Schedule De-Escalation of Enfortumab Vedotin Alone or With Pembrolizumab for the Treatment of Locally Advanced or Metastatic Urothelial Cancer

Status: active

This phase II trial tests a de-escalation schedule of enfortumab vedotin (EV) alone or in combination with pembrolizumab in treating patients with urothelial cancer that has spread to nearby tissue or lymph nodes (locally advanced) or has spread from where it first started (primary site) to other places in the body (metastatic). Enfortumab vedotin 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. 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 has a high risk of side effects. Almost half of patients develop severe or life-threatening significant side effects related to EV. Some of the common side effects with EV are peripheral neuropathy (numbness and tingling in toes and fingers), rashes, itching, fatigue and diarrhea. On clinical trials using EV, about one-half of the patients needed to hold the medication and about one-third needed to reduce the dose of the medication. This trial starts by treating patients with EV at the standard schedule initially and then slowly reducing the frequency of administering EV with the goal of minimizing side effects to remain on treatment for a longer period of time and maintain good cancer control. The alternative dosing schedule of EV alone or in combination with pembrolizumab may improve treatment tolerance and outcomes in patients with locally advanced or metastatic urothelial cancer.

Inclusion Criteria

EV MONOTHERAPY COHORT: Patients must have histologically and radiographically confirmed locally advanced or metastatic urothelial carcinoma
EV MONOTHERAPY COHORT: Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) criteria version (v)1.1
EV MONOTHERAPY COHORT: Planned to receive EV as standard treatment for advanced urothelial cancer
EV MONOTHERAPY COHORT: Eastern Cooperative Oncology Group (ECOG) performance status 0-2
EV MONOTHERAPY COHORT: Prior systemic therapy must have completed at least 14 days prior to initiating therapy
EV MONOTHERAPY COHORT: Age >= 18 years
EV MONOTHERAPY COHORT: Ability to understand and willingness to sign a written informed consent and Health Insurance Portability and Accountability Act (HIPAA) consent document
EV MONOTHERAPY COHORT: 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
EV MONOTHERAPY COHORT: Absolute neutrophil count >= 1,000/mm^3 unless patient has constitutional neutropenia
EV MONOTHERAPY COHORT: Platelets >= 100,000/ul
EV MONOTHERAPY COHORT: Hemoglobin >= 8.0 g/dL
EV MONOTHERAPY COHORT: Alanine transaminase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN) or =< 3.5 x ULN if liver metastases
EV MONOTHERAPY COHORT: Creatinine clearance >= 20 mL/min
EV/PEMBROLIZUMAB ARM: Patients must have histologically and radiographically confirmed locally advanced or metastatic urothelial carcinoma
EV/PEMBROLIZUMAB ARM: 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
EV/PEMBROLIZUMAB ARM: Planned to receive EV/pembrolizumab as standard treatment for advanced urothelial cancer
EV/PEMBROLIZUMAB ARM: ECOG performance status 0-2
EV/PEMBROLIZUMAB ARM: Prior systemic therapy must have completed at least 14 days prior to initiating therapy
EV/PEMBROLIZUMAB ARM: Age >= 18 years
EV/PEMBROLIZUMAB ARM: Ability to understand and willingness to sign a written informed consent and HIPAA consent document
EV/PEMBROLIZUMAB ARM: 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
EV/PEMBROLIZUMAB ARM: Absolute neutrophil count >= 1,000/mm^3 unless patient has constitutional neutropenia
EV/PEMBROLIZUMAB ARM: Platelets >= 100,000/ul
EV/PEMBROLIZUMAB ARM: Hemoglobin >= 8.0 g/dL
EV/PEMBROLIZUMAB ARM: ALT and AST =< 2.5 x ULN or =< 3.5 x ULN if liver metastases
EV/PEMBROLIZUMAB ARM: Creatinine clearance >= 20 ml/min

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 (hemoglobin A1C [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 < 10 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 human immunodeficiency virus (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 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 argents, corticosteroids, or immunosuppressive drugs
History of autoimmune diseases. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., 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 (e.g., 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 > 10mg prednisone (or bioequivalent), including steroids used for management of intracranial lesions. Inhaled or topical steroids are permitted in the absence of active autoimmune disease

Additional locations may be listed on ClinicalTrials.gov for NCT05923190.

United States

Pennsylvania

East Norriton

Fox Chase Cancer Center - East Norriton Hospital Outpatient Center

Status: Active

Contact: Pooja Ghatalia

Phone: 215-728-6900

Email: pooja.ghatalia@fccc.edu

Philadelphia

Fox Chase Cancer Center

Status: Active

Contact: Pooja Ghatalia

Phone: 215-728-3889

Email: Pooja.Ghatalia@tuhs.temple.edu

PRIMARY OBJECTIVE:

I. To evaluate 18-month progression free survival (PFS18) of patients in EV/pembrolizumab cohort (main cohort).

SECONDARY OBJECTIVES:

I. To assess overall survival (OS) in patients undergoing EV schedule de-escalation in the EV/pembrolizumab cohort (main cohort).

II. To assess time to next treatment in patients undergoing EV schedule de-escalation in the EV/pembrolizumab cohort (main cohort).

EXPLORATORY OBJECTIVES:

I. To demonstrate if the duration of clinical benefit (DoCB) can be maintained in patients undergoing EV schedule de-escalation in the EV monotherapy and EV/pembrolizumab cohort (main and exploratory cohort).

II. To assess progression-free survival (PFS) in all patients receiving EV monotherapy (exploratory cohort).

III. To assess overall survival (OS) in patients undergoing EV schedule de-escalation in the EV monotherapy cohort (exploratory cohort).

IV. To assess time to next treatment in patients undergoing EV schedule de-escalation in the EV monotherapy cohort (exploratory cohort).

V. Overall response rate to therapy when re-escalated to original schedule in patients who progress on the de-escalated schedule (main and exploratory cohort).

VI. Dose exposure-response and exposure-toxicity relationships to EV (main and exploratory cohort).

VII. Quality of life (QoL) with EV schedule de-escalation (main and exploratory cohort).

VIII. Safety and tolerability with EV schedule de-escalation (main and exploratory cohort).

IX. Correlation between circulating tumor deoxyribonucleic acid (DNA) (ctDNA) levels and treatment response (main and exploratory cohort).

X. Nectin-4 levels in tumor and their correlation with treatment response (main and exploratory cohort).

OUTLINE: This is a schedule de-escalation study of EV. Patients are assigned to 1 of 2 arms.

ARM I: Patients receive EV intravenously (IV) over 30-minutes on days 1, 8, and 15 of each cycle. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients experiencing disease control (complete response/partial response/stable disease) at 12 weeks receive EV IV on days 1 and 15 of each cycle. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients experiencing disease control at 24 weeks receive EV IV on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection on study and during follow-up. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial. Additionally, patients may undergo biopsy at disease progression.

ARM II: Patients receive EV IV over 30-minutes on days 1 and 8 and pembrolizumab IV over 30 minutes on day 1 of each cycle for 3 cycles. Patients experiencing disease control at 9 weeks receive EV IV on days 1 and 8 and pembrolizumab IV on day 1 of each cycle for 3 additional cycles. Patients experiencing disease control at 18 weeks receive EV IV and pembrolizumab IV on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. After 6 cycles of EV/pembrolizumab, patients experiencing a complete response or partial response at 18 weeks are encouraged to discontinue EV, and at physician discretion may receive pembrolizumab IV on day 1 of each cycle. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. After being on treatment for 2 years, pembrolizumab may be discontinued. Patients undergo blood sample collection on study and during follow-up. Patients also undergo CT or MRI throughout the trial. Additionally, patients may undergo biopsy at disease progression.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for 1 year and every 4 months thereafter for 5 years after beginning study treatment.

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Schedule De-Escalation of Enfortumab Vedotin Alone or With Pembrolizumab for the Treatment of Locally Advanced or Metastatic Urothelial Cancer

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