Testing Combination Erdafitinib and Enfortumab Vedotin in Metastatic Bladder Cancer After Treatment With Chemotherapy and Immunotherapy

• ClinicalTrials.gov Identifier: NCT04963153
• Recruitment Status: Recruiting
• First Posted: July 15, 2021
• Last Update Posted: January 13, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

Brief Summary:

This phase Ib trial evaluates the best dose, potential benefits, and/or side effects of erdafitinib in combination with enfortumab vedotin in treating patients with bladder cancer that has spread from where it first started (primary site) to other places in the body (metastatic) and possesses genetic alterations in FGFR2/3 genes. Erdafitinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal FGFR protein that signals cancer cells to multiply. This may help keep cancer cells from growing and may kill them. 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 cancer cells. Enfortumab attaches to a protein called nectin-4 on cancer cells in a targeted way and delivers vedotin to kill them. It is a type of antibody-drug conjugate. Giving erdafitinib in combination with enfortumab vedotin may shrink or stabilize metastatic bladder cancer with alterations in FGFR 2/3 genes.

Condition or disease	Intervention/treatment	Phase
Locally Advanced Bladder Urothelial Carcinoma; Locally Advanced Renal Pelvis Urothelial Carcinoma; Locally Advanced Ureter Urothelial Carcinoma; Locally Advanced Urethral Urothelial Carcinoma; Locally Advanced Urothelial Carcinoma; Metastatic Bladder Urothelial Carcinoma; Metastatic Renal Pelvis Urothelial Carcinoma; Metastatic Ureter Urothelial Carcinoma; Metastatic Urethral Urothelial Carcinoma; Metastatic Urothelial Carcinoma; Recurrent Bladder Urothelial Carcinoma; Recurrent Renal Pelvis Urothelial Carcinoma; Recurrent Ureter Urothelial Carcinoma; Recurrent Urethral Urothelial Carcinoma; Recurrent Urothelial Carcinoma; Stage IV Bladder Cancer AJCC v8; Stage IV Renal Pelvis Cancer AJCC v8; Stage IV Ureter Cancer AJCC v8; Stage IV Urethral Cancer AJCC v8	Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Enfortumab Vedotin; Drug: Erdafitinib	Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the feasibility and safety of erdafitinib when combined with enfortumab vedotin (EV) for patients with metastatic urothelial carcinoma (mUC) harboring FGFR2/3 activating genomic alterations who are progressing following platinum-based chemotherapy and PD1/L1 inhibitors.

II. To determine the maximally tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of EV when combined with erdafitinib.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To observe and record overall response rate (ORR). III. To observe and record duration of response (DOR). IV. To observe and record progression-free survival (PFS). V. To observe and record overall survival (OS).

EXPLORATORY OBJECTIVES:

I. Assess association of tumor PD-L1 and nectin-4 protein expression with response.

II. Use commercial tissue next generation sequencing (NGS) assay to confirm FGFR status as well as to describe the genomic landscape of metastatic UC.

III. Use commercial liquid NGS assay to assess genomic changes by circulating tumor (ct)-deoxyribonucleic acid (DNA) assessment to study mechanisms of resistance with treatment.

IV. Assess pharmacokinetic (PK) of monomethyl auristatin E (MMAE) and erdafitinib.

OUTLINE: This is a dose-escalation study of enfortumab vedotin in combination with fixed dose erdafitinib followed by a dose-expansion study of the drug combination.

Patients receive erdafitinib orally (PO) once daily (QD) on days 1-28 of each cycle and enfortumab vedotin intravenously (IV) over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and blood sample collection throughout the trial.

After completion of study treatment, patients are followed up every 3 months for up to 2 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase Ib Trial of Erdafitinib Combined With Enfortumab Vedotin Following Platinum and PD1/L1 Inhibitors for Metastatic Urothelial Carcinoma With FGFR2/3 Genetic Alterations
• Actual Study Start Date: October 13, 2021
• Estimated Primary Completion Date: September 1, 2023
• Estimated Study Completion Date: September 1, 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment (erdafitinib, enfortumab vedotin); Patients receive erdafitinib PO QD on days 1-28 of each cycle and enfortumab vedotin IV over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and blood sample collection throughout the trial.

Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Computed Tomography; Undergo CT; Other Names: CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT; CT Scan; tomography; Drug: Enfortumab Vedotin; Given IV; Other Names: AGS 22ME; AGS-22M6E; Anti-Nectin 4 ADC ASG-22CE; Anti-nectin-4 Monoclonal Antibody-Drug Conjugate AGS-22M6E; ASG-22CE; Enfortumab Vedotin-ejfv; Padcev; Drug: Erdafitinib; Given PO; Other Names: Balversa; JNJ-42756493

Outcome Measures

Primary Outcome Measures :

1. Incidence of adverse events [ Time Frame: Up to 2 years ]
2. Recommended phase II dose [ Time Frame: Up to 28 days ]
3. Maximum tolerated dose of enfortumab vedotin [ Time Frame: Up to 28 days ]
   The highest dose of enfortumab vedotin in combination with fixed dose erdafitinib that does not cause unacceptable side effect.

