Enfortumab Vedotin Schedule De-escalation in Metastatic Urothelial Carcinoma

Exclusion Criteria

• •Both EV monotherapy and EV/pembrolizumab arms:
• •Patients who have received prior monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs) for urothelial cancer.
• •Grade 2 or higher baseline sensory or motor neuropathy.
• •Uncontrolled diabetes (HbA1c \>8%)
• •Patients with uncontrolled and untreated central nervous system (CNS) metastases.
• •* Prior radiation to CNS metastases is permitted.
• •* Prior history of CNS disease that has responded to previous systemic therapy is permitted only if no recurrence.
• •* Patient should not have leptomeningeal disease
• •* CNS metastases have been clinically stable for at least 6 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis.
• •* If requiring steroid treatment for CNS metastases, the patient is on stable dose \< 20 mg/day of prednisone or equivalent for at least 2 weeks prior to starting treatment
• •Uncontrolled intercurrent illness including, but not limited to ongoing or active untreated infection, symptomatic congestive heart failure, unstable angina pectoris, symptomatic uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• •Subjects with a history of another invasive malignancy within 3 years before the first dose of study drug that cannot be watched and requires treatment, or any evidence of residual disease from a previously diagnosed malignancy that cannot be watched and requires treatment. Adjuvant hormonal therapy for breast cancer is allowed.
• •Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of first dose of enfortumab vedotin. Routine antimicrobial prophylaxis is permitted.
• •Known HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with enfortumab vedotin.
• •History of idiopathic pulmonary fibrosis; organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
• •Prior allogeneic stem cell or solid organ transplant.
• •Other underlying medical condition that, in the opinion of the investigator, would impair the ability of the patient to receive or tolerate the planned treatment and follow-up; any known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study.
• •Patients with active tuberculosis.
• •Pregnant or breast feeding
• •EV/Pembrolizumab exploratory arm only:
• •Patients who received prior immunotherapy for metastatic urothelial carcinoma (mUC) or for an alternative malignancy are eligible unless they developed an immune related adverse event while on therapy requiring cessation of therapy or use of disease modifying agents, corticosteroids, or immunosuppressive drugs.
• •History of autoimmune diseases. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
• •* Patients with vitiligo or residual autoimmune hypothyroidism on stable doses of hormone replacement are permitted to enroll.
• •* Patients with type 1 diabetes mellitus (T1DM) on a stable dose of insulin are permitted to enroll.
• •* Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• •On high dose steroids at the time of study enrollment, defined as \>20mg prednisone (or bioequivalent), including steroids used for management of intracranial lesions. Inhaled or topical steroids are permitted in the absence of active autoimmune disease.