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

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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

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.

Condition or disease Intervention/treatment Phase
Bladder Cancer Drug: MPDL3280A Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 96 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study Investigating Preoperative MPDL3280A in Operable Transitional Cell Carcinoma of the Bladder (ABACUS)
Actual Study Start Date : February 2016
Actual Primary Completion Date : July 2018
Estimated Study Completion Date : July 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arm Intervention/treatment
Experimental: MPDL3280A
Patients receive 2x 3-weekly cycles of MPDL3280A (one infusion on the first day of each cycle) prior to cystectomy surgery.
Drug: MPDL3280A
Intravenous infusion
Other Name: Atezolizumab




Primary Outcome Measures :
  1. 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).


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02662309


Locations
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Sponsors and Collaborators
Queen Mary University of London
Hoffmann-La Roche
Investigators
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Principal Investigator: Thomas Powles, MBBS MD MRCP Queen Mary University of London
Additional Information:
Publications of Results:
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Responsible Party: Queen Mary University of London
ClinicalTrials.gov Identifier: NCT02662309    
Other Study ID Numbers: 010463QM
2015-001112-35 ( EudraCT Number )
First Posted: January 25, 2016    Key Record Dates
Last Update Posted: February 25, 2020
Last Verified: February 2020
Keywords provided by Queen Mary University of London:
Muscle invasive bladder cancer
Transitional cell carcinoma
Additional relevant MeSH terms:
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Carcinoma
Urinary Bladder Neoplasms
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Atezolizumab
Antineoplastic Agents