A Phase 1/2 interventional study of Avelumab in Bladder Cancer, Metastatic Bladder Cancer and Invasive Bladder Cancer, sponsored by Baylor College of Medicine. Terminated at 3 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-08-24.
Sponsored by Baylor College of Medicine · Phase 1/2, Interventional, and Treatment
This is a pilot study of avelumab in patients with non-metastatic, muscle invasive bladder cancer who are eligible for radical cystectomy (RC), but are ineligible for cisplatin based neoadjuvant therapy. The target recruitment is 10 evaluable patients for this window of opportunity study. Pre- and post-treatment tumor samples from transurethral resection of the bladder tumor and RC will be used for study endpoints.
Avelumab is a fully human monoclonal PD-L1 antibody of the immunoglobulin G1 (IgG1) subclass. It works by binding to PD-L1 on tumor cells, immune cells and/or stromal cells. This prevents PD-L1 from interacting with PD-1. Inhibition of this interaction increases activation/survival of antitumor lymphocytes. It also increases innate immunity by resulting in decreased PD-1 suppression of NK cell function and bolsters antibody production by B cells due to less PD-L1 binding of PD-1 on B-cells. Additionally, avelumab has been suggested to have another mechanism involving antibody dependent cellular cytotoxicity (ADCC). ADCC in these cases involves NK cell recognition and lysis of tumor cells that have antibody bound to PD-L1. By blocking PD-L1, avelumab leads to less CD80 binding by PD-L1 and more CD80-CD28 binding in response to antigen presentation to T-cells. This results in increased costimulatory signaling and is another mechanism by which avelumab may enhance T-cell activation.
Avelumab has been shown to be efficacious across multiple metastatic tumor types, including urothelial cancer. The phase Ib study has reported survival and safety outcomes with >12 months followup using pooled data on 249 patients with metastatic UC (Apolo et al, ESMO Sept 2017). Patients had been treated with a median of 2 prior therapies in the metastatic setting and 13 patients who were cisplatin-ineligible were evaluated for safety alone. PD-L1 expression was not a criterion for enrollment. The confirmed objective response rate (ORR) was 16.1%, with 5% complete responses and 11.2% partial responses. The 6-month progression-free survival was 27%. The ORR was better than or comparable to chemotherapy in historical controls. Among responders, 70.3% were maintained > 12 months. Treatment-related adverse events (AE) occurred in 70%, with 10.7% of the total with AE's of grade >3. Immune-mediated AE's occurred in 18.5%, of which 4% were grade >3. There is currently a phase III clinical trial ongoing comparing avelumab to standard of care chemotherapy in the second line setting or beyond for metastatic UC. Two other checkpoint inhibitors have been approved in the last 2 years for first line treatment of patients with metastatic UC who are ineligible for cisplatin-based therapy.
Female patients must agree to inform study coordinator or investigator immediately if they think they have become pregnant during the study.
Exclusion Criteria:
Patients must not have any of the following:
Avelumab 10 mg/kg intravenously, over 60 minutes every 2 weeks for 3 cycles or 42 days.
Drug: Avelumab
avelumab 10 mg/kg intravenously every 2 weeks for 3 cycles or 42 days.
Also known as: MSB0010718C
Change in T Cell Subpopulations
The change in T cell subpopulations (CD8, CD4 and/or CD3) in tumor samples will be collected from FFPE tissue. FFPE tissue from the pre-study time point refers to tissue from the TURBT. FFPE tissue from the 2-3 week post-op time point refers to FFPE tissue from the RC
Time frame: pre-study time and 2-3 week post-operation
Pathological Response Rate
Number of patient with pathological response will be counted
Time frame: pre-study time and 2-3 week post-operation
2 Year Disease Free Survival (DFS)
A patient will be followed for recurrence and survival for up to 2 years after radical cystectomy.
Time frame: 2 years after radical cystectomy
Rate of High Grade(Grade 3-4) Adverse Event
High grade adverse events are defined as grade of 3-4 on the CTCAE (Common terminology criteria for adverse events) grading scale.
Time frame: 90 days post operation
| Milestone | Avelumab |
|---|---|
| Started | 1 |
| Completed | 1 |
| Not completed | 0 |
The change in T cell subpopulations (CD8, CD4 and/or CD3) in tumor samples will be collected from FFPE tissue. FFPE tissue from the pre-study time point refers to tissue from the TURBT. FFPE tissue from the 2-3 week post-op time point refers to FFPE tissue from the RC
No measurements were reported for this outcome.
Number of patient with pathological response will be counted
| Participants | Avelumab |
|---|---|
| Pathological Response Rate | 0 |
A patient will be followed for recurrence and survival for up to 2 years after radical cystectomy.
| months | Avelumab |
|---|---|
| 2 Year Disease Free Survival (DFS) | 5.48 |
High grade adverse events are defined as grade of 3-4 on the CTCAE (Common terminology criteria for adverse events) grading scale.
| Participants | Avelumab |
|---|---|
| Rate of High Grade(Grade 3-4) Adverse Event | 1 |
Collected over 90 days after radical cystectomy (RC) or end of the last cycle of Avelumab for those not receiving RC.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Avelumab | 1/1 (100%) | 1/1 (100%) | 1/1 (100%) |
| Event | Avelumab |
|---|---|
| SepsisInfections and infestations | 1/1 |
| Urinary tract obstructionRenal and urinary disorders | 1/1 |
| Event | Avelumab |
|---|---|
| AnemiaBlood and lymphatic system disorders | 1/1 |
| Creatinine increasedInvestigations | 1/1 |
| Renal and urinary disorders - Other, specifyRenal and urinary disorders | 1/1 |
| Age, Continuous(years) | Avelumab |
|---|---|
| Mean | 58 ± NA |
| Sex: Female, Male(Participants) | Avelumab |
|---|---|
| Female | 0 |
| Male | 1 |
| Ethnicity (NIH/OMB)(Participants) | Avelumab |
|---|---|
| Hispanic or Latino | 0 |
| Not Hispanic or Latino | 1 |
| Unknown or Not Reported | 0 |
| Race (NIH/OMB)(Participants) | Avelumab |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 1 |
| White | 0 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | Avelumab |
|---|---|
| United States | 1 |
| Current Smoking(Participants) | Avelumab |
|---|---|
| Count of participants | 1 |
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