Bladder Cancer
Conditions
Keywords
Non-metastatic 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.
Interventions
DRUGPembrolizumab
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.
DRUGCisplatin
35 mg/m2, IV (in the vein) every week for six weeks.
RADIATIONRadiotherapy
2.00Gy once daily for 32 fractions, 5 fractions/week over six weeks and two days (a total of 64Gy).
Sponsors
Peter MacCallum Cancer Centre, Australia
Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants Experiencing an Unacceptable Level of Toxicity as Defined Below | 12 weeks of study treatment | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Estimated Median Overall Survival | median follow up 39 months | Estimation after characterization with a Kaplan Meier curve |
| Overall Survival at 12 Months Post Study Entry | 12 months post study entry | Overall survival timepoint estimated after characterization on a Kaplan Meier curve |
| Distant Metastasis Free Survival (DMFS) at 12 Months | At 12 months post study entry | End point was characterized using a Kaplan Meier curve and 12 month time point assessed. |
| Local Disease Free Survival (LRPFS) at 12 Months | 12 months post therapy commencement | Local recurrence was defined as recurrence in the bladder or a nodal recurrence in the pelvis |
| Complete Response Rate at Week 19 of the Trial (12 Weeks Post Completion of Chemoradiotherapy). | Week 19 (12 weeks post chemotherapy) | 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 |
| 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) | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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. |
| 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. | 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. | Through study completion, an average of 7 years. | — |
Countries
Australia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab Pembrolizumab to be administered via IV 200mg 3 weekly commenced concurrently with chemoradiotherapy, and continuing until 12 week cystoscopy.
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.
Cisplatin: 35 mg/m2, IV (in the vein) every week for six weeks.
Radiotherapy: 2.00Gy once daily for 32 fractions, 5 fractions/week over six weeks and two days (a total of 64Gy). | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Pembrolizumab | — |
|---|---|---|
| Age, Continuous | 72 years | — |
| ECOG ECOG 0 | 18 Participants | — |
| ECOG ECOG 1 | 10 Participants | — |
| Histology Associated carcinoma in situ | 9 Participants | — |
| Histology Mixed Transitional/ nontransitional | 3 Participants | — |
| Histology Transitional cell/ Urothelial | 25 Participants | — |
| Prior BCG (Bacillis Calmette-Guerin vaccine) treatment | 2 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Australia | 28 participants | — |
| Sex: Female, Male Female | 2 Participants | — |
| Sex: Female, Male Male | 26 Participants | — |
| T stage T2 | 26 Participants | — |
| T stage T3 | 2 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 8 / 28 |
| other Total, other adverse events | 27 / 28 |
| serious Total, serious adverse events | 13 / 28 |
Outcome results
Primary
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
Time frame: 12 weeks of study treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pembrolizumab | The Number of Participants Experiencing an Unacceptable Level of Toxicity as Defined Below | Unacceptable toxicity - total | 9 Participants |
| Pembrolizumab | The Number of Participants Experiencing an Unacceptable Level of Toxicity as Defined Below | Grade 3 or higher adverse event | 6 Participants |
| Pembrolizumab | The Number of Participants Experiencing an Unacceptable Level of Toxicity as Defined Below | Immune mediated toxicity meeting unacceptable toxicity definition. | 2 Participants |
| Pembrolizumab | The Number of Participants Experiencing an Unacceptable Level of Toxicity as Defined Below | Cisplatin dose omissions 2 or greater | 4 Participants |
| Pembrolizumab | The Number of Participants Experiencing an Unacceptable Level of Toxicity as Defined Below | Radiation duration >7 weeks | 2 Participants |
| Pembrolizumab | The Number of Participants Experiencing an Unacceptable Level of Toxicity as Defined Below | Pembrolizumab >6 weeks delay | 1 Participants |
Comparison: The null hypothesis is that the addition of pembrolizumab to chemoradiation is not unsafe (percentage of the population experiencing unacceptable toxicity is not \>50%)
Secondary
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
Time frame: Week 19 (12 weeks post chemotherapy)
Population: Only 21 patients were evaluable at this timepoint
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Complete Response Rate at Week 19 of the Trial (12 Weeks Post Completion of Chemoradiotherapy). | 90 Percentage of evaluable population |
Secondary
Distant Metastasis Free Survival (DMFS) at 12 Months
End point was characterized using a Kaplan Meier curve and 12 month time point assessed.
Time frame: At 12 months post study entry
Population: 1 patient was not evaluable for this time point due to withdrawal of consent~1 patient was not evaluable for this time point due to death related to pre-existing chronic airways disease
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Distant Metastasis Free Survival (DMFS) at 12 Months | 85 Percentage of population |
95% CI: [64, 94]
Secondary
Estimated Median Overall Survival
Estimation after characterization with a Kaplan Meier curve
Time frame: median follow up 39 months
Population: 2 participants not evaluable for this endpoint due to withdrawal of consent (1) and death from pre-existing airways disease (1)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Estimated Median Overall Survival | 39 months |
Secondary
Local Disease Free Survival (LRPFS) at 12 Months
Local recurrence was defined as recurrence in the bladder or a nodal recurrence in the pelvis
Time frame: 12 months post therapy commencement
Population: Two participants not evaluable for this outcome measure for reasons of withdrawal of consent (1) and death from pre-existing airways disease (1)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Local Disease Free Survival (LRPFS) at 12 Months | 88 Percentage of evaluable population |
95% CI: [68, 98]
Secondary
Overall Survival at 12 Months Post Study Entry
Overall survival timepoint estimated after characterization on a Kaplan Meier curve
Time frame: 12 months post study entry
Population: Two participants not evaluable for this endpoint due to withdrawal of consent (1) and death from pre-existing airways disease (1)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Overall Survival at 12 Months Post Study Entry | 92 Percentage of evaluable population |
95% CI: [72, 98]
Secondary
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
Time frame: Week 31 of the trial (24 weeks post completion of chemoradiotherapy)
Population: two participants not evaluable for this endpoint due to withdrawal of consent (1) and death from an exacerbation of pre-existing airways disease (1)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | The Complete Response Rate Assessed at Week 31 of the Trial (24 Weeks Post Completion of Chemoradiotherapy). | 88 Percentage of evaluable population |
Other Pre-specified
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.
Other Pre-specified
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.
Time frame: Through study completion, an average of 7 years.
Other Pre-specified
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.
Time frame: Through study completion, an average of 7 years.