A Phase II Study Investigating Preoperative MPDL3280A in Operable Transitional Cell Carcinoma of the Bladder (ABACUS)


Condition: Bladder Cancer

Intervention:

  • Drug: MPDL3280A

Purpose: 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.

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02662309

Sponsor: Queen Mary University of London

Primary Outcome Measures:

  • Measure: Efficacy of MPDL3280A pre-cystectomy with respect to pathological complete response rate (pCRR)
  • Time Frame: 2-3 months (timeframe dependent on delay to surgery)
  • Safety Issue:
  • Measure: Efficacy of MPDL3280A pre-cystectomy on immune parameters
  • Time Frame: 2-3 months (timeframe dependent on delay to surgery)
  • Safety Issue:

Secondary Outcome Measures:

  • Measure: 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)
  • Safety Issue:
  • Measure: 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)
  • Safety Issue:
  • Measure: 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
  • Safety Issue:
  • Measure: Efficacy of MPDL3280A pre-cystectomy with respect to anti-tumour effects based on overall survival (OS)
  • Time Frame: Up to 2 years post-cystectomy
  • Safety Issue:

Estimated Enrollment: 85

Study Start Date: February 2016

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

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 defined by the following:
  • ANC ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
  • WBC counts > 2500/μL
  • Lymphocyte count ≥ 500/μL
  • Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to Cycle 1, Day 1)
  • Haemoglobin ≥ 9.0 g/dL (patients may be transfused or receive erythropoietic treatment to meet this criterion).
  • 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).
  • 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.
  • Calculated creatinine clearance ≥ 20 mL/min (Cockcroft-Gault formula)

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

Contact:

  • ABACUS Coordinator
  • 020 7882 8275

Locations:

  • Centre Hospitalier Universitaire (CHU) de Bordeaux
  • Bordeaux France
  • Hospices Civils de Lyon
  • Lyon France
  • Institut Paoli-Calmettes
  • Marseille France
  • Institut Claudius Régaud
  • Toulouse France
  • Universitätsklinik Köln
  • Cologne Germany
  • Universitätsklinikum Düsseldorf
  • Düsseldorf Germany
  • Universitätsklinikum des Saarlandes
  • Homburg Germany
  • Universitätsklinikum Schleswig-Holstein
  • Lübeck Germany
  • LMU: Urologische Klinik und Poliklinik
  • Munich Germany
  • Universitätsklinikum Tübingen
  • Tübingen Germany
  • Netherlands Cancer Institute (NKI)
  • Amsterdam Netherlands
  • Athaia Xarxa Manresa
  • Barcelona Spain
  • Hospital del Mar
  • Barcelona Spain
  • Hospital Germans Trias i Pujol
  • Barcelona Spain
  • Hospital Santa Creu i Sant Pau
  • Barcelona Spain
  • Hospital Vall d'Hebron
  • Barcelona Spain
  • Hospital Reina Sofía
  • Córdoba Spain
  • Hospital 12 de Octubre
  • Madrid Spain
  • CHU de Santiago
  • Santiago de Compostela Spain
  • Hospital Virgen del Rocío
  • Sevilla Spain
  • Cambridge University Hospitals NHS Trust
  • Cambridge United Kingdom
  • Clatterbridge Cancer Centre NHS Foundation Trust
  • Liverpool United Kingdom
  • Barts Health NHS Trust
  • London United Kingdom
  • University College London Hospitals NHS Foundation Trust
  • London United Kingdom
  • Oxford University Hospitals NHS Foundation Trust
  • Oxford United Kingdom
  • Sheffield Teaching Hospitals NHS Foundation Trust
  • Sheffield United Kingdom
  • University Hospital Southampton NHS Foundation Trust
  • Southampton United Kingdom

View trial on ClinicalTrials.gov


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