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    Summary
    EudraCT Number:2019-001679-36
    Sponsor's Protocol Code Number:ML41007
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-07-01
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2019-001679-36
    A.3Full title of the trial
    Treatment Of Metastic Bladder cancer at the time Of biochemical reLApse following radical cystectomy
    Behandling af metastatisk blærekræft ved biokemisk recidiv efter radikal cystektomi
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment Of Metastic Bladder cancer at the time Of biochemical reLApse following radical cystectomy
    Behandling af metastatisk blærekræft ved biokemisk recidiv efter radikal cystektomi
    A.3.2Name or abbreviated title of the trial where available
    TOMBOLA
    TOMBOLA
    A.4.1Sponsor's protocol code numberML41007
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAarhus University
    B.1.3.4CountryDenmark
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF. Hoffmann-La Roche Ltd.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAarhus University Hospital
    B.5.2Functional name of contact pointJørgen Bjerggaard Jensen
    B.5.3 Address:
    B.5.3.1Street AddressPalle-Juul Jensens Boulevard 99
    B.5.3.2Town/ cityAarhus N
    B.5.3.3Post code8200
    B.5.3.4CountryDenmark
    B.5.4Telephone number004530915682
    B.5.6E-mailBjerggaard@skejby.rm.dk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Tecentriq
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAtezolizumab
    D.3.2Product code L01XC32
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNATEZOLIZUMAB
    D.3.9.1CAS number 1380723-44-3
    D.3.9.2Current sponsor codeRO5541267
    D.3.9.3Other descriptive nameMPDL3280A
    D.3.9.4EV Substance CodeSUB178312
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Biochemical relapse in patients who have undergone radical cystectomy because of muscle-invasive transitional cell carcinoma of the urinary bladder
    Biokemisk recidiv hos patienter, der har fået foretaget cystektomi grundet urotelial carcinom i urinblæren
    E.1.1.1Medical condition in easily understood language
    Patients with relapse detected with a blood sample, who previously have undergone removal of the urinary bladder due to muscle-invasive bladder cancer
    Patienter, der tidligere har fået foretaget kirurgisk fjernelse af urinblæren grundet blærekræft, som aktuelt har biokemisk tilbagefald målt i en blodprøve
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10066754
    E.1.2Term Bladder transitional cell carcinoma stage III
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate the response rate and oncological outcome of systemic immunotherapy administered at the time of biochemical relapse (ctDNA positive test) in Study Subjects who have undergone NAC followed by radical cystectomy because of MIBC. Long term survival of Study Subjects with positive ctDNA treated with immunotherapy will be compared to available historical data from clinical immunotherapy trials where Study Subjects are treated at the time of recurrence diagnosed by conventional CT routine follow-up.
    Vi vil undersøge hvor effektiv immunterapi er til patienter med tilbagefald af muskel-invasiv kræft i urinblæren efter operation forudgået af neoadjuverende kemoterapi, hvis behandlingen påbegyndes på tidspunktet for påvisning af kræft-arvemasse i blodprøver (ctDNA). Effektiviteten vil blive sammenlignet med den effekt man kender fra tidligere studier, hvor immunterapien først gives ved synligt tilbagefald på CT-skanning.
    E.2.2Secondary objectives of the trial
    Not applicable
    Ikke relevant
    E.2.3Trial contains a sub-study No
    E.3Principal 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 untreated lymph node metastasis*
    • Study Subjects undergoing radical cystectomy due to histopathological or clinical documented muscle invasive urothelial carcinoma (including subtypes) stage cT2-4a in the urinary bladder following NAC** in cisplatin-fit Study Subjects.
