Advanced Urothelial Carcinoma
Conditions
Keywords
Urinary Bladder Neoplasms, Phosphatidylinositol 3-Kinase, immunotherapy, copanlisib, pembrolizumab, Ureteral Neoplasms
Brief summary
Patients with metastatic bladder cancer are usually treated with chemotherapy. If their cancers do not progress after chemotherapy, they can be enrolled into this study and receive a standard-of-care immunotherapy medication named avelumab plus a study drug named copanlisib.
Detailed description
Patients with advanced urothelial cancer will be treated with platinum-based chemotherapy. After chemotherapy, an imaging study will be performed to determine cancer response. If there is no disease progression, patients will be eligible for this study. After informed consent is obtained, patients are enrolled. The treatment include immunotherapy avelumab as the standard of care plus a study medication copanlisib. Both medications are administrated through intravenous infusion. Avelumab wil be given once every two weeks while copanlisib will be administrated on Day 1, 8 and 15 of every 4-week cycle. Patient will be followed up for disease progression.
Interventions
DRUGcopanlisib
intravenous infusion (IV) at 60 mg on Day 1, 8 and 15 of each 4-week treatment cycle for up to 26 cycles
DRUGAvelumab
800 mg intravenous infusion on Day 1 and 15 of each 4-week treatment cycle for up to 26 cycles
Sponsors
Bayer
VA Office of Research and Development
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a single-arm study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female 2. Age \> 18 years 3. Diagnosis: 1. Histologically or cytologically confirmed metastatic or recurrent urothelial carcinoma. OR 2. Documented stage IV disease (T4b, Any N, M0; any T, Any N, M1a-b), or Stage IIIB (T1-T4a, N2-N3, M0), or subset of stage IIIA (T1-T4a, N1, M0) 4. Completed prior first-line platinum-based chemotherapy at least 4 weeks and not more than 10 weeks after the last dose of first line chemotherapy. 5. Patients without progressive disease as per RECIST v1.1 guideline (i.e., with an ongoing CR, PR, or SD) following completion of the first-line chemotherapy. 6. Patient must be appropriate to receive Avelumab maintenance therapy 7. Measurable disease after chemotherapy is not required: 1. Patients must have had X-rays, CT/ MRI scans, PET or physical examinations completed within 28 days prior to initial administration of study medications. 2. Patients may have no evidence of disease after platinum-based chemotherapy. These patients will be included in the study for all other analyses except ORR and irORR. 3. Soft tissue disease that has been radiated within two months prior to registration is not assessable as measurable disease. Soft tissue disease that has been radiated two or more months prior to registration is assessable as measurable disease provided that the lesion has progressed following radiation. As the biology of previously irradiated tumors may be different from non-irradiated tumors, patients must have at least one measurable lesion outside the previously irradiated region in order to be considered to have measurable disease. 8. Tumor samples: a.Provision of a recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue block from the most recent primary or metastatic tumor biopsy or resection obtained prior to treatment with first line chemotherapy but within one year of enrollment, with no intervening systemic anti-cancer therapy. If an FFPE tissue block cannot be provided, 15 unstained slides (10 minimum) will be acceptable. If a suitable tissue sample is not otherwise available, then a tissue from a de novo biopsy (core needle or excisional) should have been obtained prior to initiation of this study. However, this biopsy is not required for participation in this trial if he/she meets all other inclusion and
Exclusion criteria
. When patients undergo biopsy, in addition to FFPE preparation, fresh tissue should be sent to VABHS for single-cell RNAseq and T cell receptor sequencing as specified in the addendum. 9. Estimated life expectancy of at least 3 months. 10. Eastern Cooperative Oncology Group (ECOG) performance status (PS) status 2 OR Karnofsky Performance Status scale 60%. For the safety lead-in phase, only patients with PS 0-1 will be included. 11. Adequate bone marrow function, including: 1. Leukocytes \> 3000/mm3 2. Absolute neutrophil count (ANC) \> 1,500/mm3 3. Platelets \> 100,000/mm3 4. Hemoglobin \> 9 g/dL (may have been transfused). 12. Adequate renal function, defined as estimated creatinine clearance 20 mL/minute as calculated using the Cockcroft-Gault equation. It has been shown that creatinine clearance 15 ml/minute did not significantly affect the pharmacokinetics of copanlisib. 13. Adequate liver function, including: b.Total serum bilirubin 1.5 x upper limit of normal (ULN) c.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 2.5 x ULN d.Total serum bilirubin \< 3 x ULN for patients with Gilbert's syndrome or for patients with cholestasis due to compressive adenopathy of the hepatic hilum 14. Serum pregnancy test (for females of childbearing potential) negative at screening. 15. Male patients able to father children and female patients of childbearing potential and at risk for pregnancy must agree to use 2 highly effective methods of contraception throughout the study and for at least 60 days after the last dose of assigned treatment. 16. Evidence of a signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study. 17. Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. 18. Controlled diabetes A1c \< 8.5%. For patients with newly diagnosed diabetes mellitus that cannot meet protocol requirements, a single rescreening (which includes all screening procedures) should be performed when the patient's diabetes is controlled and can meet protocol requirement for HbA1c). 19. Controlled arterial hypertension (per investigator assessment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | 6 months into the trial | The primary endpoint is PFS. PFS is defined as the time between initiation of the avelumab/copanlisib combination and tumor progression or death from any cause, with censoring of patients who are lost to follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 24 months | Overall survival is defined as the length of time from the start of this trial treatment to the time of death from any cause |
| Objective response rate | 2 months | Objective response rate is defined as the percentage of patients who have a partial or complete response at any time during this treatment of this trial |
| Disease-control rate | 2-8 months | Disease-control rate is defined as the percentage of patients who have a partial or complete response or stable disease at any time during this treatment of this trial |
| Adverse events | up to 2 years into the study | Adverse events are defined as any untoward medical occurrence of subjects which does not necessarily have a causal relationship with the treatment |
Other
| Measure | Time frame | Description |
|---|---|---|
| Molecular Correlative Studies | up to 2 years into the study | Immune cell infiltration, immune cell activation/exhaustion status, cytokine production and signaling transduction pathways will be studied. |
Countries
United States
Outcome results
None listed