Bladder Cancer, Muscle Invasive Bladder Cancer
Conditions
Keywords
Bladder Cancer, Bladder Carcinoma, Carcinoma of Bladder, Carcinoma of the Bladder, MIBC, Muscle Invasive Bladder Cancer, Muscle-Invasive Urothelial Carcinoma of the Bladder, Immunotherapy, Avelumab, Radiation and Immunotherapy, No cisplatin, Cisplatin Ineligible, Cisplatin-Ineligible, T2 Disease, T3 Disease, T4 Disease, squamous bladder cancer, adenocarcinoma bladder cancer, micropapillary bladder cancer, Inability to receive cisplatin-based chemotherapy
Brief summary
This research study is studying the effects of adding a certain type of immunotherapy to standard bladder-directed radiation as a treatment for muscle-invasive urothelial carcinoma of the bladder. The drug in this study is: Avelumab (also known as BAVENCIO®)
Detailed description
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. Investigational means that the drug is being studied. The FDA (the U.S. Food and Drug Administration) has not approved the use of avelumab and bladder-directed radiation together for this specific disease but avelumab has been approved for other uses. While bladder-directed radiation is a standard treatment option for muscle-invasive urothelial carcinoma of the bladder, the use of avelumab in combination with bladder radiation in patients with urothelial carcinoma of the bladder is investigational. Radiation is used in the treatment of muscle-invasive bladder cancer, and avelumab has been approved by the FDA in patients with more advanced stages of this disease. Avelumab is a form of immunotherapy, which means it is designed to help the immune system fight cancer cells together with standard cancer treatments like radiation. Avelumab is currently approved by the FDA for the treatment of metastatic Merckel cell carcinoma (mMCC) and platinum-refractory metastatic urothelial carcinoma. The purpose of this study is to test whether the combination of immunotherapy and bladder directed radiation is effective in treating muscle-invasive bladder cancer. The study will also measure other outcomes such as participant's overall health and quality of life during and after treatment. In addition, the investigators will determine if certain biomarkers are correlated with outcomes following treatment with immunotherapy and radiation.
Interventions
DRUGAvelumab
Avelumab is a form of immunotherapy, which means it is designed to help the patient's immune system kill cancer cells.
RADIATIONRadiation
Cancer treatment that uses ionizing radiation to kill cancer cells.
Sponsors
EMD Serono
Dana-Farber Cancer Institute
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
Subjects must meet all of the following applicable inclusion criteria to participate in the study. Inclusion Criteria: * Histologically confirmed transitional cell (urothelial) carcinoma of the bladder that is invasive into the muscularis propria (≥T2 disease) within 6 months of enrollment date. The presence of variant histologies (squamous, adenocarcinoma, micropapillary, etc.) is allowed. Note: A prior diagnosis of non-muscle-invasive bladder cancer (≤T1) managed with transurethral resection with or without intravesicular therapy (now with muscle invasion) is allowed. * Inability to receive cisplatin-based chemotherapy, as defined by creatinine clearance \<60 ml/min, ECOG PS ≤2, grade 2 or higher hearing loss, NYHA class 3 or higher, neuropathy (grade 2 or higher), or patient refusal to receive cisplatin-based chemotherapy. Additional Inclusion Criteria: * Male or female subjects aged ≥18 years * ECOG performance status ≤2 or Karnofsky score ≥60% (see Appendix A) * Life expectancy of greater than 1 year * Demonstrate normal organ and marrow function * Estimated creatinine clearance \> 30 mL/min according to the Cockcroft-Gault formula. * Women of child-bearing age must have a negative serum pregnancy test at screening. * Women of child-bearing potential and men must agree to use a highly effective method of contraception (hormonal or barrier method of birth control, or abstinence) beginning prior to study entry, for the duration of study participation, and for at least 30 days after last avelumab treatment administration if the risk of conception exists * Ability to start study treatment (first cycle of Avelumab) within 1-8 weeks of the most recent pre-study TURBT. * Ability to understand and willingness to sign a written informed consent document
Exclusion criteria
* Prior intravenous therapy for treatment of bladder cancer * Prior pelvic radiation * Any component of small cell histology in the bladder biopsy * Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment * Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroid, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) are allowed. * History of another malignancy within 5 years prior to randomization except for: non-muscle-invasive bladder cancer (i.e., ≤T1), completely resected basal cell or squamous cell skin cancer, completed resected carcinoma-in-situ of any site, or localized prostate cancer managed definitively with a non-radiation based approach. Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Clinical Response Rate | 3 months following completion of radiation; then every 3 months until 2 years after registration; then every 6 months up to a maximum of 3 years after registration | Measured by the complete clinical response rate at 3 months following completion of radiation, followed by every 3 months until 2 years after registration, then every 6 months up to a maximum of 3 years after registration. Clinical response is assessed by cystoscopy, urine cytology, and CT Chest/Abdomen/Pelvis. No evidence of disease on these assessments at a given time point suggests a Complete Clinical Response at that time point. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 3 years | Overall Survival (OS) |
| Progression Free Survival | 3 years | Progression Free Survival (PFS) as assessed by imaging, cystoscopy, and cytology. |
| Metastases-free Survival | 3 years | Metastases-free survival (MFS) as assessed by imaging. |
| Locoregional Recurrence Rate | 3 years | Locoregional recurrence rate (LRR) as assessed by imaging. |
| Change in Quality of Life Outcomes | Baseline; 3 months following completion of radiation; 2 years after treatment | Quality of Life Outcomes (QoL) as measured by patient report on questionnaires. Patients are given a statement and must assign a number to assess how the statement applies to them in the past 7 days. 0=Not at all; 1=A little bit; 2=Somewhat; 3=Quite a bit; 4=Very much. QoLs were collected at baseline, end of radiation, 3 months post-radiation completion, then every 3 months through year 2 after treatment. Median scores and interquartile ranges were calculated for baseline, 3 months post-radiation completion, and 2 years post-treatment. 3 months post-RT was selected to coincide with the primary outcome timeframe. Year 2 was selected due to the number of patients that reached this point during follow up; most patients did not surpass year 2. Higher score means worse outcome for questions regarding diarrhea, urinary frequency & burning, and being bothered by treatment. Higher score means better outcome for questions regarding being content with quality of life and control over bowels. |
Countries
United States
Participant flow
Recruitment details
14 patients were enrolled out of 17 that consented to the study. The target enrollment was 24 patients prior to study closure due to slow accrual.
Pre-assignment details
Patients must have muscle invasive (T2-T4a) urothelial bladder carcinoma. They must also not be eligible for cisplatin-based chemotherapy.
Participants by arm
| Arm | Count |
|---|---|
| Avelumab and Bladder-Directed Radiation * Avelumab will be administered every 2 weeks intravenously for 6 doses unless there is unacceptable toxicity
* Two radiation dose regimens are allowed, and the regimen selected is at the discretion of the treating radiation oncologist | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | Avelumab and Bladder-Directed Radiation |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 14 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| ECOG Performance Status ECOG = 0 | 5 Participants |
| ECOG Performance Status ECOG = 1 | 5 Participants |
| ECOG Performance Status ECOG = 2 | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 14 |
| other Total, other adverse events | 14 / 14 |
| serious Total, serious adverse events | 4 / 14 |
Outcome results
Primary
Complete Clinical Response Rate
Measured by the complete clinical response rate at 3 months following completion of radiation, followed by every 3 months until 2 years after registration, then every 6 months up to a maximum of 3 years after registration. Clinical response is assessed by cystoscopy, urine cytology, and CT Chest/Abdomen/Pelvis. No evidence of disease on these assessments at a given time point suggests a Complete Clinical Response at that time point.
Time frame: 3 months following completion of radiation; then every 3 months until 2 years after registration; then every 6 months up to a maximum of 3 years after registration
Population: 2 participants withdrew consent prior to completing protocol therapy and therefore could not be evaluated for the primary endpoint.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab and Bladder-Directed Radiation | Complete Clinical Response Rate | Subjects that reached Complete CR at 3 months following completion of radiation | 5 Participants |
| Avelumab and Bladder-Directed Radiation | Complete Clinical Response Rate | Subjects that never reached Complete CR during FU | 3 Participants |
| Avelumab and Bladder-Directed Radiation | Complete Clinical Response Rate | Subjects that reached Complete CR during FU but after 3 months following completion of radiation | 4 Participants |
Secondary
Change in Quality of Life Outcomes
Quality of Life Outcomes (QoL) as measured by patient report on questionnaires. Patients are given a statement and must assign a number to assess how the statement applies to them in the past 7 days. 0=Not at all; 1=A little bit; 2=Somewhat; 3=Quite a bit; 4=Very much. QoLs were collected at baseline, end of radiation, 3 months post-radiation completion, then every 3 months through year 2 after treatment. Median scores and interquartile ranges were calculated for baseline, 3 months post-radiation completion, and 2 years post-treatment. 3 months post-RT was selected to coincide with the primary outcome timeframe. Year 2 was selected due to the number of patients that reached this point during follow up; most patients did not surpass year 2. Higher score means worse outcome for questions regarding diarrhea, urinary frequency & burning, and being bothered by treatment. Higher score means better outcome for questions regarding being content with quality of life and control over bowels.