    • Alder ≥18 år
    • Mentalt sund og rask
    • Behersker det danske sprog i skrift og i tale
    • Afgivelse af mundtligt og skriftligt samtykke
    • God almentilstand (performancestatus 0-2)
    • Kandidat til neoadjuverende kemoterapi efterfulgt af radikal cystektomi
    • PET/CT-skanning forud for cystektomi uden tegn på spredning af sygdommen eller spredning udelukkende til lokale lymfeknuder
    • Blærekræft af typen urotelialt karcinom, der opstår i blærens slimhinde med vækst ned i urinblærens muskel uden at være vokset fast i omkringliggende organer og strukturer svarende til stadie T2-T4a
    E.4Principal 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
    • Patienter, hvor man ikke formoder, at cystektomi kan fjerne al kendt sygdom
    • Samtidig anden kræftdiagnose fraset hudkræft eller kendt prostatakræft, hvor blodprøver er normal (PSA<0,1)
    • Kendte kontraindikationer mod immunterapi
    • Patienter, der er fundet egnet til neoadjuverende kemoterapi efterfulgt af cystektomi, men hvor forbehandling med kemoterapi er fravalgt
    E.5 End points
    E.5.1Primary end point(s)
    Complete response (CR) after treatment with investigational agent initiated by ctDNA positive status after radical cystectomy (with or without concomitant visible metastases on CT). Data will be compared to available historical data on response to PD-1 / PD-L1 targeted agents. CR in the current study is defined as ctDNA negative status in the last plasma samples taken during IO treatment combined with negative imaging (CT) at the same time point 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.
    Fuldendt respons (FR) efter behandling med den undersøgte lægemiddel, der blev påbegyndt ved ctDNA-positiv status efter radikal cystektomi (med eller uden samtidig synlige metastaser på CT). Data vil blive sammenlignet med tilgængelige historiske data om respons på PD-1 / PD-L1-målrettede midler. FR i den aktuelle undersøgelse er defineret som ctDNA-negativ status i de seneste plasmaprøver taget under IO-behandling kombineret med negativ billedbehandling (CT) på samme tidspunkt efter behandlingen. Således bør enhver metastase synlig på CT ved behandlingsstart gennemgå fuldstændig respons. Hos undersøgelsesdeltagere uden synlige metastaser på CT ved behandlingstidspunktet bør der opnås uændret status på CT.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 months after investigational treatment initiation
    12 måneder efter behandlingsopstart med studiemedicin
    E.5.2Secondary end point(s)
    • Duration of freedom from clinical relapse in Study Subjects showing decrease or stabilization of ctDNA level after treatment with investigational agent
    • Overall survival after cystectomy in Study Subjects having biochemical relapse
    • Cancer specific survival after cystectomy in Study Subjects having biochemical relapse
    • Recurrence free survival after cystectomy in Study Subjects having biochemical relapse
    • Cancer specific survival after cystectomy in Study Subjects having biochemical relapse stratified for potential predictive biomarkers for response to treatment
    • Response rate to investigated agent stratified for PD-L1 expression and other predictive biomarkers like TMB, immune cell infiltration, tumor subtypes etc.
    • Response rate to neoadjuvant chemotherapy measured as down staging to T0 or T<2 at cystectomy and correlation with level of ctDNA in plasma and urine samples
    • Time to recurrence seen on imaging (symptomatic or asymptomatic)
    • Quality of life assessment using the EORTC QLQ 30 (Quality of life in cancer patients) and QLQ-BLM30 (Quality of life in patients with Muscle Invasive Bladder Cancer)
    • Cost-effectiveness modelling analysis
    • Prolonged CR defined as ctDNA negative status in the plasma samples taken 12 months following completion of IO combined with negative imaging (CT) at the same time point, without administration of other oncologic treatment
    Yderligere målepunkter omfatter langtidsoverlevelse, effekt af behandling samt vurdering af metoder til at forudsige effekt ud fra forskellige analyser, der kan laves på patientens svulstvæv.
    E.5.2.1Timepoint(s) of evaluation of this end point
    January, 01 2028 LVLS
    1. januar 2028, LVLS
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    January 1, 2028, LVLS
    1. januar 2028, LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 282
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state282
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 282
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None. Standard of care.
    Ingen. Alene standard behandling
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-08-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-26
    P. End of Trial
    P.End of Trial StatusOngoing
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