The purpose of this study is to evaluate the safety and pharmacokinetics of enfortumab
vedotin as well as assess the immunogenicity and antitumor activity in subjects with
metastatic urothelial cancer and other malignant solid tumors that express Nectin-4.
All subjects will receive a single 30 minute IV infusion of enfortumab vedotin once weekly
for the first 3 weeks of every 4 weeks (i.e., on Days 1, 8, and 15). A cycle is 4 weeks.
This is a 3 part study. Part A will evaluate enfortumab vedotin in subjects with
histologically confirmed malignant solid tumors (excluding sarcomas) that are resistant or
have recurred. Subjects will continue treatment until disease progression, intolerability of
enfortumab vedotin, investigator decision or consent withdrawal. Part A will follow a
modified Continual Reassessment Method (mCRM).
Part B, will evaluate enfortumab vedotin in 3 different expansion cohorts: 1) Urothelial
cancer subjects with renal insufficiency defined as a Creatinine Clearance ≥ 15 ml/min and <
30 ml/min, 2) subjects with Metastatic Non Small Cell Lung Cancer (NSCLC) and 3) subjects
with Metastatic Ovarian Cancer. With the exception of the renal insufficiency cohort,
enrollment into Part B will occur at the recommended phase 2 dose (RP2D) established in Part
A. Enrollment into the renal insufficiency cohort will begin at starting dose and escalated
using a 3 + 3 dose escalation design. Subjects will continue treatment until disease
progression, intolerability of enfortumab vedotin or consent withdrawal.
Part C will evaluate enfortumab vedotin at the RP2D (determined from Part A) in subjects who
have been previously treated with immune checkpoint inhibitors (CPI) in the metastatic
setting. Subjects will continue treatment until disease progression, intolerability of
enfortumab vedotin, investigator decision or consent withdrawal.
All subjects will be followed post-treatment every 4 months via disease assessment or
telephone contact to obtain information on disease progression and death.
Inclusion Criteria:
- Dose Escalation, Renal insufficiency and CPI-Treated Expansion cohorts: Histologically
confirmed Transitional Cell Carcinoma of the Urothelium (TCCU) (i.e., cancer of the
bladder, renal pelvis, ureter, or urethra). Subjects with Urothelial Carcinoma with
squamous differentiation or mixed cell types are eligible.
- Ovarian Expansion Cohort: Subjects with recurrent disease or histologically or
cytologically confirmed Stage III/IV diagnosis of epithelial ovarian cancer, fallopian
tube cancer, or primary peritoneal carcinoma who have previously progressed while
receiving or within 6 months of completing a platinum-containing regimen.
- NSCLC Expansion Cohort: Histologic or cytologic diagnosis of NSCLC (squamous or
non-squamous or NSCLC-not specified)
- Dose Escalation, Renal insufficiency, NSCLC and CPI-Treated Expansion Cohorts: For
subjects with urothelial cancer and NSCLC: Subjects must submit a tumor tissue for
Nectin-4 expression. Enrollment for these subjects is not dependent on the
immunohistochemistry using the H-Score (IHC H-Score).
- Ovarian Expansion Cohort: Subjects must have tumor tissue positive (IHC H-score ≥150)
for Nectin-4 expression
- For Dose Escalation, NSCLC and Ovarian Expansion Cohorts: Subject must have failed at
least one prior chemotherapy regimen for metastatic disease (urothelial and bladder
cancer subjects are not required to have failed prior chemotherapy regimen if
considered unfit for cisplatin-based chemotherapy)
- For the CPI-Treated Expansion Cohort: Subject must have received prior treatment with
a CPI in the metastatic setting.
- Subjects must have measurable disease according to RECIST (version 1.1)
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Life expectancy of ≥ 3 months
- Negative pregnancy test (women of childbearing potential)
- Hematologic function, as follows (no red blood cell or platelet transfusions are
allowed within 14 days of the first dose of enfortumab vedotin):
- Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L
- Platelet count ≥ 100 x 10^9/L
- Hemoglobin ≥ 9 g/dL
- Renal function, as follows: Dose Escalation, NSCLC, Ovarian, and CPI Treated Expansion
Cohorts: creatinine clearance of ≥ 30 mL/min by the Cockcroft-Gault equation or as
measured by 24 hour urine collection. For the Renal Insufficiency Expansion Cohort:
creatinine clearance estimate ≥15 ml/min and <30 ml/min by Cockcroft-Gault equation or
as measured by 24 hour urine collection.
