Pembrolizumab With Chemoradiotherapy as Treatment for Muscle Invasive Bladder Cancer (PCR-MIB)

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.

Study Overview

• Status: Completed
• Conditions: Bladder Cancer
• Intervention / Treatment: Drug: Pembrolizumab; Drug: Cisplatin; Radiation: Radiotherapy

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Chris O'Brien Lifehouse
    • Liverpool, New South Wales, Australia, 2170
      • Liverpool Hospital
    • Randwick, New South Wales, Australia, 2013
      • Prince of Wales Hospital
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health
    • Melbourne, Victoria, Australia, 3002
      • Peter MacCallum Cancer Centre
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Be willing and able to provide written informed consent for the trial.
2. Be 18 years of age on day of signing informed consent.
3. 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.
4. 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.
5. Have elected not to undergo radical cystectomy, or are unsuitable for radical cystectomy.
6. Planned for chemoradiotherapy as definitive treatment.
7. Have a performance status of 0 or 1 on the ECOG Performance Scale

8. 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)
9. 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.
10. 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.
11. 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.
12. 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:

1. 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.
2. Evidence of tumour-related moderate/severe hydronephrosis unless stented or with nephrostomy to preserve renal function.
3. Extensive or multifocal bladder carcinoma in situ (CIS) precluding curative chemoradiotherapy.
4. Bulky T3/T4a tumours unsuitable for curative treatment (i.e. >10 cms in any dimension); node positive disease
5. 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
6. Prior pelvic radiotherapy
7. 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.

8. 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
9. 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.
10. 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.
11. Has a known history of active TB (Bacillus Tuberculosis)
12. Hypersensitivity to pembrolizumab or any of its excipients.
13. 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.
14. 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)

15. 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.
16. Has known history of, or any evidence of active, non-infectious pneumonitis.
17. Has an active infection requiring systemic therapy.
18. 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.
19. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
20. 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.
21. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
22. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
23. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
24. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pembrolizumab; Pembrolizumab to be administered via IV 200mg 3 weekly commenced concurrently with chemoradiotherapy, and continuing until 12 week cystoscopy.	Drug: Pembrolizumab; 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.; Drug: Cisplatin; 35 mg/m2, IV (in the vein) every week for six weeks.; Radiation: Radiotherapy; 2.00Gy once daily for 32 fractions, 5 fractions/week over six weeks and two days (a total of 64Gy).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	12 weeks of study treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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: i) 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	Week 19 (12 weeks post chemotherapy)
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: i) 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	Week 31 of the trial (24 weeks post completion of chemoradiotherapy)
Estimated Median Overall Survival	Estimation after characterization with a Kaplan Meier curve	median follow up 39 months
Overall Survival at 12 Months Post Study Entry	Overall survival timepoint estimated after characterization on a Kaplan Meier curve	12 months post study entry
Distant Metastasis Free Survival (DMFS) at 12 Months	End point was characterized using a Kaplan Meier curve and 12 month time point assessed.	At 12 months post study entry
Local Disease Free Survival (LRPFS) at 12 Months	Local recurrence was defined as recurrence in the bladder or a nodal recurrence in the pelvis	12 months post therapy commencement

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Abundance and Composition of Tumour Infiltrating Lymphocytes, as Assessed by Immunohistochemical Analysis, of Patients Pre-treatment Tissue Samples.	Resected tumour specimens will be available from the patients enrolled on the trial. These pre-treatment specimens will be comprehensively profiled for the abundance and composition of tumour infiltrating lymphocytes (CD4, CD8, CD3, CD20 and FoxP3 positive cells) by immunohistochemistry using the state-of-the-art Vectra Automated Imaging system which enables multiplexed immunohistochemical analysis.	Through study completion, an average of 7 years.
Changes in Gene Expression in CD3+ Cells Pre and Post-treatment as Assessed by RNAseq Analysis to Assess for Gene Expression Changes Associated With Immune Activation.		Through study completion, an average of 7 years.
Changes in the Immune Regulatory Molecules OX-40/LAG3/PD1/ICOS on T Cell Subsets as Assessed by Flow Cytometry.	Blood samples collected prior to treatment, at the end of chemoradiotherapy, and after 24 weeks will be collected from the patients on the trial. PBMCs will be isolated using Ficoll, and changes in specific immune subpopulations (number/ratio) determined by multi-parameter FACS. Changes in the immune regulatory molecules OX-40/LAG3/PD1/ICOS on T cell subsets will be assessed by flow cytometry.	Through study completion, an average of 7 years.

Collaborators and Investigators

• Sponsor: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
• Collaborators: Peter MacCallum Cancer Centre, Australia
• Investigators: Principal Investigator: Farshad Foroudi, MBBS, Austin Health; Principal Investigator: Nathan Lawrentschuk, MBBS, Austin Health

Publications and helpful links

General 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.

Helpful Links

• Sponsor's website

Study record dates

Study Major Dates

• Study Start (Actual): July 11, 2017
• Primary Completion (Actual): May 12, 2022
• Study Completion (Actual): August 26, 2024

Study Registration Dates

• First Submitted: January 13, 2016
• First Submitted That Met QC Criteria: January 20, 2016
• First Posted (Estimated): January 25, 2016

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 16, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Non-metastatic muscle invasive bladder cancer
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urologic Neoplasms; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Pembrolizumab
• Other Study ID Numbers: ANZUP 1502

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No