The primary purpose of this study is to determine the antitumor activity of enfortumab
vedotin as measured by confirmed objective response rate (ORR).
This study will also assess other measures of antitumor activity; overall survival (OS); as
well as the safety and tolerability of enfortumab vedotin.
This study will consist of 3 periods: screening/baseline, treatment and follow-up.
Screening/baseline period will take place up to 28 days prior to the first dose of study
treatment.
In the treatment period, starting at cycle 1, participants will receive enfortumab vedotin on
days 1, 8, and 15 every 28-day cycle until one of the treatment discontinuation criteria are
met. Disease assessment will be performed at screening/baseline and repeated every 8 weeks
(56 days ± 7 days) from the first dose of study treatment throughout the study until the
participant has radiologically confirmed disease progression, initiates a new subsequent
anticancer therapy, dies, withdraws consent, is lost to follow-up or the study closes,
whichever occurs first.
Participants who discontinue study treatment for reasons other than radiologically-confirmed
disease progression by RECIST Version 1.1 will enter into a post treatment follow-up period
and continue to receive imaging scans every 8 weeks (56 days ± 7 days) until the subject has
radiologically confirmed disease progression, initiates a new anticancer therapy, dies,
withdraws consent, is lost to follow-up or the study closes, whichever occurs first.
After 1 year on study treatment, the frequency of disease assessment will be reduced to every
12 weeks (84 days ± 7 days).
After radiologically-confirmed disease progression or initiation of subsequent anticancer
therapy, whichever occurs first, participants will be contacted every 12 weeks in the
long-term follow-up period for survival status until death, withdrawal of consent, lost to
follow-up or study closure, whichever occurs first.
Inclusion Criteria:
- Subject is considered an adult according to local regulation at the time of signing
the informed consent form (ICF).
- Subject has measurable disease by RECIST Version 1.1.
- Subject has accessible archival tumor tissue from either the primary tumor or a
metastatic site, for which source and availability have been confirmed prior to study
treatment. If no archival tumor tissue is available, the subject will have a biopsy to
obtain tumor tissue prior to study treatment. If the subject is unable to undergo a
biopsy due to safety concerns, enrollment into the study must be discussed with the
medical monitor.
- Subject has ECOG performance status of 0 or 1.
- Subject has the following baseline laboratory data. If a subject has received a recent
blood transfusion, the hematology tests must be obtained ≥ 28 days after any blood
transfusion.
- absolute neutrophil count (ANC) ≥ 1.0 × 10^9/L
- platelet count ≥ 100 × 10^9/L
- hemoglobin ≥ 9 g/dL
- serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for
subjects with Gilbert's disease
- creatinine clearance (CrCl) ≥ 30 mL/min as estimated per institutional standards
or as measured by 24-hour urine collection (glomerular filtration rate [GFR] can
also be used instead of CrCl).
- alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN
- Subject agrees not to participate in another interventional study while receiving
study treatment in the present study.
- Additional contraceptive requirements exist for male and female subjects.
Disease Specific Inclusion Criteria:
- Evidence of progression on or after the last regimen received.
- Locally advanced or metastatic disease that is not amenable to curative intent
treatment.
Cohort 1: HR+/HER2- breast cancer
- Subject has histologically- or cytologically-confirmed HR+/HER2- (estrogen receptor
[ER] positive and/or progesterone receptor [PR] positive, and HER2 negative) breast
cancers and are not considered a candidate for further hormonal therapy. Subject will
be considered HR+ if biopsies show ≥ 1% expression of ER or PR as per current American
Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines.
- Subject has progressed, relapsed, or discontinued for toxicity during or after at
least 1 prior cytotoxic regimen, either a taxane or anthracycline in the incurable,
unresectable locally advanced or metastatic setting, and has not received > 2 prior
lines of cytotoxic therapy in the locally advanced or metastatic setting. No limit
applies to endocrine therapies.
- Prior cytotoxic regimen received in the neoadjuvant or adjuvant setting will
count as a prior cytotoxic regimen if disease recurrence occurred during or
within 6 months of completing the regimen.
- Subject has progressed, relapsed, or discontinued for toxicity during or after
receiving endocrine or hormonally directed therapy with cyclin-dependent kinase (CDK)
inhibitors.
Cohort 2: triple negative breast cancer (TNBC)
- Subject has histologically- or cytologically-confirmed TNBC; defined as unequivocal
TNBC histology (ER-negative/PR-negative/HER2-negative). This is defined by < 1%
expression of ER and PR by immunohistochemistry (IHC), and that are, for HER2, either
0 to 1+ by IHC, or IHC 2+ and fluorescence in situ hybridization (FISH) negative (not
amplified) as per current ASCO/CAP guidelines.
