Bladder Carcinoma, Bladder Urothelial Carcinoma, Muscle Invasive Bladder Carcinoma, Renal Pelvis and Ureter Urothelial Carcinoma, Stage II Bladder Cancer AJCC v8, Stage III Bladder Cancer AJCC v8, Stage IVA Bladder Cancer AJCC v8, Urothelial Carcinoma
Conditions
Brief summary
This phase II trial compares the effect of erdafitinib alone to using the combination of erdafitinib and atezolizumab in treating patients with bladder cancer whose tumor invades the muscular bladder wall (muscle invasive)and who are ineligible for treatment with a chemotherapy drug called cisplatin. This trial also determines whether these treatment approaches are better than the usual approach for treating this type of cancer. The usual approach for treatment of someone with muscle invasive bladder cancer is chemotherapy with a drug called cisplatin followed by surgery (most common), or chemoradiation (radiation combined with chemotherapy) to the bladder (in some patients). However, half of the patients cannot get cisplatin due to safety concerns. This study has a screening step. The purpose of this step is to test patient's tumor to find out if it has a specific change (alteration) in the fibroblast growth factor receptor (FGFR) gene to determine patient's eligibility for this trial. Alteration of the FGFR gene causes bladder cancer cells to grow and divide abnormally. Erdafitinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal FGFR protein. This may help keep cancer cells from growing and may kill them. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving erdafitinib alone or in combination with atezolizumab may help to shrink tumor cells at the time of surgery better than the usual treatment in muscle invasive bladder cancer.
Detailed description
PRIMARY OBJECTIVE: I. To evaluate pathologic complete response (pCR) rates at radical cystectomy (RC) following neoadjuvant erdafitinib with or without atezolizumab in cisplatin-ineligible patients with muscle-invasive bladder cancer (MIBC) and susceptible FGFR3/2. SECONDARY OBJECTIVES: I. To determine the rate of pathologic downstaging (=\< pT1N0M0) among patients who receive RC. II. To determine the clinical complete response (cCR) rate in patients who do not undergo planned RC. III. To determine pCR + cCR. IV. To evaluate 2-year disease-free survival (DFS). V. To evaluate the overall survival (OS) rate at 2 years. VI. To evaluate the safety and tolerability of study treatment as well as surgical complications in the RC group. EXPLORATORY OBJECTIVES: I. To correlate the reduction of plasma circulating tumor deoxyribonucleic acid (DNA) (ctDNA) during study treatment and the surveillance period with disease outcomes (pCR and cCR, pathologic downstaging, 2-year DFS and OS). II. To correlate tumor response with baseline tissue, ctDNA FGFR3/2 mutation status, and molecular signature. III. To characterize the baseline tumor tissue immune profile of FGFR3/2-aberrant tumors including programmed death-ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and T cell infiltration (PD-L1 expression, peripheral blood mononuclear cell (PBMC), T cell receptor \[TCR\] repertoire). IV. To characterize the changes in the above tumor tissue immune profile following study treatment. V. To correlate baseline tumor tissue TMB with disease outcomes (pCR and cCR, pathologic downstaging, 2-year DFS and OS). OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive erdafitinib orally (PO). Patients undergo collection of blood and computed tomography (CT)/magnetic resonance imaging (MRI) at various time points throughout the trial and colposcopy at baseline. ARM II: Patients receive erdafitinib PO and atezolizumab intravenously (IV). Patients undergo collection of blood and CT/MRI at various time points throughout the trial and colposcopy at baseline.
