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Bladder CancerPhase 2PCR-MIBNCT02662062

Pembrolizumab With Chemoradiotherapy as Treatment for Muscle Invasive Bladder Cancer

A Phase 2 study testing Pembrolizumab, Cisplatin and Radiotherapy in people with Bladder Cancer, run by Australian and New Zealand Urogenital and Prostate Cancer Trials Group at 7 sites in Australia.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Bladder Cancer
What is being tested?
Pembrolizumab, Cisplatin and Radiotherapy
Could I receive a placebo?
No, everyone receives an active treatment
How many people
28 participants
Where
7 sitesAustralia
Study dates
11 Jul 2017to 26 Aug 2024
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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
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  • 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.

Trial locations and contacts

7 sites in 1 country.

7 sites in 1 country

Australia7 sites

  • Chris O'Brien Lifehouse

    Camperdown, New South Wales, 2050

  • Austin Health

    Heidelberg, Victoria, 3084

  • Liverpool Hospital

    Liverpool, New South Wales, 2170

  • Peter MacCallum Cancer Centre

    Melbourne, Victoria, 3002

  • Sir Charles Gairdner Hospital

    Nedlands, Western Australia, 6009

  • Prince of Wales Hospital

    Randwick, New South Wales, 2013

  • Royal North Shore Hospital

    St Leonards, New South Wales, 2065

Other trials in Australia

About this study

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.

Read more

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.

Conditions
Bladder Cancer
Being tested
Pembrolizumab, Cisplatin, Radiotherapy
Keywords
Non-metastatic muscle invasive bladder cancer
Medical subject headings
Urinary Bladder Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PembrolizumabDrug

    200 mg/m2, IV (in the vein) on day 1 every three weeks (Weeks 1, 3, 7, 10, 13, 16 and 19). until progression or unacceptable toxicity develops.

  • CisplatinDrug

    35 mg/m2, IV (in the vein) every week for six weeks.

  • RadiotherapyRadiation

    2.00Gy once daily for 32 fractions, 5 fractions/week over six weeks and two days (a total of 64Gy).

Study groups in NCT02662062
Study groupRoleWhat they receive
PembrolizumabExperimentalPembrolizumab to be administered via IV 200mg 3 weekly commenced concurrently with chemoradiotherapy, and continuing until 12 week cystoscopy.
Receives: Drug: Pembrolizumab; Drug: Cisplatin; Radiation: Radiotherapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. The Number of Participants Experiencing an Unacceptable Level of Toxicity as Defined Below

    Unacceptable toxicity was predefined as fitting one of the following categories.

    • Grade 3 or worse adverse event per CTCAE V 5.0 (excluding urinary adverse events Grade 3 and Grade 4)
    • Cisplatin is withheld for 2 or more doses
    • Cisplatin is withheld or dose reduced such that <66% of the intended total cisplatin dose is delivered
    • Radiation therapy extended beyond 7 weeks
    • Any single pembrolizumab dose is delayed for >6 weeks

    Measured: 12 weeks of study treatment

Secondary outcomes (6)

  1. Complete Response Rate at Week 19 of the Trial (12 Weeks Post Completion of Chemoradiotherapy).

    Complete response defined at this time point by fulfillment of all of the following criteria:

    1. the bi-manual examination under anesthesia is negative (performed at the time of cystoscopy) ii) All biopsies are negative for any tumor at the site(s) of pre-treatment tumor(s) iii) There is an absence of metastatic disease on most recently performed imaging of chest/abdomen and pelvis

    Measured: Week 19 (12 weeks post chemotherapy)

  2. The Complete Response Rate Assessed at Week 31 of the Trial (24 Weeks Post Completion of Chemoradiotherapy).

    Complete response defined at this time point by fulfillment of all of the following criteria:

    1. the bi-manual examination under anesthesia is negative (performed at the time of cystoscopy) ii) All biopsies are negative for any tumor at the site(s) of pre-treatment tumor(s) iii) There is an absence of metastatic disease on most recently performed imaging of chest/abdomen and pelvis

    Measured: Week 31 of the trial (24 weeks post completion of chemoradiotherapy)

  3. Estimated Median Overall Survival

    Estimation after characterization with a Kaplan Meier curve

    Measured: median follow up 39 months

  4. Overall Survival at 12 Months Post Study Entry

    Overall survival timepoint estimated after characterization on a Kaplan Meier curve

    Measured: 12 months post study entry

  5. Distant Metastasis Free Survival (DMFS) at 12 Months

    End point was characterized using a Kaplan Meier curve and 12 month time point assessed.

    Measured: At 12 months post study entry

  6. Local Disease Free Survival (LRPFS) at 12 Months

    Local recurrence was defined as recurrence in the bladder or a nodal recurrence in the pelvis

    Measured: 12 months post therapy commencement

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Jan 2016 (estimated)
  2. Study start11 Jul 2017
  3. Primary completion12 May 2022
  4. Study completion26 Aug 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
28 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02662062
Sponsor's protocol ID
ANZUP 1502
Acronym
PCR-MIB
Status last verified
May 2024
First submitted
13 Jan 2016
Last updated
27 Jan 2025
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Weickhardt A, Foroudi F, Lawrentschuk N, Xie J, Sidhom M, Pal A, Grimison P, Zhang A, Ng S, Tang C, Hovey E, Chen C, Hruby G, Guminski A, McJannett M, Conduit C, Tran B, Davis ID, Hayne D. Pembrolizumab with Chemoradiation as Treatment for Muscle-invasive Bladder Cancer: Analysis of Safety and Efficacy of the PCR-MIB Phase 2 Clinical Trial (ANZUP 1502). Eur Urol Oncol. 2024 Jun;7(3):469-477. doi: 10.1016/j.euo.2023.09.011. Epub 2023 Oct 7.

    PubMed 37806844

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Pembrolizumab, Cisplatin and Radiotherapy in people with Bladder Cancer, run by Australian and New Zealand Urogenital and Prostate Cancer Trials Group at 7 sites in Australia.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 22 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 27 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 27 Jan 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The Number of Participants Experiencing an Unacceptable Level of Toxicity as Defined Below (time frame: 12 weeks of study treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02662062, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jan 2025.

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