Secondary Outcome Measures :

1. Overall response rate [ Time Frame: Up to 2 years from study enrollment ]
   Will be summarized using descriptive statistics including two-sided 95% confidence interval (CI) based on Clopper-Pearson method.
2. Duration of response [ Time Frame: Time from complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 2 years from study enrollment ]
   Will be summarized using mean, standard deviation, median, and range.
3. Progression free survival [ Time Frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years ]
   Kaplan-Meier curve estimates of medians and their corresponding 95% CIs will be calculated.
4. Overall survival [ Time Frame: Up to 2 years from study enrollment ]
   Kaplan-Meier curve estimates of medians and their corresponding 95% CIs will be calculated.

Other Outcome Measures:

1. PD-L1 and Nectin-4 expression [ Time Frame: Up to 2 years from study enrollment ]
2. Tumor subtyping, tumor microenvironment, and mutations associated with treatment response [ Time Frame: Up to 2 years from study enrollment ]
   Will be evaluated based on pre-treatment sequencing data.
3. Mechanisms of resistance and response [ Time Frame: Up to 2 years from study enrollment ]
   Will be evaluated through peripheral blood circulating tumor deoxyribonucleic acid (DNA). Methods of analysis may include but not limited to, immunohistochemistry, next-generation sequencing of DNA and ribonucleic acid (RNA), and immunoassays.
4. Pharmacokinetics (PK) [ Time Frame: Up to 2 years from study enrollment ]
   PK analysis will be performed to explore the relationship between drug exposure, toxicity and response.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patients must have histologically or cytologically documented locally advanced (T4b, any N; or any T, N 2-3) or metastatic (M1, Stage IV; or metastatic recurrence after locoregional treatment) urothelial carcinoma (including renal pelvis, ureters, urinary bladder, urethra). Patients with mixed histologies are required to have a dominant transitional cell pattern

• Patients who had disease progression during or following treatment with at least one platinum-containing regimen (e.g., gemcitabine and cisplatin [GC], methotrexate, vinblastine, doxorubicin and cisplatin [MVAC], carboplatin and gemcitabine [Carbo-Gem]) and an immune checkpoint inhibitor (PD-1/ PD-L1 inhibitor including but not limited to: atezolizumab, pembrolizumab, durvalumab, avelumab, and nivolumab)

  • Received a first-line platinum-containing regimen in the metastatic setting or for inoperable locally advanced disease
  • Or received neo/adjuvant platinum-containing therapy for localized muscle-invasive UC, with recurrence/progression =< 12 months following completion of therapy
  • Patients who received immune checkpoint inhibitor therapy in the neoadjuvant/adjuvant setting and had recurrent or progressive disease either during therapy or within 12 months of therapy completion are eligible. This criterion does not apply if the checkpoint inhibitor is contraindicated
• Patients with metastatic urothelial carcinoma who are cisplatin-ineligible and progressed on upfront immune checkpoint inhibitor; or ineligible/refused immune checkpoint inhibitor therapy will be eligible for this trial
• Patient who received prior antibody drug conjugate such as sacituzumab govitecan are allowed
• Patients must have measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Previously irradiated lesions cannot be counted as target lesions unless there has been demonstrated progression in the lesion since radiotherapy and no other lesions are available for selection as target lesions
• Patients must have FGFR2/3 activating alterations identified by tumor tissue or plasma ctDNA profiling using a Clinical Laboratory Improvement Act (CLIA) certified College of American Pathologists (CAP) accredited platform

• Age >= 18 years, for ability to comply with protocol

  • Because no dosing or adverse event data are currently available on the use of erdafitinib in combination with enfortumab vedotin in patients < 18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Absolute neutrophil count >= 1,500/mcL (within 14 days prior to beginning trial treatment)
• Platelets >= 100,000/mcL (within 14 days prior to beginning trial treatment)
• Hemoglobin >= 9 g/dL (within 14 days prior to beginning trial treatment)
• Measured or calculated creatine clearance (CrCl) >= 30 ml/min (glomerular filtration rate [GFR] can also be used in place of creatinine CrCl) (within 14 days prior to beginning trial treatment)
• Total bilirubin =< 1.5 x ULN (institutional upper limit of normal) OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 x ULN (within 14 days prior to beginning trial treatment)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional ULN (=< 5 x ULN for subjects with liver metastasis) (within 14 days prior to beginning trial treatment)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression (CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis)

• Patients with a history of prostate cancer (T2NXMX or lower with Gleason score =< 7) treated with definitive intent (surgically or with radiation therapy) at least 1 year prior to study entry are eligible, provided that the subject is considered prostate cancer-free and the following criteria are met:

