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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02662062




Registration number
NCT02662062
Ethics application status
Date submitted
13/01/2016
Date registered
25/01/2016
Date last updated
5/07/2019

Titles & IDs
Public title
Pembrolizumab With Chemoradiotherapy as Treatment for Muscle Invasive Bladder Cancer
Scientific title
Pembrolizumab With Chemoradiotherapy as Treatment for Muscle Invasive Bladder Cancer
Secondary ID [1] 0 0
ANZUP 1502
Universal Trial Number (UTN)
Trial acronym
PCR-MIB
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bladder Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Bladder - transitional cell cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Pembrolizumab
Treatment: Drugs - Cisplatin
Treatment: Other - Radiotherapy

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


Treatment: Drugs: 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.

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

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

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
19 weeks of treatment with Pembrolizumab
Secondary outcome [1] 0 0
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).
Timepoint [1] 0 0
Week 19 (12 weeks post chemotherapy) and Week 31 (24 weeks post chemotherapy) where cystoscopic examinations take place.
Secondary outcome [2] 0 0
The number of patients to develop metastatic disease (i.e. the rate of metastatic disease), as assessed by CT scan.
Timepoint [2] 0 0
Through study completion, an average of 7 years.
Secondary outcome [3] 0 0
The number of patients having a salvage cystectomy (i.e. the rate of salvage cystectomy), as assessed by cystoscopy.
Timepoint [3] 0 0
Through study completion, an average of 7 years.

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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 design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC,WA
Recruitment hospital [1] 0 0
Chris O'Brien Lifehouse - Camperdown
Recruitment hospital [2] 0 0
Liverpool Hospital - Liverpool
Recruitment hospital [3] 0 0
Prince of Wales Hospital - Randwick
Recruitment hospital [4] 0 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [5] 0 0
Austin Health - Heidelberg
Recruitment hospital [6] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [7] 0 0
Sir Charles Gairdner Hospital - Nedlands, Perth
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
2170 - Liverpool
Recruitment postcode(s) [3] 0 0
2013 - Randwick
Recruitment postcode(s) [4] 0 0
2065 - St Leonards
Recruitment postcode(s) [5] 0 0
3084 - Heidelberg
Recruitment postcode(s) [6] 0 0
3002 - Melbourne
Recruitment postcode(s) [7] 0 0
6009 - Nedlands, Perth

Funding & Sponsors
Primary sponsor type
Other
Name
Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Peter MacCallum Cancer Centre, Australia
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT02662062
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Farshad Foroudi, MBBS
Address 0 0
Austin Health
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Andrew Weickhardt, MBBS, FRACP
Address 0 0
Country 0 0
Phone 0 0
+61 3496 5763
Fax 0 0
Email 0 0
andrew.weickhardt@onjcri.org.au
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02662062