- Total bilirubin ≤ 1.5 x ULN (upper limit of normal)
- Serum albumin ≥2.5 g/dL
- Aspartate aminotransferase (AST) ≤ 1.5 x ULN
- Alanine aminotransferase (ALT) ≤ 1.5 x ULN
- International normal ratio (INR) < 1.3 or ≤ institutional ULN (or ≤ 3.0 if on
therapeutic anticoagulation)
- Sexually active fertile subjects, and their partners, must agree to use medically
accepted double-barrier methods of contraception (e.g., barrier methods, including
male condom, female condom, or diaphragm with spermicidal gel) during the study and at
least 6 months after termination of study therapy
- Competent to comprehend, sign, and date an independent ethics committee/institutional
review board/research ethics board (IEC/IRB/REB) approved informed consent form
Exclusion Criteria:
- Preexisting sensory neuropathy Grade ≥ 2
- Preexisting motor neuropathy Grade ≥ 2
- Uncontrolled central nervous system metastases
- Use of any investigational drug within 14 days prior to the first dose of study drug
- Any anticancer therapy within 14 days prior to the first dose of study drug,
including: small molecules, immunotherapy, chemotherapy, monoclonal antibody therapy,
radiotherapy or any other agents to treat cancer (anti-hormonal therapy given as
adjuvant therapy for early-stage estrogen receptor (ER) positive breast cancer is not
considered cancer therapy for the purpose of this protocol)
- Subjects with immunotherapy related adverse events requiring high doses of steroids (≥
40 mg/day of prednisone) are not eligible.
- Any P-glycoprotein (P-gp) inducers/inhibitors or strong cytochrome P4503A (CYP3A)
inhibitors within 14 days prior to the first dose of study drug
- Thromboembolic events and/or bleeding disorders ≤ 14 days (e.g., deep vein thrombosis
(DVT) or pulmonary embolism (PE)) prior to the first dose of study drug
- Documented history of a cerebral vascular event (stroke or transient ischemic attack),
unstable angina, myocardial infarction, or cardiac symptoms (including congestive
heart failure) consistent with New York Heart Association Class III-IV within 6 months
prior to the first dose of enfortumab vedotin.
- Known Human Immunodeficiency Virus (HIV) or Acquired Immune Deficiency Syndrome (AIDS)
- Subjects with a positive Hepatitis B surface antigen and/or antihepatitis B core
antibody. Subjects with a negative polymerase chain reaction (PCR) assay are permitted
with appropriate antiviral prophylaxis.
- Active Hepatitis C infection. Subjects who have been treated for Hepatitis C infection
can be included if they have documented sustained virologic response of ≥ 12 weeks.
- Decompensated liver disease as evidenced by clinically significant ascites refractory
to diuretic therapy, hepatic encephalopathy, or coagulopathy
- Known sensitivity to any of the ingredients of the investigational product enfortumab
vedotin (ASG-22CE)
- Major surgery within 28 days prior to first dose of study drug
- History of another 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, localized prostate cancer treated with curative intent with
no evidence of progression, low-risk or very low risk localized prostate cancer under
active surveillance/watchful waiting without intent to treat, or carcinoma in situ of
any time (if complete resection was performed) are allowed.
- History of uncontrolled diabetes mellitus or diabetic neuropathy within 3 months of
the first dose of study drug. 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.
- 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.
- Condition or situation which may put the subject at significant risk, may confound the
study results, or may interfere significantly with subject's participation in the
study
- Any medical, psychiatric, addictive or other kind of disorder which compromises the
ability of the subject to give written informed consent and/or to comply with
procedures
- Has ocular conditions such as:
- Active infection or corneal ulcer (e.g. keratitis)
- Monocularity
- History of corneal transplantation
- Contact lens dependent (if using contact lens, must be able to switch to glasses
during the entire study duration)
- Uncontrolled glaucoma (topical medications allowed)
- Uncontrolled or evolving retinopathy, wet macular degeneration, uveitis,
papilledema, or optic disc disorder
