De-escalated Pembrolizumab Monotherapy after Pembrolizumab Plus Enfortumab Vedotin for the Treatment of Unresectable, Locally Advanced, or Metastatic Urothelial Cancer in Patients with Circulating Tumor Deoxyribonucleic Acid Response, CT-READ Trial

Status: active

This phase II trial studies how well lowering treatment (de-escalated) to pembrolizumab therapy alone (monotherapy) in patients with a circulating tumor deoxyribonucleic acid (ctDNA) response to pembrolizumab plus enfortumab vedotin (PEV) works in treating urothelial cancer that cannot be removed by surgery (unresectable), that has spread to nearby tissue or lymph nodes (locally advanced), or that has spread from where it first started (primary site) to other places in the body (metastatic). PEV is a front line (1L) treatment for locally advanced or metastatic urothelial cancer that has been proven to improve survival; however, enfortumab vedotin (EV) can sometimes cause serious reactions. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. EV is a monoclonal antibody, enfortumab, linked to an anticancer drug called vedotin. It works by helping the immune system to slow or stop the growth of tumor cells. Enfortumab attaches to a protein called nectin-4 on tumor cells in a targeted way and delivers vedotin to kill them. It is a type of antibody-drug conjugate. ctDNA is a type of blood test that looks for fragments of cancer DNA in the bloodstream. Research has shown that changes in ctDNA levels can help predict how well a patient is responding to treatment. When ctDNA levels go down, it often means the treatment is working. Researchers hope that monitoring ctDNA response will help them identify which patients respond to PEV and can de-escalate to pembrolizumab monotherapy, which may be a safer, more tolerable, and/or more effective way to treat unresectable, locally advanced, or metastatic urothelial cancer.

Inclusion Criteria

Have histologically documented unresectable, locally advanced, or metastatic urothelial carcinoma
Measurable disease according to the New Response Evaluation Criteria in Solid Tumors (RECIST version [v] 1.1) * Participants with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy
Must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator's judgment
Archival tumor tissue comprising muscle-invasive urothelial carcinoma, or a biopsy of metastatic urothelial carcinoma must be available for tumor-informed ctDNA analysis
Meets Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2
Hemoglobin (Hb) ≥ 8.0 g/dL
Absolute neutrophil count (ANC) ≥ 1.5x10^9 cells/L
Creatinine clearance (CrCl) ~30 mL/min
Total bilirubin ≤ 1.5 mg/dL
Alanine aminotransferase (ALT) within normal limits
Aspartate aminotransferase (AST) within normal limits

Exclusion Criteria

Previously received enfortumab, vedotin, or other monomethyl auristatin E (MMAE)- based antibody-drug conjugates (ADCs)
Received prior treatment with a programmed cell death ligand-1 (PD-[L]-1) inhibitor for any malignancy, including earlier stage urothelial carcinoma (UC), defined as a PD-1 inhibitor or PD-L1 inhibitor within 12 months
Has received anti-cancer treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1-3 that is not completed within 28 days prior to cycle 1 day 1
Has uncontrolled diabetes or ≥ grade III peripheral neuropathy
Patient’s estimated life expectancy is less than 12 weeks
Has untreated central nervous system metastases
Experiences ongoing clinically significant toxicity associated with prior treatment that has not resolved to ≤ grade 1 or returned to baseline
Is currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal). Routine antimicrobial prophylaxis is permitted
Has known active hepatitis B, active hepatitis C, or human immunodeficiency virus (HIV) infection
Has history of another invasive malignancy requiring treatment within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy (excluding localized prostate cancer or basal cell carcinoma of skin or squamous cell carcinoma of the skin)
Has documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class IV within 6 months
Received radiotherapy within 2 weeks
Received major surgery (defined as requiring general anesthesia and >24-hour inpatient hospitalization) within 2 weeks
Known severe (≥ grade 3) hypersensitivity to any EV excipient contained in the drug formulation of EV
Has active keratitis or corneal ulcerations
Has a history of autoimmune disease that has required systemic immunosupressive treatment in the past 2 years, or uncontrolled autoimmune disease
Participants must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions: * Participants that received neoadjuvant chemotherapy with recurrence > 12 months from completion of therapy are permitted * Participants that received adjuvant chemotherapy or ICPIs therapy following cystectomy with recurrence > 12 months from completion of therapy are permitted
Has a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
Has received prior allogeneic stem cell or solid organ transplant
Received a live attenuated vaccine within 30 days

PRIMARY OBJECTIVE:

I. To evaluate the durability of responses on pembrolizumab monotherapy, after 24 weeks of 1L PEV in metastatic urothelial cancer (mUC).

SECONDARY OBJECTIVE:

I. To examine the incidence of treatment-related adverse events (TRAEs) and changes in quality of life (QoL) following de-escalation to pembrolizumab monotherapy subsequent to 24 weeks of 1L PEV in mUC.

TRANSLATIONAL OBJECTIVE:

I. To examine the role of changes in levels and mutational profiles of ctDNA in monitoring treatment responses and uncovering resistance mechanisms to 1L PEV in patients with mUC.

EXPLORATORY OBJECTIVE:

I. To assess the objective response rate to EV re-introduction in patients with radiographic progression on pembrolizumab monotherapy.

OUTLINE: This is a dose-de-escalation study of pembrolizumab monotherapy following 1L PEV.

1L PEV: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and enfortumab vedotin IV over 30 minutes on days 1 and 8 of each cycle. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo blood sample collection, ctDNA testing, and computed tomography (CT) and/or other radiological imaging. Patients with ≥ 50% ctDNA decrease and stable disease (SD), complete response (CR), or partial response (PR) on imaging proceed to de-escalated pembrolizumab monotherapy. Patients with < 50% ctDNA decrease and SD, CR, or PR on imaging continue with PEV treatment with ctDNA and radiographic monitoring.

DE-ESCALATED PEMBROLIZUMAB MONOTHERAPY: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients who experience radiographic progression on pembrolizumab monotherapy undergo rechallenge with PEV.

Additionally, patients undergo blood sample collection, ctDNA testing, and CT and/or other radiological imaging throughout the study. Patients also undergo archival tissue sample collection during screening.

After completion of study treatment, patients are followed up at 6 weeks and then for up to 2 years from enrollment or until progression, whichever occurs first.

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De-escalated Pembrolizumab Monotherapy after Pembrolizumab Plus Enfortumab Vedotin for the Treatment of Unresectable, Locally Advanced, or Metastatic Urothelial Cancer in Patients with Circulating Tumor Deoxyribonucleic Acid Response, CT-READ Trial

Inclusion Criteria

Exclusion Criteria

United States

Oklahoma

Oklahoma City

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De-escalated Pembrolizumab Monotherapy after Pembrolizumab Plus Enfortumab Vedotin for the Treatment of Unresectable, Locally Advanced, or Metastatic Urothelial Cancer in Patients with Circulating Tumor Deoxyribonucleic Acid Response, CT-READ Trial

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