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    Summary
    EudraCT Number:2019-004628-39
    Sponsor's Protocol Code Number:ABACUS-2
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-10-07
    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 ConcernedUK - MHRA
    A.2EudraCT number2019-004628-39
    A.3Full title of the trial
    A phase II study of neoadjuvant immune checkpoint inhibitors in urothelial cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase II study investigating use of the drug MPDL3280A before surgery in patients with rare subtypes of bladder cancer and urinary cancers
    A.3.2Name or abbreviated title of the trial where available
    ABACUS-2
    A.4.1Sponsor's protocol code numberABACUS-2
    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 SponsorQueen Mary University of London
    B.1.3.4CountryUnited Kingdom
    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
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationQueen Mary University of London
    B.5.2Functional name of contact pointProfessor Thomas Powles
    B.5.3 Address:
    B.5.3.1Street AddressExperimental Cancer Medicine, Barts Cancer Institute,
    B.5.3.2Town/ cityCharterhouse Square, London
    B.5.3.3Post codeEC1M 6BQ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02078828297
    B.5.6E-mailk.mousa@qmul.ac.uk
    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 nameTecentriq
    D.3.4Pharmaceutical form 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.3.9.3Other descriptive nameMPDL3280A; Tecentriq®
    D.3.9.4EV Substance CodeAS1
    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) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Tumours of the urothelial tract requiring surgery (T1 high grade-T4a of the bladder, rare histological subtypes) and upper urinary tract (high grade or high risk)
    E.1.1.1Medical condition in easily understood language
    Rare subtypes of bladder cancer and urinary cancers
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10046384
    E.1.2Term Ureteral cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10026426
    E.1.2Term Malignant neoplasm of renal pelvis
    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 determine atezolizumab's ability to reduce the size of urothelial cancer in the bladder (rare histological subtypes) and upper urinary tract before surgery (measured as pathological complete response rate), and assess the impact of the drug on the body's immune system.
    E.2.2Secondary objectives of the trial
    - Assess the safety and tolerability of atezolizumab in this patient population by collecting information about adverse events and surgical complications.
    - Assess the anti-tumour effect of atezolizumab by examining the radiological response (looking at pre- and posttreatment MRI/CT scan images), “disease free survival” rates, and overall patient survival.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Willing and able to provide written informed consent
    2. Ability to comply with the protocol
    3. Age ≥ 18 years
    4. Residual disease after TURBT or URS (surgical opinion, endoscopy or radiological presence).
    5. Fit and planned for radical surgery with curative intent in the opinion of the investigator (according to local guidelines).
    6. N0 or M0 disease CT or MRI (within 4 weeks of registration)
    7. Representative formalin-fixed paraffin embedded (FFPE) tumour samples with an associated pathology report that are determined to be available and sufficient for central testing.
    8. Patients who refuse neoadjuvant cisplatin-based chemotherapy or in whom neoadjuvant cisplatin- based therapy is not appropriate.
    9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
    10. Negative pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential.
    11. For female patients of childbearing potential to use a highly effecting form(s) of contraception (i.e. one that results in a low failure rate [<1% per year] when used consistently and correctly) and to continue its use for 90 days after the last dose of atezolizumab.
    12. Adequate hematologic and end-organ function within 4 weeks prior to the first study treatment defined by the following:
    a) ANC ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
    b) WBC counts > 2500/μL
    c) Lymphocyte count ≥ 500/μL
    d) Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to Cycle 1, Day 1)
    e) Haemoglobin ≥ 9.0 g/dL (patients may be transfused or receive erythropoietic treatment to meet this criterion).
    f) AST or ALT, and alkaline phosphatase ≤ 2.5 times the institutional upper limit of normal (ULN) (patients with known Gilbert disease who have serum bilirubin level ≤ 3 × the institutional ULN may be enrolled).
    g) INR and aPTT ≤ 1.5 × the institutional ULN. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
    h) Calculated creatinine clearance ≥ 20 mL/min (Cockcroft-Gault formula)
    E.4Principal exclusion criteria
    1. Pregnant and lactating female patients.
    2. Major surgical procedure within 4 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis.
    3. Previously intravenous chemotherapy for urothelial cancer.
    4. Patients with prior allogeneic stem cell or solid organ transplantation.
    5. Prior treatment with CD137 agonists, anti-CTLA-4, anti−programmed death−1 (PD-1), or anti−PD-L1 therapeutic antibody or pathway-targeting agents.