  • Patients who have undergone radical prostatectomy must have undetectable prostate specific antigen (PSA) for > 1 year and at screening
  • Patients who have had radiation must have a PSA doubling time > 1 year (based on at least 3 values determined >1 month apart) and a total PSA value that does not meet Phoenix criteria for biochemical recurrence (i.e., < 2.0 ng/mL above nadir)
  • Patients with untreated low-risk prostate cancer (Gleason score =< 6) on active surveillance with PSA doubling time >1 year (based on at least 3 values determined > 1 month apart) are also eligible
• Patients who have undergone an ophthalmologic examination and have no active eye disease which would be likely to increase the risk of eye toxicity
• The effects of erdafitinib and enfortumab vedotin on the developing human fetus are unknown. For this reason and because FGFR inhibitors and humanized antibody-drug conjugate (ADC) agents are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 3 months after completion of erdafitinib and enfortumab vedotin administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 5 months after completion of erdafitinib and enfortumab vedotin administration
• Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

• Patients who have had chemotherapy, targeted therapies, immunotherapy, or treatment with an investigational anticancer agent within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (including ongoing sensory or motor neuropathy of grade 2 or higher) (i.e., have residual toxicities > grade 1 or returned to baseline) with the exception of alopecia
• Patients who have previously received enfortumab vedotin or other MMAE-based ADCs
• Patients who have had prior treatment with an FGFR inhibitor
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to erdafitinib and enfortumab vedotin
• Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• Patients with a history of any corneal or retinal abnormality likely to increase the risk of eye toxicity
• Patients with uncontrolled intercurrent illness and currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of starting treatment. Routine antimicrobial prophylaxis is permitted
• Patients with psychiatric illness/social situations that would limit compliance with study requirements
• Subjects who have received radiotherapy within 2 weeks prior to start of treatment. Subject must have recovered adequately from the toxicity from the intervention prior to starting study treatment
• Patients with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) >= 8% or HbA1c 7% to < 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained
• Subjects who have received major surgery within 4 weeks prior to start of treatment. Subject must have recovered adequately from complications from the intervention prior to starting study treatment
• Subjects who have received a prior allogeneic stem cell or solid organ transplant
• Has persistent phosphate level > ULN during screening (within 14 days of treatment and prior to cycle 1 day 1) and despite medical management

• Has a history of or current uncontrolled cardiovascular disease including:

  • Unstable angina, myocardial infarction, or known congestive heart failure class II-IV within the preceding 12 months; cerebrovascular accident or transient ischemic attack within the preceding 3 months
  • Any of the following: sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes, cardiac arrest, Mobitz II second degree heart block or third degree heart block; known presence of dilated, hypertrophic, or restrictive cardiomyopathy
  • QTc prolongation as confirmed by triplicate assessment at screening (Fridericia;QTc > 480 milliseconds)
• Subjects with a 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

Contacts and Locations

Locations

United States, California

Los Angeles County-USC Medical Center; Recruiting

Los Angeles, California, United States, 90033

Contact: Site Public Contact 323-865-0451

Principal Investigator: Anishka D'Souza

USC / Norris Comprehensive Cancer Center; Recruiting

Los Angeles, California, United States, 90033

Contact: Site Public Contact 323-865-0451

Principal Investigator: Anishka D'Souza

United States, Florida

Moffitt Cancer Center; Recruiting

Tampa, Florida, United States, 33612

Contact: Site Public Contact 800-679-0775 ClinicalTrials@moffitt.org

Principal Investigator: Rohit Jain

United States, Pennsylvania

University of Pittsburgh Cancer Institute (UPCI); Recruiting

Pittsburgh, Pennsylvania, United States, 15232

Contact: Site Public Contact 412-647-8073

Principal Investigator: Risa L. Wong

United States, Utah

Huntsman Cancer Institute/University of Utah; Suspended

Salt Lake City, Utah, United States, 84112

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Rohit Jain; University Health Network Princess Margaret Cancer Center LAO

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT04963153
• Other Study ID Numbers: NCI-2021-07069; NCI-2021-07069 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); MCC 21460; 10483 ( Other Identifier: University Health Network Princess Margaret Cancer Center LAO ); 10483 ( Other Identifier: CTEP ); UM1CA186644 ( U.S. NIH Grant/Contract )
• First Posted: July 15, 2021
• Last Update Posted: January 13, 2023
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
• URL: https://grants.nih.gov/policy/sharing.htm

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Carcinoma; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Urethral Neoplasms; Ureteral Neoplasms; Pelvic Neoplasms; Recurrence; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Pathologic Processes; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases; Urethral Diseases; Ureteral Diseases; Immunoconjugates; Immunologic Factors; Physiological Effects of Drugs