| Eligibility |
Inclusion Criteria:
- Patients must have histologically or cytologically documented locally advanced (T4b,
any N; or any T, N 2-3) or metastatic (M1, Stage IV; or metastatic recurrence after
locoregional treatment) urothelial carcinoma (including renal pelvis, ureters, urinary
bladder, urethra). Patients with mixed histologies are required to have a dominant
transitional cell pattern
- Patients who had disease progression during or following treatment with at least one
platinum-containing regimen (e.g., gemcitabine and cisplatin [GC], methotrexate,
vinblastine, doxorubicin and cisplatin [MVAC], carboplatin and gemcitabine
[Carbo-Gem]) and an immune checkpoint inhibitor (PD-1/ PD-L1 inhibitor including but
not limited to: atezolizumab, pembrolizumab, durvalumab, avelumab, and nivolumab)
- Received a first-line platinum-containing regimen in the metastatic setting or
for inoperable locally advanced disease
- Or received neo/adjuvant platinum-containing therapy for localized
muscle-invasive UC, with recurrence/progression =< 12 months following completion
of therapy
- Patients who received immune checkpoint inhibitor therapy in the
neoadjuvant/adjuvant setting and had recurrent or progressive disease either
during therapy or within 12 months of therapy completion are eligible. This
criterion does not apply if the checkpoint inhibitor is contraindicated
- Patients with metastatic urothelial carcinoma who are cisplatin-ineligible and
progressed on upfront immune checkpoint inhibitor; or ineligible/refused immune
checkpoint inhibitor therapy will be eligible for this trial
- Patient who received prior antibody drug conjugate such as sacituzumab govitecan are
allowed
- Patients must have measurable disease, as defined by Response Evaluation Criteria in
Solid Tumors (RECIST) version (v)1.1. Previously irradiated lesions cannot be counted
as target lesions unless there has been demonstrated progression in the lesion since
radiotherapy and no other lesions are available for selection as target lesions
- Patients must have FGFR2/3 activating alterations identified by tumor tissue or plasma
ctDNA profiling using a Clinical Laboratory Improvement Act (CLIA) certified College
of American Pathologists (CAP) accredited platform
- Age >= 18 years, for ability to comply with protocol
- Because no dosing or adverse event data are currently available on the use of
erdafitinib in combination with enfortumab vedotin in patients < 18 years of age,
children are excluded from this study
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Absolute neutrophil count >= 1,500/mcL (within 14 days prior to beginning trial
treatment)
- Platelets >= 100,000/mcL (within 14 days prior to beginning trial treatment)
- Hemoglobin >= 9 g/dL (within 14 days prior to beginning trial treatment)
- Measured or calculated creatine clearance (CrCl) >= 30 ml/min (glomerular filtration
rate [GFR] can also be used in place of creatinine CrCl) (within 14 days prior to
beginning trial treatment)
- Total bilirubin =< 1.5 x ULN (institutional upper limit of normal) OR direct bilirubin
=< ULN for subjects with total bilirubin levels > 1.5 x ULN (within 14 days prior to
beginning trial treatment)
- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) =<
2.5 x institutional ULN (=< 5 x ULN for subjects with liver metastasis) (within 14
days prior to beginning trial treatment)
- 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 treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression (CNS
metastases have been clinically stable for at least 4 weeks prior to screening and
baseline scans show no evidence of new or enlarged metastasis)
- Patients with a history of prostate cancer (T2NXMX or lower with Gleason score =< 7)
treated with definitive intent (surgically or with radiation therapy) at least 1 year
prior to study entry are eligible, provided that the subject is considered prostate
cancer-free and the following criteria are met:
- Patients who have undergone radical prostatectomy must have undetectable prostate
specific antigen (PSA) for > 1 year and at screening
- Patients who have had radiation must have a PSA doubling time > 1 year (based on
at least 3 values determined >1 month apart) and a total PSA value that does not
meet Phoenix criteria for biochemical recurrence (i.e., < 2.0 ng/mL above nadir)
- Patients with untreated low-risk prostate cancer (Gleason score =< 6) on active
surveillance with PSA doubling time >1 year (based on at least 3 values
determined > 1 month apart) are also eligible
- Patients who have undergone an ophthalmologic examination and have no active eye
disease which would be likely to increase the risk of eye toxicity
- The effects of erdafitinib and enfortumab vedotin on the developing human fetus are
unknown. For this reason and because FGFR inhibitors and humanized antibody-drug
conjugate (ADC) agents are known to be teratogenic, women of child-bearing potential
must agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry, for the duration of study participation, and 3
months after completion of erdafitinib and enfortumab vedotin administration. 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. Men
treated or enrolled on this protocol must also agree to use adequate contraception
prior to the study, for the duration of study participation, and 5 months after
completion of erdafitinib and enfortumab vedotin administration
- Ability to understand and willingness to sign a written informed consent document
Exclusion Criteria:
- Patients who have had chemotherapy, targeted therapies, immunotherapy, or treatment
with an investigational anticancer agent within 2 weeks (6 weeks for nitrosoureas or
mitomycin C) prior to entering the study
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(including ongoing sensory or motor neuropathy of grade 2 or higher) (i.e., have
residual toxicities > grade 1 or returned to baseline) with the exception of alopecia.
