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Preoperative MPDL3280A in Transitional Cell Carcinoma of the Bladder (ABACUS)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02662309
Recruitment Status : Active, not recruiting
First Posted : January 25, 2016
Last Update Posted : February 25, 2020
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by (Responsible Party):
Queen Mary University of London

Tracking Information
First Submitted Date  ICMJE January 18, 2016
First Posted Date  ICMJE January 25, 2016
Last Update Posted Date February 25, 2020
Actual Study Start Date  ICMJE February 2016
Actual Primary Completion Date July 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 24, 2020)
Efficacy of MPDL3280A pre-cystectomy with respect to pathological complete response rate (pCRR) [ Time Frame: 2-3 months (timeframe dependent on delay to surgery) ]
Pathological complete response rate defined as no microscopic evidence of residual disease in the bladder based on histological evaluation of the resected bladder specimen collected during cystectomy (post-treatment).
Original Primary Outcome Measures  ICMJE
 (submitted: January 21, 2016)
  • Efficacy of MPDL3280A pre-cystectomy with respect to pathological complete response rate (pCRR) [ Time Frame: 2-3 months (timeframe dependent on delay to surgery) ]
    Assessment based on pre-treatment tumour sample collected at screening (archival) and post-treatment tumour sample taken at cystectomy. Pathological complete response rate (pCRR) defined as ≥20% reduction in residual disease of the bladder based on histological evaluation of the resected bladder specimen collected during cystectomy (post-treatment).
  • Efficacy of MPDL3280A pre-cystectomy on immune parameters [ Time Frame: 2-3 months (timeframe dependent on delay to surgery) ]
    Dynamic changes in T cell subpopulations (CD8 and/or CD3) measured in tumour samples collected pre- and post-treatment.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 24, 2020)
  • Efficacy of MPDL3280A pre-cystectomy with respect to anti-tumour effects as measured by radiological response (RR) [ Time Frame: Approx 34 weeks (timeframe dependent on delay to pre-cystectomy visit) ]
    CT or MRI scan taken at screening and pre-cystectomy visits. RR is defined as a >30% decrease in tumour diameter from the baseline scan.
  • Efficacy of MPDL3280A pre-cystectomy with respect to anti-tumour effects based on disease free survival (DFS) [ Time Frame: Up to 2 years post-cystectomy ]
    Disease and survival data is reviewed at post-surgery visits and at 1 and 2 years post-cystectomy.
  • Efficacy of MPDL3280A pre-cystectomy with respect to anti-tumour effects based on overall survival (OS) [ Time Frame: Up to 2 years post-cystectomy ]
    Disease and survival data is reviewed at post-surgery visits and at 1 and 2 years post-cystectomy.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 21, 2016)
  • Safety and tolerability of MPDL3280A when given to this patient population pre-cystectomy [ Time Frame: Approx 34 weeks (from screening registration, throughout treatment and up to 24 weeks post-cystectomy - timeframe dependent on delay to surgery) ]
    Incidence, nature and severity of adverse events (AEs) and surgical complications will be reviewed.
  • Efficacy of MPDL3280A pre-cystectomy with respect to anti-tumour effects as measured by radiological response (RR) [ Time Frame: Approx 34 weeks (timeframe dependent on delay to pre-cystectomy visit) ]
    CT or MRI scan taken at screening and pre-cystectomy visits. RR is defined as a >30% decrease in tumour diameter from the baseline scan.
  • Efficacy of MPDL3280A pre-cystectomy with respect to anti-tumour effects based on disease free survival (DFS) [ Time Frame: Up to 2 years post-cystectomy ]
    Disease and survival data is reviewed at post-surgery visits and at 1 and 2 years post-cystectomy.
  • Efficacy of MPDL3280A pre-cystectomy with respect to anti-tumour effects based on overall survival (OS) [ Time Frame: Up to 2 years post-cystectomy ]
    Disease and survival data is reviewed at post-surgery visits and at 1 and 2 years post-cystectomy.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Preoperative MPDL3280A in Transitional Cell Carcinoma of the Bladder
Official Title  ICMJE A Phase II Study Investigating Preoperative MPDL3280A in Operable Transitional Cell Carcinoma of the Bladder (ABACUS)
Brief Summary ABACUS is an open-label, international, multi-centre, window of opportunity phase II trial for patients with histologically confirmed (T2-T4a) transitional cell carcinoma of the bladder. The trial aims to test the efficacy of preoperative MPDL3280A and will include extensive biomarker work on samples from these patients. Eligible patients will receive two 3-weekly cycles of MPDL3280A pre-cystectomy. Following cystectomy, patients will be followed up for safety, survival, and disease data.
Detailed Description MPDL3280A (also called atezolizumab) is an immune check point inhibitor which targets programmed death-ligand 1 (PD-L1). Overexpression of PD-L1 prevents the immune system from eradicating cancerous cells as it blocks antigen recognition. MPDL3280A inhibits this interaction, allowing immune-mediated tumour cell killing.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Bladder Cancer
Intervention  ICMJE Drug: MPDL3280A
Intravenous infusion
Other Name: Atezolizumab
Study Arms  ICMJE Experimental: MPDL3280A
Patients receive 2x 3-weekly cycles of MPDL3280A (one infusion on the first day of each cycle) prior to cystectomy surgery.
Intervention: Drug: MPDL3280A
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: August 13, 2018)
96
Original Estimated Enrollment  ICMJE
 (submitted: January 21, 2016)
85
Estimated Study Completion Date  ICMJE July 2020
Actual Primary Completion Date July 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Willing and able to provide written informed consent
  2. Ability to comply with the protocol
  3. Age ≥ 18 years
  4. Histopathologically confirmed transitional cell carcinoma (T2-T4a) of the bladder. Patients with mixed histologies are required to have a dominant transitional cell pattern.
  5. Residual disease after TURBT (surgical opinion, cystoscopy or radiological presence).
  6. Fit and planned for cystectomy (according to local guidelines).
  7. N0 or M0 disease CT or MRI (within 4 weeks of registration)
  8. Representative formalin-fixed paraffin embedded (FFPE) bladder tumour samples with an associated pathology report that are determined to be available and sufficient for central testing.
  9. Patients who refuse neoadjuvant cisplatin based chemotherapy or in whom neoadjuvant cisplatin based therapy is not appropriate.
  10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
  11. Negative pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential.
  12. 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 MPDL3280A.
  13. Adequate hematologic and end-organ function within 4 weeks prior to the first study treatment

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 bladder 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 (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome).
  12. Malignancies other than UBC 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 (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA < 10 ng/mL undergoing active surveillance and treatment naive).
  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 (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted).
  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. Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible. Patients who are receiving denosumab prior to enrollment must be willing and eligible to receive a bisphosphonate instead while on study.
  22. History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
  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 MPDL3280A formulation
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France,   Netherlands,   Spain,   United Kingdom
Removed Location Countries Germany
 
Administrative Information
NCT Number  ICMJE NCT02662309
Other Study ID Numbers  ICMJE 010463QM
2015-001112-35 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Queen Mary University of London
Study Sponsor  ICMJE Queen Mary University of London
Collaborators  ICMJE Hoffmann-La Roche
Investigators  ICMJE
Principal Investigator: Thomas Powles, MBBS MD MRCP Queen Mary University of London
PRS Account Queen Mary University of London
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP