Clinical Trial 21460

• Overview

  Study 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

  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 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. 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.

  Objective:

  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. 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.

• Treatments

  Therapies:

  Antibody-Drug Conjugate; Therapy (NOS)

  Medications:

  Enfortumab Vedotin (Padcev); Erdafitinib (); JNJ-42756493 (Erdafitinib)

• Inclusion 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., GC, MVAC, Carbo-Gem) and a immune checkpoint inhibitor (PD-1/ PD-L1 inhibitor including, but not limited to: atezolizumab, pembrolizumab, durvalumab, avelumab, and nivolumab)
  • Patients with metastatic urothelial carcinoma who are cisplatin-ineligible and progressed on upfront immune checkpoint inhibitor; or ineligible/refused 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
  • 18 years of age or older
  • Eastern Cooperative Oncology Group (ECOG) performance status == 60%)
  • Adequate organ function as defined per protocol
  • 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 = 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., 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
  • Women of child bearing potential must agree to use adequate contraception
  • Other criteria may apply

• Exclusion Criteria

  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
  • Patients 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 > Patients 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
  • Patients 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)
  • Patients 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
  • Other criteria may apply

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