E-mail

Cancer

Recruiting

Bladder Urothelial Carcinoma; Stage III Bladder Cancer AJCC v8; Stage IIIA Bladder Cancer AJCC v8; Stage IIIB Bladder Cancer AJCC v8 (CIRB-21-0039)

Baptist Health Louisville

Andrew J Hart

Principal Investigator

Renee Dickerson

Overview

EA8185: Phase II Study of Bladder-SparIng ChemoradiatioN with MEDI4736 (Durvalumab) in Clinical Stage III, Node PosItive BladdeR CancEr (INSPIRE)

Description

This phase II trial studies the benefit of adding an immunotherapy drug called MEDI4736 (durvalumab) to standard chemotherapy and radiation therapy in treating bladder cancer which has spread to the lymph nodes. Drugs used in standard chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Immunotherapy with durvalumab may help the body's immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread. Giving chemotherapy and radiation therapy with the addition of durvalumab may work better in helping tumors respond to treatment compared to chemotherapy and radiation therapy alone. Patients with limited regional lymph node involvement may benefit from attempt at bladder preservation, and use of immunotherapy and systemic chemotherapy.

Learn more at clinicaltrials.gov

Eligibility Criteria

Inclusion

Step 1 (Registration) Inclusion

Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at the time of registration

Patient must have histologically proven pure or mixed urothelial cancer of the bladder

NOTE: Small cell carcinoma is excluded, however other variant histologies are permitted provided a component of urothelial carcinoma is present

Prior to receiving any induction chemotherapy, patient must have documented node-positive and non-metastatic disease (any T, any N, M0)

NOTE: Node positivity will be defined by the official interpretation of imaging studies by a radiologist. A positive lymph node is defined as lymph node (LN) >= 1.0 cm in short axis. LN Biopsy is not mandatory but encouraged if feasible and safe per physician discretion. Patients with a negative biopsy of nodes determined to be suspicious on imaging are not eligible. Please note that for non-muscle invasive disease on transurethral resection of a bladder tumor (TURBT), node-positive disease MUST be biopsy proven for patient to be eligible

Induction Chemotherapy Requirements

For patients registered to this protocol post-completion of induction systemic chemotherapy:

Patient must have received at least 3 cycles of induction chemotherapy (cisplatin-based chemotherapy OR non-cisplatin based chemotherapy) with no evidence of progressive disease (PD) on post-chemotherapy imaging. The end of last cycle of induction chemotherapy must be within 12 weeks of registration

Patient who have received more than 3 cycles of induction systemic chemotherapy are also eligible

Patient must have had a CR, PR or SD to induction chemotherapy on standard imaging

NOTE: Patients who have only received 2 cycles of induction chemotherapy and demonstrated clinical response (complete response [CR] OR partial response [PR], OR stable disease [SD]) may be considered for enrollment only after consultation and approval by the study chair under exceptional circumstances where 3rd cycle cannot be delivered. Documentation of correspondences with the study chair must be kept on file. We encourage all patients to get 3 cycles of induction chemotherapy

For patients registered to this protocol prior to starting induction systemic chemotherapy:

Patient must agree to a planned treatment with 3 cycles of induction chemotherapy (physician's choice)

Patient will again be restaged after completion of induction chemotherapy and prior to randomization to chemoRT +/- durvalumab

Patient must have a CR, PR or SD to induction chemotherapy on standard imaging prior to randomization to chemoradiotherapy

Patient must not have presence of concomitant active upper tract tumors or urethra tumors. History of previously adequately treated non-muscle invasive bladder cancer (NMIBC) are eligible; previously treated urothelial cancer or histological variant at any site outside of the urinary bladder are allowed, provided they have been Ta/T1/carcinoma in situ (CIS) and post treatment follow up imaging and endoscopic evaluation shows no evidence of disease

Patients with previous exposure to immune checkpoint inhibitor for non-muscle invasive disease are eligible. If given for NMIBC, the last dose must have been completed > 12 months prior to registration

For patients registered on the study

Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used

All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy

A patient of childbearing potential is defined as any patient, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

For patients registered prior to induction chemotherapy only:

Patients must not expect to conceive or father children by using accepted and effected method(s) of contraception or by abstaining from sexual intercourse from the time of registration for the duration of their participation in the study and continue for at least 3 months after the last dose of protocol treatment

Leukocytes >= 3,000/mcL (obtained < 14 days prior to registration)

Absolute neutrophil count (ANC) >= 1,500/mcL (obtained < 14 days prior to registration)

Hemoglobin >= 9 g/dL (obtained < 14 days prior to registration)

Platelets >= 100,000/mcL (obtained < 14 days prior to registration)

Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained < 14 days prior to registration)

Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained < 14 days prior to registration)

Must have adequate renal function as evidenced by calculated (Cockcroft's formula) creatinine clearance or 24 hours actual creatinine clearance >= 30mL/min. The creatinine used to calculate the clearance result must have been obtained within 14 days prior to registration. Actual body weight, not ideal body weight, must be used in the calculation

Patients with human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial

Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Site is encouraged to discuss with the study chair if needed prior to registration

Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class IIB or better

Step 2 (Randomization) Inclusion Criteria

Patient must have an ECOG performance status of 0-2 at the time of randomization

Patient must undergo selection of concurrent chemotherapy regimen

Patient must agree to undergo CT simulation and treatment planning. If this is the first case registered at the site, then a pre-treatment radiation therapy (RT) review will be required and will take up to 3 business days. The patient cannot start radiation treatment prior to successful completion of this pre-treatment review. Therefore, careful planning is necessary to meet the deadline of starting radiation within 20 business days of randomization and within 12 weeks of the end of induction chemotherapy

NOTE: Chemoradiotherapy should be planned to start up to 12 weeks after the end of induction chemotherapy, but after imaging and cystoscopic restaging, randomization, and any pretreatment radiation quality assurance (QA) that is required

Patients must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used

All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy

Patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse at least one week prior to the start of treatment and continue for at least 3 months after the last dose of the protocol treatment

Leukocytes >= 3,000/mcL (obtained < 14 days prior to randomization)

Absolute neutrophil count (ANC) >= 1,500/mcL (obtained < 14 days prior to randomization)

Hemoglobin >= 9 g/dL (obtained < 14 days prior to randomization)

Platelets >= 100,000/mcL (obtained < 14 days prior to randomization)

Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained < 14 days prior to randomization)

AST (SGOT)/ALT (SGPT) =< 2.5 x institutional ULN (obtained < 14 days prior to randomization)

Must have adequate renal function as evidenced by calculated (Cockcroft's formula) creatinine clearance or 24 hours actual creatinine clearance >= 30 mL/min. The creatinine used to calculate the clearance result must have been obtained within 14 days prior to randomization. Actual body weight, not ideal body weight, must be used in the calculation

Step 3 (Post chemoRT+/- Durvalumab, prior to starting adjuvant Durvalumab versus [vs.] observation) Inclusion Criteria

Patient must have evaluation to determine clinical outcome post chemoRT+/- durvalumab with imaging and cystoscopy with biopsy confirmation to ensure no progression and absence of >= T2 disease in the bladder

Patient must have achieved either complete clinical response OR have demonstrated clinical benefit prior to continuing onto adjuvant durvalumab

Patients who are to go on the adjuvant durvalumab arm must have recovered to at least grade 2 or less immune related adverse events (AE) prior to starting treatment except for immune related alopecia, clinically asymptomatic endocrinopathies. For patients who may have gotten immune related AEs during chemoRT+ durvalumab, registration could be delayed up to additional 4 weeks to ensure recovery to at least grade 2 or lower prior to starting adjuvant therapy. However patients with durvalumab related AEs that require permanent discontinuation of durvalumab will not continue on the adjuvant treatment regardless of the response

ANC >= 1,000 mcL (within 4 weeks of start of day 1 [D1] of adjuvant treatment)

Hemoglobin >= 8 g/dL (within 4 weeks of start of D1 of adjuvant treatment)

Platelets >= 70,000 mcL (within 4 weeks of start of D1 of adjuvant treatment)

Patient on the chemoRT arm must have achieved either complete clinical response OR have demonstrated clinical benefit prior to be placed on the observation alone arm

Exclusion

Step 1 (Registration) Exclusion

Patient must not have received any previous radiation therapy to the pelvic area

For patients with autoimmune conditions, patient must not have history of prior documented autoimmune disease within 2 years prior to registration

NOTE: Patient with vitiligo, Grave's disease, eczema or psoriasis (not requiring systemic treatment within 2 years prior to registration) are not excluded. Patients with history of completely resolved childhood asthma or atopy are not excluded. Patients with asthma not requiring more than 10 mg/d or equivalent of prednisone are not excluded. Patients with well-controlled hypothyroidism on thyroxine replacement will be eligible as well. Patients with known history of hypoadrenalism on maintenance steroids will be eligible. Patients with type I diabetes mellitus will be eligible, provided their disease is well controlled. History of autoimmune related alopecia is also not an exclusion criteria

Patient with active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) are not eligible

Patient with a history of and/or confirmed pneumonitis are not eligible

Patient with a history of primary immunodeficiency are not eligible

Patient with history of allogeneic organ transplant are not eligible

Patient must not have clinically significant liver disease that precludes patient from treatment regimens prescribed on the study (including, but not limited to, active viral, alcoholic or other autoimmune hepatitis, cirrhosis or inherited liver disease)

Patient must not have any unresolved toxicity (National Cancer Institute [NCI] CTCAE grade >= 2) from previous anti-cancer therapy with the exception of alopecia, vitiligo, and the laboratory values

NOTE: Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study chair

NOTE: Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the study chair. Documentation of correspondences with the study chair must be kept on file

Step 2 (Randomization) Exclusion Criteria

Patient must have no signs of progression (CR/PR or SD) based on restaging imaging and cystoscopy after completion of induction chemotherapy, which consists of:

Computed tomography (CT) chest, abdomen, or pelvis. Magnetic resonance imaging (MRI) pelvis can be used instead of CT per treating physician discretion. The imaging must be done within 6 weeks prior to randomization

Cystoscopic evaluation and attempt to perform maximal transurethral resection of bladder tumor (TURBT) performed by the participating urologist ideally within 8 weeks but up to 10 weeks is allowed prior to randomization. If maximal TURBT is not possible for medical reasons, the enrollment must be discussed and approved with the study chair. Documentation of correspondences with the study chair must be kept on file

Patients who achieve CR upon cystoscopy per urologist with no visible tumor (i.e. no need for additional TURBT), are allowed to proceed in the study as adequate resection with no residual disease in bladder

For patients with autoimmune conditions: Patient must not have a history of active or prior documented autoimmune disease within 2 years prior to registration

NOTE: Patient with vitiligo, Grave's disease, eczema or psoriasis (not requiring systemic treatment within 2 years prior to registration) are not excluded. Patients with history of completely resolved childhood asthma or atopy are not excluded. Patients with asthma not requiring more than 10mg/d or equivalent of prednisone are not excluded. Patient with well-controlled hypothyroidism on thyroxine replacement will be eligible as well. Patients with known history of hypoadrenalism on maintenance steroids will be eligible.