- Subject has progressed, relapsed, or discontinued for toxicity during or after at
least 1 prior cytotoxic regimen, either a taxane or anthracycline in the incurable,
unresectable locally advanced or metatstatic setting, and has not received > 2 prior
lines of cytotoxic therapy in the locally advanced or metastatic setting.
- Prior cytotoxic regimen received in the neoadjuvant or adjuvant setting will
count as a prior cytotoxic regimen if disease recurrence occurred during or
within 6 months of completing the regimen.
- Subject has received prior therapy with an anti-programmed cell death protein-1 (PD-1)
or an anti-programmed cell death-ligand 1 (PD-L1) based on subject's tumor PD-1 or
PD-L1 expression and local treatment guidelines and has progressed or discontinued
treatment due to toxicity, or therapy is contraindicated for subject.
Cohort 3: squamous non-small cell lung cancer (NSCLC)
- Subject has histologically or cytologically-confirmed squamous NSCLC.
- Subjects with mixed histology NSCLC are eligible provided there is not any
component of neuroendocrine histology.
- Subjects with known epidermal growth factor receptor (EGFR), anaplastic lymphoma
kinase (ALK), reactive oxygen species (ROS), BRAF, or other actionable mutations
are eligible if treated with mutation targeted therapy and have progressed,
relapsed, or discontinued treatment due to toxicity.
- Subject has either:
- progressed, relapsed, or discontinued treatment due to toxicity after 1 platinum
based therapy for locally advanced or metastatic disease, and has not received >
2 prior lines of cytotoxic therapy in the locally advanced or metastatic setting.
(a.) Maintenance therapy does not constitute a new chemotherapy regimen provided
there was no progression after the initial platinum-based regimen.(b.) Changing
chemotherapy agents during platinum-based treatment for the management of
toxicities does not constitute a new chemotherapy regimen provided no progression
had occurred while on the initial therapy, or
- progressed or relapsed within 6 months of last dose of platinum-based adjuvant,
neoadjuvant, or concomitant chemoradiation regimen for early stage or locally
advanced stage disease.
- Subject has received prior therapy with an anti-programmed cell death protein-1 (PD-1)
or anti-programmed cell death-ligand 1 (PD-L1) based on subject's tumor PD-1 or PD-L1
expression and local treatment guidelines and has progressed, relapsed, or
discontinued treatment due to toxicity, or therapy is contraindicated for subject.
Cohort 4: non-squamous non-small cell lung cancer
- Subject has histologically- or cytologically-confirmed non-squamous NSCLC.
- Subjects with mixed histology NSCLC are eligible provided there is not any
component of neuroendocrine histology.
- Subjects with known EGFR, ALK, ROS, BRAF, or other actionable mutations are
eligible if treated with mutation targeted therapy and have progressed, relapsed,
or discontinued treatment due to toxicity.
- Subject has either:
- progressed, relapsed, or discontinued treatment due to toxicity after 1
platinumbased therapy for locally advanced or metastatic disease, and has not
received > 2 prior lines of cytotoxic therapy in the locally advanced or
metastatic setting.(a.) Maintenance therapy does not constitute a new
chemotherapy regimen provided there was no progression after the initial
platinum-based regimen. (b.) Changing chemotherapy agents during platinum-based
treatment for the management of toxicities does not constitute a new chemotherapy
regimen provided no progression has occurred while on the initial therapy, or
- progressed or relapsed within 6 months of last dose of platinum-based adjuvant,
neoadjuvant, or concomitant chemoradiation regimen for early stage or locally
advanced stage disease.
- Subject has received prior therapy with an anti-PD-1 or anti-PD-L1 based on subject's
tumor PD-1 or PD-L1 expression and local treatment guidelines and has progressed,
relapsed, or discontinued treatment due to toxicity, or therapy is contraindicated for
subject.
Cohort 5: head and neck cancer
- Subject has histologically- or cytologically-confirmed head and neck cancer.
- Primary tumor site must arise from the oral cavity, oropharynx, hypopharynx, and
larynx; tumors arising from the nasopharynx are excluded.
- Subject has progressed, relapsed, or discontinued treatment due to toxicity after 1
platinum-based therapy for locally advanced or metastatic disease, and has not
received > 2 prior lines of cytotoxic therapy in the locally advanced or metastatic
setting.