Time frame: Baseline; 3 months following completion of radiation; 2 years after treatment
Population: One participant declined to complete QoL forms during treatment and follow up.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | Baseline Median Score I am bothered by side effects of treatment | 0 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | Baseline Median Score I am content with the quality of my life right now | 2 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | Baseline Median Score I have control of my bowels | 3 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | Baseline Median Score I urinate more frequently than usual | 2.5 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | Basline Median Score I have diarrhea | 0 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | Baseline Median Score It burns when I urinate | 0 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | 3 months post-RT Median Score I am bothered by side effects of treatment | 0 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | 3 months post-RT I am content with the quality of my life right now | 3 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | 3 months post-RT Median Score I have control of my bowels | 1.5 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | 3 months post-RT Median Score I urinate more frequently than usual | 2 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | 3 months post-RT Median Score I have diarrhea | 0.5 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | 3 months post-RT Median Score It burns when I urinate | 0 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | 2 Year Median Score I am bothered by side effects of treatment | 0 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | 2 Year Median Score I am content with the quality of my life right now | 3 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | 2 Year Median Score I have control of my bowels | 3 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | 2 Year Median Score I urinate more frequently than usual | 0 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | 2 Year Median Score I have diarrhea | 0 score on a scale |
| Avelumab and Bladder-Directed Radiation | Change in Quality of Life Outcomes | 2 Year Median Score It burns when I urinate | 0 score on a scale |
Secondary
Locoregional Recurrence Rate
Locoregional recurrence rate (LRR) as assessed by imaging.
Time frame: 3 years
Population: 2 participants withdrew consent prior to completing protocol therapy, and 1 participant withdrew consent during FU. Therefore, they could not be evaluated for overall survival.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab and Bladder-Directed Radiation | Locoregional Recurrence Rate | Locoregional recurrence after treatment | 1 Participants |
| Avelumab and Bladder-Directed Radiation | Locoregional Recurrence Rate | No locoregional recurrence after treatment | 11 Participants |
Secondary
Metastases-free Survival
Metastases-free survival (MFS) as assessed by imaging.
Time frame: 3 years
Population: 2 participants withdrew consent prior to completing protocol therapy.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab and Bladder-Directed Radiation | Metastases-free Survival | Metastases after treatment | 5 Participants |
| Avelumab and Bladder-Directed Radiation | Metastases-free Survival | No metastases after treatment | 7 Participants |
Secondary
Overall Survival
Overall Survival (OS)
Time frame: 3 years
Population: 2 participants withdrew consent prior to completing protocol therapy.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab and Bladder-Directed Radiation | Overall Survival | Deaths due to progressive disease during FU | 5 Participants |
| Avelumab and Bladder-Directed Radiation | Overall Survival | Deaths due to unrelated condition during FU | 2 Participants |
| Avelumab and Bladder-Directed Radiation | Overall Survival | Subjects alive at time of study closure | 4 Participants |
| Avelumab and Bladder-Directed Radiation | Overall Survival | Subjects alive at time of study withdrawal during FU | 1 Participants |
Secondary
Progression Free Survival
Progression Free Survival (PFS) as assessed by imaging, cystoscopy, and cytology.
Time frame: 3 years
Population: 2 participants withdrew consent prior to completing protocol therapy.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab and Bladder-Directed Radiation | Progression Free Survival | Disease progression after treatment | 5 Participants |
| Avelumab and Bladder-Directed Radiation | Progression Free Survival | No disease progression after treatment | 7 Participants |