Clinical trial NCT04138628: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Bladder Cancer
Bladder Cancer, Metastatic
Keywords: Muscle Invasive Bladder Cancer (MIBC)
biomarkers
ctDNA
immunotherapy
circulating tumor DNA
liquid biopsies
Lead sponsor: Aarhus University Hospital
Sponsor class: OTHER
Collaborators: name: Aarhus University Hospital
name: Herlev Hospital
name: Rigshospitalet, Denmark
name: Odense University Hospital
name: Aalborg University Hospital
First posted: 2019-10-24
Enrollment: 282
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single country Investigator Initiated, Open-label, Single-arm, Non-randomized, Phase II study
Primary purpose: DIAGNOSTIC

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.

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

Primary outcomes:
measure: Complete response (CR) after treatment with investigational agent initiated by ctDNA positive status after radical cystectomy (with or without concomitant visible metastases on CT).
timeFrame: Time from treatment initiation with investigational agent until 12 months after initiation
Secondary outcomes:
measure: Duration of freedom from clinical relapse in Study Subjects showing decrease or stabilization of ctDNA level after treatment with investigational agent
timeFrame: 12 months
measure: Overall survival after cystectomy in Study Subjects having biochemical relapse
timeFrame: 5 years
measure: Cancer specific survival after cystectomy in Study Subjects having biochemical relapse
timeFrame: 5 years
measure: Recurrence free survival after cystectomy in Study Subjects having biochemical relapse
timeFrame: 5 years
measure: Cancer specific survival after cystectomy in Study Subjects having biochemical relapse stratified for potential predictive biomarkers for response to treatment
timeFrame: 5 years
measure: Response rate to investigated agent stratified for PD-L1 expression and other predictive biomarkers like TMB, immune cell infiltration, tumor subtypes etc.
timeFrame: 12 months
measure: Time to recurrence seen on imaging (symptomatic or asymptomatic)
timeFrame: 5 years
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Aalborg Universitetshospital
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Herlev
country: Denmark
facility: Herlev Hospital
city: Odense
country: Denmark
facility: Odense Universitetshospital
Study officials:
affiliation: Dept. Of Urology, Aarhus University Hospital, Denmark
name: Jørgen B Jensen, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Dept. Of Molecular Medicine (MOMA) Aarhus University Hospital, Denmark
name: Lars Dyrskjøt, Professor
role: STUDY_CHAIR
affiliation: Dept. Of Oncology, Aarhus University Hospital, Denmark
name: Mads Agerbæk, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Dept. Of Molecular Medicine (MOMA) Aarhus University Hospital, Denmark
name: Karin Birkenkamp-Demtröder, Ass. professor
role: STUDY_CHAIR
References: