Pembrolizumab With Chemoradiotherapy as Treatment for Muscle Invasive Bladder Cancer

  • End date
    Jan 30, 2024
  • participants needed
  • sponsor
    Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Updated on 30 January 2021
radical cystectomy
direct bilirubin
neutrophil count
conjugated bilirubin
bladder cancer
invasive bladder cancer
transitional cell carcinoma
transurethral resection
bladder tumor
bladder carcinoma


This study will enrol patients with maximally resected (via transurethral resection (TURBT) non-metastatic muscle invasive bladder cancer, who either wish to attempt bladder preservation therapy or are ineligible for cystectomy. Patients must have adequate organ function and performance status to receive cisplatin based chemoradiotherapy, and no contraindications to the use of pembrolizumab. The study will enrol 30 patients to be treated with pembrolizumab and radiotherapy.

All patients will be planned to be treated with 64Gy of radiation therapy in 32 fractions over 6 weeks and 2 days. All patients will receive cisplatin 35mg/m2 IV concurrently weekly with radiation therapy for 6 doses total. Pembrolizumab will commence concurrently with radiation and be given 200mg IV every 21 days, continuing until the 12 week cystoscopy and assessment.

Surveillance cystoscopy will be performed 12 weeks after the commencement of chemoradiotherapy, and assess the rate of complete response to therapy. A safety follow up visit will occur 4 and 12 weeks post cystoscopy. From week 31 survival follow up will commence with clinical assessment, cystoscopy and CT staging performed at intervals until 5 years.

The objective of the study is to assess the safety and feasibility of combining pembrolizumab with chemoradiotherapy. The primary endpoint assessed will be safety, as defined by a satisfactorily low rate of unacceptable toxicity (G3-4 adverse events or failure of completion of planned chemotherapy and radiotherapy according to defined parameters). The secondary endpoint will be efficacy, as assessed by complete response rate of the primary tumour at first post chemoradiotherapy cystoscopic assessment. Exploratory analysis will include assessment of tumour histopathological, molecular, genetic and immunological parameters.

It is expected that it will take two years to accrue the required 30 patients.

Condition urinary tract neoplasm, bladder cancer, bladder disorder, Urothelial Cancer, Bladder Disorders, Bladder Carcinoma, Urologic Cancer, carcinoma of the bladder, bladder tumor
Treatment cisplatin, Radiotherapy, Pembrolizumab
Clinical Study IdentifierNCT02662062
SponsorAustralian and New Zealand Urogenital and Prostate Cancer Trials Group
Last Modified on30 January 2021


Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have bladder cancer?
Do you have any of these conditions: bladder tumor or bladder disorder or bladder cancer or carcinoma of the bladder or Urothelial Cancer or urinary tract neoplasm or Bladder Carcinoma or...?
Be willing and able to provide written informed consent for the trial
Be 18 years of age on day of signing informed consent
Have histologically-confirmed diagnosis of muscle-invasive T2-T4a, Nx or N0 urothelial cell carcinoma of the bladder. Subjects with tumors of mixed transitional/non-transitional cell histology are allowed, but transitional cell carcinoma must be the predominant histology (>50%). Subjects with predominant or exclusively non-transitional cell histology are not allowed
Must have undergone maximal transurethral resection of the bladder tumour, as is judged as safe as possible by the urologist performing the resection, within 42 days of treatment. Where patient has only had a biopsy/partial resection and is otherwise eligible for entry into the study, the case should be rediscussed with the referring urologist to see whether further resection would be feasible prior to embarking with the chemo-radiotherapy
Have elected not to undergo radical cystectomy, or are unsuitable for radical cystectomy
Planned for chemoradiotherapy as definitive treatment
Have a performance status of 0 or 1 on the ECOG Performance Scale
Demonstrate adequate organ function as defined below, all screening labs should be performed within 10 days of registering the patient on the trial
Absolute neutrophil count (ANC): 1.5 X 10^9/L
Platelets: 100 X 10^9/L
Hemoglobin: 9 g/dL without transfusion or EPO dependency
Calculated creatinine clearance 50 mL/min
Serum total bilirubin: 1.5 X ULN OR
Direct bilirubin ULN for participants with total bilirubin levels: > 1.5 ULN
AST and ALT: 2.5 X ULN
Albumin: >25 g/dL
International Normalized Ration (INR) or Prothrombin Time (PT): 1.5 X ULN unless participant is receiving anticoagulant therapy (as long as PT or PTT is within therapeutic range of intended use of anticoagulants)
Activated Partial Thromboplastin Time (aPTT): 1.5 X ULN unless participant is receiving anticoagulant therapy (as long as PT or PTT is within therapeutic range of intended use of anticoagulants)
Female participant of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to registering the patient. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Female participants of childbearing potential should be willing to use two methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
Male participants should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
Willing to consent to the use of their collected tumour specimen, blood and urine as detailed in the protocol for future scientific research including but not limited to DNA, RNA and protein based biomarker detection

Exclusion Criteria

Has concurrent extra-vesical (i.e. urethra, ureter or renal pelvis) urothelial cell carcinoma of the urothelium. Patients who have involvement of the prostatic urethra with urothelial cell cancer (TCC) that was visibly completely resected and no evidence of stromal invasion of the prostate remain eligible
Evidence of tumour-related moderate/severe hydronephrosis unless stented or with nephrostomy to preserve renal function
Extensive or multifocal bladder carcinoma in situ (CIS) precluding curative chemoradiotherapy
Bulky T3/T4a tumours unsuitable for curative treatment (i.e. >10 cms in any dimension); node positive disease
Evidence of distant metastatic disease on CT chest/abdomen/pelvis performed within 42 days prior to study entry. Patients with pelvic lymph nodes deemed to be 'positive' are not eligible for the study unless histological confirmation of the largest most suspicious node is negative for malignancy. Patients with known CNS metastatic disease are excluded from the study
Prior pelvic radiotherapy
Has had prior intravenous chemotherapy, targeted small molecule therapy, or radiation therapy for treatment of bladder cancer. Prior intravesical use of BCG and mitomycin is permissible
Unsuitable for concurrent cisplatin based chemoradiotherapy based on
CTCAE v.4.03, Grade >2 audiometric hearing loss (25dB in two consecutive wave ranges) if previously performed
CTCAE v.4.03, Grade >2 peripheral neuropathy
Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of treatment
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to registering the patient. Patients with adrenal insufficiency receiving replacement dose steroids are allowed on the trial
Has a known history of active TB (Bacillus Tuberculosis)
Hypersensitivity to pembrolizumab or any of its excipients
Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
Prior or concurrent known additional malignancy of any site unless disease free for 5 years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, Stage T1a well differentiated prostatic carcinoma in men (Gleason = 3+3, PSA <5)
Has any history of active autoimmune disease, Stevens-Johnson syndrome or Guillain-Barre. Exceptions to this are
Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone
Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen who are also be eligible for this study
Has known history of, or any evidence of active, non-infectious pneumonitis
Has an active infection requiring systemic therapy
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected)
Has received a live vaccine within 30 days of planned start of study therapy
Note: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-
Mist) are live attenuated vaccines, and are not allowed
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