Pembrolizumab With Chemoradiotherapy as Treatment for Muscle Invasive Bladder Cancer

NCT02662062 | Completed Phase 2 Results DMC

• 1 other identifier: ANZUP 1502
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 7

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.

Conditions

Bladder Cancer

Keywords

Non-metastatic muscle invasive bladder cancer

Outcome Measures

Primary Outcomes (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

  12 weeks of study treatment

Secondary Outcomes (6)

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

  Week 19 (12 weeks post chemotherapy)

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

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

• Estimated Median Overall Survival

  median follow up 39 months

• Overall Survival at 12 Months Post Study Entry

  12 months post study entry

• Distant Metastasis Free Survival (DMFS) at 12 Months

  At 12 months post study entry

Other Outcomes (3)

• The Abundance and Composition of Tumour Infiltrating Lymphocytes, as Assessed by Immunohistochemical Analysis, of Patients Pre-treatment Tissue Samples.

  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.

  Through study completion, an average of 7 years.

Study Arms (1)

Pembrolizumab

EXPERIMENTAL

Pembrolizumab to be administered via IV 200mg 3 weekly commenced concurrently with chemoradiotherapy, and continuing until 12 week cystoscopy.

Drug: Pembrolizumab; Drug: Cisplatin; Radiation: Radiotherapy

Interventions

Pembrolizumab DRUG

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.

Pembrolizumab

Cisplatin DRUG

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

Pembrolizumab

Radiotherapy RADIATION

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

Pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Australian and New Zealand Urogenital and Prostate Cancer Trials Group: lead
• Peter MacCallum Cancer Centre, Australia: collaborator

Study Sites (7)

Chris O'Brien Lifehouse

Camperdown, New South Wales, 2050, Australia

Location

Liverpool Hospital

Liverpool, New South Wales, 2170, Australia

Location

Prince of Wales Hospital

Randwick, New South Wales, 2013, Australia

Location

Royal North Shore Hospital

St Leonards, New South Wales, 2065, Australia

Location

Austin Health

Heidelberg, Victoria, 3084, Australia

Location

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3002, Australia

Location

Sir Charles Gairdner Hospital

Nedlands, Western Australia, 6009, Australia

Location

Related Publications (1)

• 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.

  PMID: 37806844 RESULT

Related Links

• Sponsor's website

MeSH Terms

Conditions

Urinary Bladder Neoplasms

Interventions

pembrolizumab; Cisplatin; Radiotherapy

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Therapeutics

Results Point of Contact

• Title: Dr Anthony Uccellini - ANZUP Research fellow
• Organization: ANZUP

trials@anzup.org.au

61 2 9046 8954

Study Officials

• Farshad Foroudi, MBBS

  Austin Health

  PRINCIPAL INVESTIGATOR

• Nathan Lawrentschuk, MBBS

  Austin Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 13, 2016
• First Posted: January 25, 2016
• Study Start: July 11, 2017
• Primary Completion: May 12, 2022
• Study Completion: August 26, 2024
• Last Updated: January 27, 2025
• Results First Posted: January 27, 2025

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

AU (7)