ctDNA-guided Enfortumab Vedotin plus Pembrolizumab in Untreated Patients with Advanced Urothelial Carcinoma. The FUTURE Study

Prior treatment

• Pregnancy or breast-feeding. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before the start of EV+pembro treatment, and a negative result must be documented before start of treatment
• Known active or untreated brain metastases. Patients with previously treated brain metastases may be considered only if clinically stable and allowed according to local standard of care and investigator judgment.
• Ongoing unresolved toxicities from previous anti-cancer therapy defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 6.0 grade ≤ 1 or baseline
• Major contraindications to EV+pembro, including but not limited to: - uncontrolled diabetes - ongoing sensory or motor neuropathy Grade 2 or higher - active keratitis or corneal ulcerations - prior treatment with a PD-(L)-1 inhibitor for any malignancy, including earlier stage UC - prior therapy with EV

Other illness

• Any kind of active infection requiring IV systemic therapy
• Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or known history of active Hepatitis B virus (HBV) or Hepatitis C virus (HCV)
• Conditions requiring high doses of steroids (>10 mg/day of prednisone or equivalent) or other immunosuppressive medications are excluded. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for subjects with adrenal insufficiency
• History of autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
• 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

Lab values

• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications

Other

• Subjects with no detectable plasma ctDNA (defined as the presence of driver molecular alterations detected by informed tissue based NGS analysis, longitudinally tracked leveraging dPCR system)
• Subjects with an estimated life expectancy <6 months
• Subjects not willing or unable to sign a consent form.

• Male and Female patients ≥18 years old
• Eastern Cooperative Oncology Group performance status of 0- 2
• Women of childbearing potential and men must agree to use adequate contraception since signing of the informed consent form until at least 6 months (180 days) after the last study drug administration. The investigator or a designated associate is requested to advise the subject how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommend method (or combination of methods) as per standard of care
• Adequate hematologic reserve: Platelet count ≥ 100.000/ul, WBC ≥ 4000/ul. Anemia will be corrected to minimum hemoglobin of 9 g/dL with red cell transfusions, if necessary.
• Adequate liver function with a bilirubin ≤ 1.5 ULN (≤3× ULN for subjects with Gilbert’s disease) and SGOT/SGPT ≤2.5 × ULN (≤5 × ULN for subjects with liver metastases).
• Adequate renal function with creatinine ≤1.5× ULN OR calculated creatinine clearance (CrCl) ≥30 mL/min for participant with creatinine levels >1.5× institutional ULN
• Informed consent obtained before any study-specific procedures. Patients must be able to understand and be willing to sign a written informed consent
• Histologically documented urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Subjects with squamous or sarcomatoid differentiation or mixed cell types are eligible.
• Advanced/metastatic disease stage with measurable disease according to Response Evaluation Criteria in Solid Tumors criteria version 1.1
• No prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions: a. Subjects that received neoadjuvant chemotherapy with recurrence >12 months from completion of therapy are permitted b. Subjects that received adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy are permitted
• Patients considered by the investigator eligible to receive firstline therapy with EV+pembro according to standard of care
• Archival tumor tissue comprising muscle-invasive urothelial carcinoma or a biopsy of metastatic urothelial carcinoma must be provided together with collection of blood samples for the detection of the presence of ctDNA
• Detectable plasma ctDNA (defined as the presence of driver molecular alterations detected by informed tissue based NGS analysis, longitudinally tracked leveraging dPCR system)
• Life expectancy greater than 6 months