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Cancer clinical trial

A PHASE III, OPEN-LABEL, MULTICENTRE, RANDOMISED STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF MPDL3280A (ANTI PD-L1 ANTIBODY) COMPARED WITH CHEMOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC UROTHELIAL BLADDER CANCER AFTER FAILURE WITH PLATINUM-CONTAINING CHEMOTHERAPY.

Summary:
Urothelial Bladder Cancer (UBC) is the most common urinary system cancer worldwide and the seventh most
common of all cancers in the UK. 10,000 people are diagnosed with bladder cancer each year in the UK and the
overall 5 year survival rate for those with metastatic UBC is approximately 5.4%.
Cisplatin-based combination chemotherapy is the preferred therapy for patients with metastatic UBC. Nonetheless, a
significant number of patients are not appropriate for this type of treatment. For cisplatin-ineligble patients, treatment
options include carboplatin-based, non-platinum-based, single-agent chemotherapy regimens or even best supportive care (BSC).
Despite the limited survival benefit conferred by cytotoxic chemotherapy, platinum based regimens remain the
standard first line option for most patients with locally advanced and metastatic UBC. These regimens are often
associated with substantial side effects and are generally poorly tolerated by elderly and poor performance-status
patients. Therefore, there is a significant unmet clinical need for an improvement to the therapy options for these
patients.
This study aims to discover whether MPDL3280A offers an improved survival rate compared to chemotherapy for
patients with advanced or metastatic UBC who have previously progressed during or following a platinum containing
treatment. MPDL3280A is an antibody which is designed to help the bodies existing immune system identify and
remove tumour cells more effectively.
A total of approximately 767 patients will be recruited into this study globally. Half the participants will receive
MPDL3280A as an infusion once every 3 weeks and the other half will receive one of three existing chemotherapies.
All patients will be treated until their disease worsens and then followed up every 3 months until the end of the study.
In the UK, it is expected that 75 participants will be enrolled across 18 study centres.

Inclusion criteria:
Inclusion Criteria
Patients must meet the following criteria for study entry:
• Signed Informed Consent Form
• Ability to comply with protocol
• Age ≥18 years
• Histologically or cytologically documented locally advanced (T4b, any N; or any T, N 2 3) or metastatic (M1, Stage IV)
transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra)
Patients with mixed histologies are required to have a dominant transitional cell pattern.
Locally advanced bladder cancer must be inoperable based on involvement of pelvic sidewall or adjacent viscera
(clinical stage T4b) or bulky nodal metastasis (N2 N3).
• Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks preferred) or at
least 15 unstained slides, with an associated pathology report, for central testing and determined to be evaluable for
tumor PD-L1 expression prior to study enrollment; patients with fewer than 15 unstained slides available at baseline
(but no fewer than 10) may be eligible following discussion with Medical Monitor.
Tumor tissue should be of good quality based on total and viable tumor content. Fine needle aspiration, brushing, cell
pellet from pleural effusion, bone metastases, and lavage samples are not acceptable. For core needle biopsy
specimens, at least three cores should be submitted for evaluation.
Patients who do not have tissue specimens meeting eligibility requirements may undergo a biopsy during the
screening period. Acceptable samples include core needle biopsies for deep tumor tissue (minimum 3 cores) or
excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.
Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not acceptable.
Patients having additional tissue samples from procedures performed at different times during the course of their UBC
will be requested (but not required) to also submit these samples for central testing. Tissue samples obtained at
multiple times for individual patients will greatly contribute to an improved understanding of the dynamics of PD-L1
expression and relationship with intervening anticancer therapy.
• Disease progression during or following treatment with at least one platinum containing regimen (e.g., GC, MVAC,
CarboGem, etc.) for inoperable locally advanced or metastatic urothelial carcinoma or disease recurrence
A regimen is defined as patients receiving at least 2 cycles of a platinum containing regimen.
Patients who received prior adjuvant/neoadjuvant chemotherapy and progressed within 12 months of treatment with a
platinum-containing adjuvant/neoadjuvant regimen will be considered as second-line patients.
Patients may have received no more than two prior regimens of treatment (including the required platinum-based
regimen) for their advanced UC.
Patients with disease progression following chemoradiotherapy must demonstrate progression outside the prior
radiotherapy port.
• ECOG performance status of 0 or 1
• Life expectancy ≥ 12 weeks
• Measurable disease, as defined by RECIST v1.1
Previously irradiated lesions should not be counted as target lesions.
• Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days
prior to the first study treatment:
ANC ≥ 1500 cells/ L (without granulocyte colony stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
WBC counts > 2500/ L
Lymphocyte count ≥ 500/ L
Platelet count ≥ 100,000/ L (without transfusion within 2 weeks prior to Cycle 1, Day 1)
Hemoglobin ≥ 9.0 g/dL
Patients may be transfused or receive erythropoietic treatment to meet this criterion.
AST, ALT, and alkaline phosphatase ≤ 2.5 x the upper limit of normal (ULN), with the following exceptions:
Patients with documented liver metastases: AST and/or ALT ≤ 5 x ULN
Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5 x ULN
Serum bilirubin ≤ 1.0 x ULN
Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled.
INR and aPTT ≤ 1.5 x 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 ≥ 30 mL/min (Cockcroft-Gault formula)
• For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by
patient and/patient and/or partner) to use a highly effective 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 6 months after the last dose of MPDL3280A