Subjects with =< grade 2 immunotherapy- related hypothyroidism or panhypopituitarism
may be enrolled when well-maintained/controlled on a stable dose of hormone
replacement therapy (if indicated). Subjects with ongoing >= grade 3
immunotherapy-related hypothyroidism or panhypopituitarism are excluded. Subjects with
ongoing immunotherapy related colitis, uveitis, myocarditis, or pneumonitis or
subjects with other immunotherapy related adverse events (AEs) requiring high doses of
steroids (> 20 mg/day of prednisone or equivalent) are excluded
- Patients who have previously received enfortumab vedotin or other MMAE-based ADCs
- Patients who have had prior treatment with an FGFR inhibitor
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to erdafitinib and enfortumab vedotin
- Patients receiving any medications or substances that are strong inhibitors or
inducers of CYP3A are ineligible. Because the lists of these agents are constantly
changing, it is important to regularly consult a frequently updated medical reference.
As part of the enrollment/informed consent procedures, the patient will be counseled
on the risk of interactions with other agents, and what to do if new medications need
to be prescribed or if the patient is considering a new over-the-counter medicine or
herbal product
- Patients with a history of any corneal or retinal abnormality likely to increase the
risk of eye toxicity
- Patients with uncontrolled intercurrent illness and currently receiving systemic
antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time
of starting treatment. Routine antimicrobial prophylaxis is permitted
- Patients with psychiatric illness/social situations that would limit compliance with
study requirements
- Subjects who have received radiotherapy within 2 weeks prior to start of treatment.
Subject must have recovered adequately from the toxicity from the intervention prior
to starting study treatment
- Patients with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin
A1c (HbA1c) >= 8% or HbA1c 7% to < 8% with associated diabetes symptoms (polyuria or
polydipsia) that are not otherwise explained
- Subjects who have received major surgery within 4 weeks prior to start of treatment.
Subject must have recovered adequately from complications from the intervention prior
to starting study treatment
- Subjects who have received a prior allogeneic stem cell or solid organ transplant
- Has persistent phosphate level > ULN during screening (within 14 days of treatment and
prior to cycle 1 day 1) and despite medical management
- Has a history of or current uncontrolled cardiovascular disease including:
- Unstable angina, myocardial infarction, or known congestive heart failure class
II-IV within the preceding 12 months; cerebrovascular accident or transient
ischemic attack within the preceding 3 months
- Any of the following: sustained ventricular tachycardia, ventricular
fibrillation, Torsades de Pointes, cardiac arrest, Mobitz II second degree heart
block or third degree heart block; known presence of dilated, hypertrophic, or
restrictive cardiomyopathy
- QTc prolongation as confirmed by triplicate assessment at screening
(Fridericia;QTc > 480 milliseconds)
- Subjects with a history of another invasive malignancy within 3 years before the first
dose of study drug, or any evidence of residual disease from a previously diagnosed
malignancy. Subjects with nonmelanoma skin cancer or carcinoma in situ of any type (if
complete resection was performed) are allowed
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