Interventions
BIOLOGICALAtezolizumab
Given IV
PROCEDUREBiospecimen Collection
Undergo collection of blood
PROCEDUREComputed Tomography
Undergo CT
PROCEDURECystoscopy
Undergo cystoscopy
DRUGErdafitinib
Given PO
PROCEDUREMagnetic Resonance Imaging
Undergo MRI
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have muscle-invasive disease, tumor stage T2-T4, N0-1, based on transurethral resection of bladder tumor (TURBT) performed within 8 weeks prior to enrollment * Clinical stage T2-T4, N0 or N1, M0 by CT chest abdomen pelvis (or CT chest and MRI abdomen pelvis). Ultrasound, fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET), and plain x-rays are not acceptable methods of evaluating clinical staging in the absence of CT or MRI scans * Histologically-confirmed urothelial carcinoma. Urothelial carcinoma with variant differentiation is allowed regardless of percentage. Other variant histology is allowed if urothelial carcinoma is the predominant histology (\>= 50%), except neuroendocrine (any neuroendocrine carcinoma would be an
Exclusion criteria
) * Patients must be eligible and planned for curative-intent RC, as determined by a urologic oncologist * Patients who are ineligible for or decline cisplatin-based chemotherapy. * Cisplatin-ineligibility defined as \>= 1 of the following criteria (modified from the Galsky criteria): Eastern Cooperative Oncology Group (ECOG) performance status (PS) of \>= 2, either estimated or measured creatinine clearance (CrCl) or glomerular filtrate rate (GFR) \< 60 mL/min, Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5 grade \>= 2 audiometric hearing loss or grade \>= 2 peripheral neuropathy * For cisplatin-eligible patients who decline cisplatin-based neoadjuvant chemotherapy (NAC), the subject's refusal for cisplatin must be clearly documented. Subjects must be informed that cisplatin-based NAC can improve cure rates, and it is unknown whether FGFR3/2 aberrant MIBC have better cure rates with neoadjuvant erdafitinib than cisplatin-based NAC * Patients with susceptible FGFR3/2 alterations, based on tumor tissue testing, or blood ctDNA testing, performed by the local institution. (Given presence of intratumoral heterogeneity in FGFR3 status, a sample of the deeper part of the invasive tumor is preferred for tissue FGFR screening using baseline TURBT sample) * FGFR3 gene mutations (R248C, S249C, G370C, Y373C) or FGFR gene fusions (FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7), as defined by the current Food and Drug Administration (FDA) indication for erdafitinib, determined by a laboratory certified by Clinical Laboratory improvement Amendments (CLIA). The principal investigator (PI) will review all clinical testing report to confirm eligibility * The FGFR screening assay is chosen by the local investigators depending on what is available (FoundationOne CDx, TSO500, Therascreen or others). If local FGFR screening capabilities are not available, study team may be able to provide funding support * FGFR status will be confirmed centrally and retrospectively using whole exome sequencing (WES) and ribonucleic acid (RNA) sequencing at the National Clinical Laboratory Network (NCLN) genomics lab, however patients can proceed with randomization and study treatment prior to confirmation testing results being made available * Patients with the following prior therapies are allowed: * PD-1/PD-1 immune checkpoint inhibitors (ICIs) for non-muscle invasive bladder cancer (NMIBC) is allowed if last dose was given \>1 year prior to randomization * Hormone-replacement therapy or oral contraceptives * Herbal therapy \>1 week prior to cycle 1, day 1 (herbal therapy intended as anti-cancer therapy must be discontinued at least 1 week prior to cycle 1, day 1) * Age \>= 18 years; because no dosing or adverse event data are currently available on the use of erdafitinib in combination with atezolizumab in patients \< 18 years of age, children are excluded from this study * ECOG performance status =\< 2 (Karnofsky \>= 60%) * Absolute neutrophil count \>= 1,500/mcL (without granulocyte colony stimulating factor support) (within 14 days of study registration) * Platelets \>= 100,000/mcL (within 14 days of study registration) * Hemoglobin \>= 9 g/dL (stable for 2 weeks without transfusion or erythropoiesis-stimulating agent) (within 14 days of study registration) * Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level \>= 3 x ULN may be enrolled) (within 14 days of study registration) * Aspartate aminotransferase (AST) (serum aspartate aminotransferase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 2.5 x institutional ULN or =\< 5 x ULN for patients with liver metastases (within 14 days of study registration) * Alkaline phosphatase =\< 2.5 x ULN (=\< 5 x ULN for patients with documented liver or bone metastases) (within 14 days of study registration) * Serum creatinine =\< 1.5 x institutional ULN (within 14 days of study registration) OR creatinine clearance \>= 30 mL/min by Cockcroft-Gault (within 14 days of study registration) * Glomerular filtration rate (GFR) \>= 30 mL/min/1.73 m\^2 given this is a cisplatin-ineligible patient population (within 14 days of study registration) * International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =\< 1.5 x ULN (This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation, such as low-weight heparin or warfarin, should be on a stable dose.) (within 14 days of study registration) * Serum albumin \>= 2.5 g/dL (within 14 days of study registration) * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load * 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 * Patients should be New York Heart Association Functional Classification of class II or better * Patients should be greater than 4 weeks from receiving a live attenuated vaccine. Please note that non-live vaccines for seasonal influenza and vaccines intended to prevent SARS-CoV-2 and coronavirus disease 2019 (COVID-19) are allowed * Patients with nonmetastatic concomitant upper tract urothelial carcinoma (in addition to MIBC with susceptible FGFR alterations) are eligible for this trial * The effects of erdafitinib and atezolizumab on the developing human fetus are unknown. For this reason and because FGFR inhibitors and monoclonal antibodies are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, 1 month after completion of erdafitinib single agent, and 5 months after erdafitinib and atezolizumab combination. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately * Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity who have a legally-authorized representative (LAR) and/or family member available will also be eligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological complete response (pCR) | Up to 2 years | Will be compared between the two arms using one-sided Z test with unpooled variance. Proportions with 95% confidence intervals will be provided for the two treatment arms. To avoid potential bias, the primary analysis will include all randomized, eligible patients even if they do not receive treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical complete response (cCR) rate among patients who do not undergo RC | At week 10 | cCR is defined as no residual disease beyond low grade Ta disease on cystoscopy and tumor bed bladder biopsy (week 10), computed tomography (CT) chest abdomen pelvis post study treatment. Response will be presented using summary statistics. Response may be assessed by investigators and by an Independent Radiologic Review Committee. |
| Pathologic complete response (pCR) + clinical complete response (cCR) rate | At week 10 | Response will be presented using summary statistics. Response may be assessed by investigators and by an Independent Radiologic Review Committee. |
| Disease-free survival (DFS) | Time until death due to bladder cancer, assessed up to 2 years | DFS events include local recurrence, distant recurrence, and bladder cancer-related death. Will be presented with 95% confidence intervals for estimated medians. Kaplan-Meier method will be conducted. |
| Overall survival (OS) rate | Time from treatment start date until death, assessed at 2 years | Will be presented with 95% confidence intervals for estimated medians. Kaplan-Meier method will be conducted. |
| Incidence of adverse events | After the first dose of study drug, through the Treatment Phase, and for 30 days following the last dose of study drug, assessed up to 2 years | The incidence of adverse events will be tabulated and reviewed and graded according the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Will be presented using summary statistics. |
| Rate of pathologic downstaging (=< pT1N0M0) among all patients who receive radical cystoscopy (RC) | Time until death due to bladder, assessed up to 2 years | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Clinical staging (cT2N0 vs. cT3/T4 or N) | Up to 2 years | Fisher exact test and Wilcoxon rank sum test will be conducted for correlation. |
| Histology (pure urothelial vs. presence of nonurothelial variant histology) | Up to 2 years | Fisher exact test and Wilcoxon rank sum test will be conducted for correlation. |
| FGFR signature | Up to 2 years | Fisher exact test and Wilcoxon rank sum test will be conducted for correlation. |
| FGFR 3/2 alteration type (mutation versus [vs.] fusion) | Up to 2 years | Fisher exact test and Wilcoxon rank sum test will be conducted for correlation. |
Outcome results
None listed