Exclusion criteria:
•Any approved anticancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to initiation of
study treatment; the following exceptions are allowed:
Palliative radiotherapy for bone metastases completed >7 days prior to baseline imaging
Hormone-replacement therapy or oral contraceptives
•Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28
days prior to enrollment
•Active or untreated central nervous system (CNS) metastases as determined by CT or MRI evaluation during
screening and prior radiographic assessments
•Leptomeningeal disease
•Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly
or more frequently)
•Patients with indwelling catheters (e.g., PleurX) are allowed.
•Uncontrolled tumor-related pain
•Uncontrolled hypercalcemia (see the full protocol for more details and exceptions).
•Malignancies other than UBC within 5 years prior to randomization, with the exception of those with a negligible risk of
metastasis or death and treated with expected curative outcome
•Pregnant and lactating women
•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)
•Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater),
myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina (see full
protocol for exceptions).
•Severe infections within 4 weeks prior to randomization including but not limited to hospitalization for complications of
infection, bacteremia, or severe pneumonia
•Received therapeutic oral or IV antibiotics within 2 weeks prior to randomization
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive
pulmonary disease) are eligible.
•Major surgical procedure within 4 weeks prior to randomization or anticipation of need for a major surgical procedure
during the course of the study other than for diagnosis
•Inability to understand the local language(s) for which the EORTC QLQ-C30 and EQ 5D questionnaires are available
(see Appendix 5 for English versions)
Exclusion Criteria Related to Paclitaxel
•Prior treatment with paclitaxel
Prior treatment with docetaxel is allowed except for patients who progressed while receiving docetaxel
•History of severe hypersensitivity to paclitaxel or to other drugs formulated with polyoxyethylated castor oil
Exclusion Criteria Related to Docetaxel
•Prior treatment with docetaxel
Prior treatment with paclitaxel is allowed except for patients who progressed while receiving paclitaxel
History of severe hypersensitivity to docetaxel or to other drugs formulated with polysorbate 80
•Grade ≥2 peripheral neuropathy as defined by NCI CTCAE v4.0 criteria
•Inability to discontinue use of strong cytochrome P450 (CYP)3A4 inhibitors including but not limited to ketoconazole,
itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or
voriconazole
Exclusion Criteria Related to Vinflunine
•Prior treatment with vinflunine
•History of severe hypersensitivity to vinflunine or other vinca alkaloids
Exclusion Criteria Related to MPDL3280A
•History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or
fusion proteins
•Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of
the MPDL3280A formulation
•History of autoimmune disease (see the full protocol for more details and exceptions).
•Patients with prior allogeneic stem cell or solid organ transplantation
•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.
•Positive test for HIV
•Patients with active hepatitis B or hepatitis C
•Active tuberculosis
•Administration of a live, attenuated vaccine within 4 weeks prior to randomization or anticipation that such a live
attenuated vaccine will be required during the study
•Prior treatment with CD137 agonists, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway targeting agents (see
full protocol for exceptions).
•Treatment with systemic corticosteroids or other systemic immunosuppressive or immunostimulatory medications
(see full protocol for more details and exceptions)

Principal Investigator for this trial: Dr Santhanam Sundar

Research Ethics Committee Reference: 14/LO/1798

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076

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