    6. Patients must not have had oral or IV steroids for 14 days prior to study entry. The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone) is allowed.
    7. Received therapeutic oral or intravenous (IV) antibiotics within 14 days prior to enrolment (Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible).
    8. Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study.
    9. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]−2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment.
    10. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrolment.
    11. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease.
    12. Malignancies other than UC within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer.
    13. Severe infections within 4 weeks prior to enrolment in the study including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia.
    14. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to enrolment, unstable arrhythmias, or unstable angina.
    15. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan.
    16. Patients with uncontrolled Type 1 diabetes mellitus. Patients with Type 1 diabetes controlled on a stable insulin regimen are eligible.
    17. Patients with active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
    18. Positive test for HIV
    19. Patients with active tuberculosis
    20. History of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the
    absorption of the study drug.
    21. Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected serum calcium > the
    institutional ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.
    22. History of autoimmune disease
    23. Patients with a history of autoimmune-related hypothyroidism, unless on a stable dose of thyroid-replacement
    hormone.
    24. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or
    fusion proteins
    25. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
    E.5 End points
    E.5.1Primary end point(s)
    This study has a clinical and a biological primary endpoint:
    Clinical:
    • Bladder Cohort rare histological subtypes:
    To assess the efficacy of atezolizumab pre-cystectomy with respect to pCR rate in patients with carcinoma of the urothelium of the bladder (T1 high grade-T4a) with mixed or rare histological subtypes
    • UTUC Cohort:
    To assess the efficacy of atezolizumab pre-surgery with respect to pCR rate in patients with high grade or high risk upper urinary tract urothelial carcinoma
    Biological:
    To assess the effect of 2 x 3 weekly cycles of atezolizumab pre-cystectomy on immune parameters in patients with T1 high grade-T4aN0M0 carcinoma of the bladder rare histological subtypes and before radical surgery for upper tract disease on immune parameters in patients with high risk upper urinary tract urothelial carcinoma
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoints (clinical and biological) will be analysed once at least 29 evaluable patients have had a cystectomy and have had their 4 week post-cystectomy visit for the bladder cohort. For the UTUC cohort, the primary endpoints (clinical and biological) will be analysed once at least 18 evaluable patients have had radical surgery and have had their 4 week post- radical surgery visit.
    E.5.2Secondary end point(s)
    1)To evaluate the safety and tolerability of atezolizumab when given in the neoadjuvant setting before radical surgery in this population.
    2) To assess the efficacy of atezolizumab given in the neoadjuvant setting before radical surgery with respect to anti-tumour effects as measured by Investigator assessed radiological response (RR).
    3) To assess the efficacy of atezolizumab given in the neoadjuvant setting before radical surgery with respect to anti-tumour effects based on Investigator assessed disease-free survival (DFS).
    4) To assess the efficacy of atezolizumab given in the neoadjuvant setting before radical surgery with respect to overall survival (OS).
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) For the bladder cohort, the TSC will meet and review safety data after 10 patients and after the final patient have undergone radical surgery and completed their 4 week post-radical surgery visit.
    For the UTUC cohort, the TSC will meet and review safety data after 10 patients and after the final patient have undergone nephroureterectomy and completed their 4 week post-nephroureterectomy visit. The TSC can make recommendations on continuing recruitment into the UTUC cohort taking into consideration the rarity of the UTUC patient populations or safety signals.
    The rest of the safety endpoint will be analysed at the end of the study. Adverse events are collected during treatment and up to 24 weeks post surgery.
    2-4) Assessed at the end of the study.
    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 Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial1
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA17
    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
    The end of study is defined as last patient last visit and is expected to occur around 26 months after the last patient enrols in the study at their 2 year post-radical surgery follow up, plus 6 months.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 48
    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 state58
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 58
    F.4.2.2In the whole clinical trial 58
    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, this is a window of opportunity trial. On completion of the study, participating patients will be considered for further treatment at the discretion of the treating physician. Atezolizumab is still in development and is not available in this indication outside the clinical trial setting.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-12-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-16
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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