospital
Aalborg University Hospital
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Principal Investigator: Jørgen B Jensen, Professor Dept. Of Urology, Aarhus University Hospital, Denmark
Principal Investigator: Lars Dyrskjøt, Professor Dept. Of Molecular Medicine (MOMA) Aarhus University Hospital, Denmark
Principal Investigator: Mads Agerbæk, MD Dept. Of Oncology, Aarhus University Hospital, Denmark
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Responsible Party: Jørgen Bjerggaard Jensen, MD, DMSc, Professor, Consultant in Urology, Aarhus University Hospital Identifier: NCT04138628    
Other Study ID Numbers: DaBlaCa-14
2019-001679-36 ( EudraCT Number )
First Posted: October 24, 2019    Key Record Dates
Last Update Posted: June 23, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Jørgen Bjerggaard Jensen, Aarhus University Hospital:
Muscle Invasive Bladder Cancer (MIBC)
circulating tumor DNA
liquid biopsies
Additional relevant MeSH terms:
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Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Antineoplastic Agents