Gemcitabine plus carboplatin after progression on enfortumab vedotin and pembrolizumab for advanced urothelial cancer

Phase II Study of Second-line Gemcitabine Plus Carboplatin After Progression on Enfortumab Vedotin With Pembrolizumab in Advanced or Metastatic Urothelial Carcinoma

This trial tests whether the chemotherapy combination gemcitabine and carboplatin can shrink or control advanced urothelial cancer in people whose cancer got worse after enfortumab vedotin plus pembrolizumab.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 55 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Fox Chase Cancer Center (Academic / other)
• Drugs / interventions: enfortumab, pembrolizumab, chemotherapy, radiation
• Locations: 2 sites (Philadelphia, Pennsylvania and 1 other locations)
• Trial ID: NCT07043972 on ClinicalTrials.gov

What this trial studies

This is an open-label, single-arm phase 2 trial using a two-stage design to measure response to gemcitabine plus carboplatin in adults with locally advanced or metastatic urothelial carcinoma previously treated with enfortumab vedotin and pembrolizumab. Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin AUC 5 on day 1 of a 21-day cycle until progression or unacceptable toxicity. Tumor response is assessed by RECIST v1.1 every 9 weeks, and the study includes interim futility analysis after 19 treated patients. Safety, survival, quality of life, and blood-based biomarkers including circulating tumor DNA will also be collected.

Who should consider this trial

Good fit: Adults with histologically confirmed locally advanced or metastatic urothelial carcinoma who have measurable disease and who previously received enfortumab vedotin plus pembrolizumab, with ECOG performance status 0-2 and adequate organ and marrow function, are eligible.

Not a fit: Patients who cannot tolerate platinum-based chemotherapy, have poor organ function or ECOG >2, or have non-urothelial histology are unlikely to benefit from this regimen.

Why it matters

Potential benefit: If effective, this regimen could offer a practical chemotherapy option to control disease and potentially extend survival for patients who progress after enfortumab vedotin plus pembrolizumab.

How similar studies have performed: Platinum-based combinations like gemcitabine plus carboplatin have shown activity in urothelial cancer historically, but their effectiveness specifically after prior enfortumab vedotin plus pembrolizumab has not been well established.

Eligibility criteria

Inclusion Criteria:

* Patients must have metastatic or locally advanced histologically and radiographically confirmed urothelial carcinoma
* Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with RECIST criteria v1.1
* Patients must have received treatment with enfortumab vedotin plus pembrolizumab in the first line setting. Study treatment may be started within 28 days of last treatment with EV-P or with continuing toxicities if considered by the Sponsor-Investigator to be safe and within the best interest of the patient.
* Age \> 18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Patients must have normal organ and marrow function as defined below.

  * Absolute neutrophil count \> 1,000/mm3 unless patient has constitutional neutropenia
  * Platelets \> 80,000/ul
  * Hemoglobin \> 8.0 g/dL
  * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<2.5 x ULN or \<3.5 x upper limit of normal (ULN) if liver metastases
  * Creatinine Clearance \>20 mL/min
* Ability to understand and willingness to sign a written informed consent and HIPAA consent document
* Optional: Archival tumor biospecimen, when available, must be procured for correlative evaluation. If tumor tissue is not available or accessible despite good faith efforts, patient may still be treated on study. Formalin fixed paraffin embedded (FFPE) tissue block(s) or at least 15 unbaked, unstained slides are required. Tissue samples taken from a metastatic lesion prior to the start of screening are acceptable.

Exclusion Criteria:

* Patients who have had systemic treatment including EV-P or radiotherapy within 2 weeks prior to entering the study
* Patients who have had systemic treatment including EV-P or radiotherapy within 2 weeks prior to entering the study
* Patients who have received more than one line of prior therapy or prior platinum-based chemotherapy for locally advanced or metastatic urothelial carcinoma (neoadjuvant platinum-based therapy including cisplatin is allowed)
* Patients who have not recovered from adverse events to less than Grade 2 secondary to agents administered more than 2 weeks prior to treatment initiation.
* Patients may not be receiving any other investigational agents
* Patients with uncontrolled and untreated CNS metastases:

  * Prior radiation to central nervous system (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 metastases
* 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 adherence 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 tumor- directed 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 chemotherapy (routine antimicrobial prophylaxis is permitted)
* Pregnant or breast feeding.

Where this trial is running

Philadelphia, Pennsylvania and 1 other locations

• Fox Chase Cancer Center — Philadelphia, Pennsylvania, United States (Recruiting)
• Temple University Hospital at Broad Street — Philadelphia, Pennsylvania, United States (Recruiting)

Study contacts

• Principal investigator: Daniel Geynisman, MD — Fox Chase Cancer Center
• Study coordinator: Daniel Geynisman, MD

Conditions Urothelial Carcinoma; phase II; locally advanced urothelial cancer; gemcitabine plus carboplatin; enfortumab vedotin plus pembrolizumab; metastatic urothelial cancer