- Platinum regimens administered as part of multimodal therapy in the curative
setting will count as a regimen if relapse occurred ≤ 6 months after completion.
- Subject has received prior therapy with an anti-PD-1 or anti-PD-L1 based on subject's
tumor PD-1 or PD-L1 expression and local treatment guidelines and has progressed,
relapsed, or discontinued treatment due to toxicity, or therapy is contraindicated for
subject.
Cohort 6: gastric or gastroesophageal junction (GEJ) or esophageal cancer
- Subject has histologically- or cytologically-confirmed gastric, GEJ, or esophageal
cancer.
- Subject has progressed, relapsed, or discontinued due to toxicity after 1
platinum-based therapy for locally advanced or metastatic disease, and has not
received > 2 prior lines of cytotoxic therapy in the locally advanced or metastatic
setting.
- Neoadjuvant or adjuvant regimens will count as a prior regimen if relapsed or
progressed ≤ 6 months after completion.
- Subject must have received a HER2 directed therapy if known to have HER2 positive
cancer.
Exclusion Criteria:
- Subject has preexisting sensory or motor neuropathy Grade ≥ 2.
- Subject has active central nervous system (CNS) metastases. Subjects with treated CNS
metastases are permitted on study if all the following are true:
- CNS metastases have been clinically stable for ≥ 6 weeks prior to screening
- If requiring steroid treatment for CNS metastases, the subject is on a stable
dose ≤ 20 mg/day of prednisone or equivalent for ≥ 2 weeks
- Baseline imaging scans show no evidence of new or enlarged brain metastasis
- Subject does not have leptomeningeal disease
- Subject has ongoing clinically significant toxicity (Grade 2 or higher with the
exception of alopecia) associated with prior treatment (including systemic therapy,
radiotherapy or surgery).
- Subjects with ongoing ≥ Grade 3 immunotherapy-related hypothyroidism or
panhypopituitarism are excluded. Subjects with ongoing immunotherapy-related colitis,
uveitis, myocarditis or pneumonitis, or subjects with other immunotherapy-related AEs
requiring high doses of steroids (> 20 mg/day of prednisone or equivalent), are
excluded. Subject with ≤ Grade 2 immunotherapy-related hypothyroidism or
panhypopituitarism may be enrolled when well maintained/controlled on a stable dose of
hormone replacement therapy (if indicated).
- Subject has a history of uncontrolled diabetes mellitus within 3 months before the
first dose of study treatment. Uncontrolled diabetes is defined as hemoglobin A1c
(HbA1c) ≥ 8% or HbA1c between 7 and < 8% with associated diabetes symptoms (polyuria
or polydipsia) that are not otherwise explained.
- Subject has prior treatment with enfortumab vedotin or other monomethyl auristatin E
(MMAE) based antibody-drug conjugates (ADCs).
- Subject has a second malignancy diagnosed within 3 years before first dose of study
drug, or any evidence of residual disease from a previously diagnosed malignancy.
Subjects with non-melanoma skin cancer, localized prostate cancer treated with
curative intent with no evidence of progression, low-risk or very low-risk (per
standard guidelines) localized prostate cancer under active surveillance/watchful
waiting without intent to treat, or carcinoma in situ of any type (if complete
resection was performed) are allowed.
- Subject is currently receiving systemic antimicrobial treatment for viral, bacterial,
or fungal infection at the time of first dose of study treatment. Routine
antimicrobial prophylaxis is permitted.
- Subject has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg]
reactive) or active hepatitis C (e.g., hepatitis C virus [HCV] RNA [qualitative] is
detected).
- Subject has known history of human immunodeficiency virus (HIV) infection (HIV 1 or
2).
- Subject has 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 study drug.
- Subject has major surgery within 4 weeks prior to first dose of study drug.
- Subject had radiotherapy, chemotherapy, biologics, investigational agents, and/or
antitumor treatment with immunotherapy that is not completed 2 weeks prior to first
dose of study drug.
- Subject has known hypersensitivity to enfortumab vedotin or to any excipient contained
in the drug formulation of enfortumab vedotin (including histidine, trehalose
dihydrate and polysorbate 20) OR subject has known hypersensitivity to
biopharmaceutical produced in Chinese hamster ovary cells.
- Subject has known active keratitis or corneal ulcerations. Subject with superficial
punctate keratitis is allowed if the disorder is being adequately treated.
- Subject has any condition which makes the subject unsuitable for study participation.
