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

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ClinicalTrials.gov Identifier: NCT02662062
Recruitment Status : Recruiting
First Posted : January 25, 2016
Last Update Posted : January 20, 2021
Sponsor:
Collaborator:
Peter MacCallum Cancer Centre, Australia
Information provided by (Responsible Party):
Australian and New Zealand Urogenital and Prostate Cancer Trials Group

Tracking Information
First Submitted Date  ICMJE January 13, 2016
First Posted Date  ICMJE January 25, 2016
Last Update Posted Date January 20, 2021
Study Start Date  ICMJE August 2016
Estimated Primary Completion Date September 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 20, 2016)
Number of patients with grade 3 or 4 acute toxicities (excluding grade 3 or 4 urinary toxicities) that are related to study drug, graded according to CTCAE v4.03. [ Time Frame: 19 weeks of treatment with Pembrolizumab ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2016)
  • The efficacy of the addition of pembrolizumab to concurrent chemoradiation regimen using the best response achieved, as assessed by cystoscopy at weeks 19 and 31 of the trial (12 and 24 weeks post completion of chemoradiotherapy). [ Time Frame: Week 19 (12 weeks post chemotherapy) and Week 31 (24 weeks post chemotherapy) where cystoscopic examinations take place. ]
  • The number of patients to develop metastatic disease (i.e. the rate of metastatic disease), as assessed by CT scan. [ Time Frame: Through study completion, an average of 7 years. ]
  • The number of patients having a salvage cystectomy (i.e. the rate of salvage cystectomy), as assessed by cystoscopy. [ Time Frame: Through study completion, an average of 7 years. ]
Original Secondary Outcome Measures  ICMJE
 (submitted: January 20, 2016)
  • The efficacy of the addition of pembrolizumab to concurrent chemoradiation regimen using the best response achieved, as assessed by cystoscopy at weeks 19 and 31 of the trial (12 and 24 weeks post completion of chemoradiotherapy). [ Time Frame: Week 19 and Week 31 where cystoscopic examinations take place. ]
  • The number of patients to develop metastatic disease (i.e. the rate of metastatic disease), as assessed by CT scan. [ Time Frame: Through study completion, an average of 7 years. ]
  • The number of patients having a salvage cystectomy (i.e. the rate of salvage cystectomy), as assessed by cystoscopy. [ Time Frame: Through study completion, an average of 7 years. ]
Current Other Pre-specified Outcome Measures
 (submitted: January 20, 2016)
  • The abundance and composition of tumour infiltrating lymphocytes, as assessed by immunohistochemical analysis, of patients pre-treatment tissue samples. [ Time Frame: Through study completion, an average of 7 years. ]
    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.
  • 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. [ Time Frame: 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. [ Time Frame: Through study completion, an average of 7 years. ]
    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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Pembrolizumab With Chemoradiotherapy as Treatment for Muscle Invasive Bladder Cancer
Official Title  ICMJE Pembrolizumab With Chemoradiotherapy as Treatment for Muscle Invasive Bladder Cancer
Brief 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. 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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Bladder Cancer
Intervention  ICMJE
  • 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).
Study Arms  ICMJE Experimental: Pembrolizumab
Pembrolizumab to be administered via IV 200mg 3 weekly commenced concurrently with chemoradiotherapy, and continuing until 12 week cystoscopy.
Interventions:
  • Drug: Pembrolizumab
  • Drug: Cisplatin
  • Radiation: Radiotherapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 20, 2016)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2024
Estimated Primary Completion Date September 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Andrew Weickhardt, MBBS, FRACP +61 3496 5763 andrew.weickhardt@onjcri.org.au
Contact: Ian Davis, MBBS, FRACP +613 9094 9546 ian.davis@monash.edu
Listed Location Countries  ICMJE Australia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02662062
Other Study ID Numbers  ICMJE ANZUP 1502
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Study Sponsor  ICMJE Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Collaborators  ICMJE Peter MacCallum Cancer Centre, Australia
Investigators  ICMJE
Principal Investigator: Farshad Foroudi, MBBS Austin Health
Principal Investigator: Nathan Lawrentschuk, MBBS Austin Health
PRS Account Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP