An Open-Label, Multicenter, Multicohort, Phase 2 Study to Evaluate Enfortumab Vedotin in Subjects with Previously Treated Locally Advanced or Metastatic Malignant Solid Tumors (EV-202)
Primary Objective:
To determine the antitumor activity of enfortumab vedotin as measured by confirmed ORR per investigator assessment.
Secondary Objective:
To assess other measures of antitumor activity of enfortumab vedotin per investigator assessment; To assess the OS; To assess the safety and tolerability of enfortumab vedotin
Esophagus
Lung
- Rutgers Cancer Institute of New Jersey
- Principal Investigator
- Missak Haigentz MD
- Principal Investigator
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.
- For cohort 9 only: Subject should submit archival or fresh tumor tissue sample for
programmed cell death-ligand 1 (PD-L1) central testing during screening if no local
PD-L1 test result is available. Central test result for PD-L1 will be required prior
to subject enrollment. For cohort 9 subjects with local PD-L1 test result confirming
CPS ≥ 1, archival or fresh tissue sample for exploratory analysis should be submitted
within 5 days of enrollment.
- 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 evidence of radiographic progression on or after the last regimen
received.
- 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 locally advanced or metastatic disease that is not amenable to curative
intent treatment.
- Subject must have received a taxane or anthracycline in the neoadjuvant, adjuvant or
incurable, 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 progressed, relapsed, or discontinued for toxicity during or after at
least 1 prior standard of care cytotoxic regimen 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. Poly(ADP-ribose) polymerases (PARP) inhibitors do not count as a
line of cytotoxic therapy.
- Subject has progressed, relapsed, or discontinued for toxicity during or after
receiving endocrine therapy or with hormonally-directed therapy with cyclin-dependent
kinase (CDK) inhibitors. Prior therapy with CDK inhibitors is not required.
Cohort 2: triple negative breast cancer (TNBC)
- Subject has evidence of radiographic progression on or after the last regimen
received.
- 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 locally advanced or metastatic disease that is not amenable to curative
intent treatment.
- Subject must have received a taxane or anthracycline in the neoadjuvant, adjuvant or
incurable, 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 progressed, relapsed, or discontinued for toxicity during or after at
least 1 prior standard of care cytotoxic regimen 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. Poly(ADP-ribose)
polymerases (PARP) inhibitors do not count as a line of cytotoxic therapy.
- 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 evidence of radiographic progression on or after the last regimen
received.
- 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 locally advanced or metastatic disease that is not amenable to curative
intent treatment.
- Subject has progressed, relapsed, or discontinued treatment due to toxicity after 1
platinum-based standard of care regimen for locally advanced or metastatic disease,
and has not received > 2 prior lines of cytotoxic anticancer therapy in the locally
advanced or metastatic setting.
1. Subjects with locally advanced disease who previously received curative intent
treatment with platinum-based standard of care regimen in the adjuvant or
neoadjuvant setting or as part of concomitant chemoradiation therapy are eligible
if they have progressed or relapsed within 6 months of completion.
2. Maintenance therapy does not constitute a new chemotherapy regimen provided there
was no progression after the initial platinum-based regimen.
3. 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.
- 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 4: non-squamous non-small cell lung cancer
- Subject has evidence of radiographic progression on or after the last regimen
received.
- 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 locally advanced or metastatic disease that is not amenable to curative
intent treatment.
- Subject has progressed, relapsed, or discontinued treatment due to toxicity after 1
platinum-based standard of care regimen for locally advanced or metastatic disease,
and has not received > 2 prior lines of cytotoxic anticancer therapy in the locally
advanced or metastatic setting.
1. Subjects with locally advanced disease who previously received curative intent
treatment with platinum-based standard of care regimen in the adjuvant or
neoadjuvant setting or as part of concomitant chemoradiation therapy are eligible
if they have progressed or relapsed within 6 months of completion.
2. Maintenance therapy does not constitute a new chemotherapy regimen provided there
was no progression after the initial platinum-based regimen.
3. 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.
- 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: second-line or later head and neck cancer
- Subject has evidence of radiographic progression on or after the last regimen
received.
- 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. Salivary gland tumors
and/or parotid gland tumors are not eligible for Cohort 5.
- Subject has locally advanced or metastatic disease that is not amenable to curative
intent treatment.
- Subject has progressed, relapsed, or discontinued treatment due to toxicity after 1
platinum-based standard of care regimen for locally advanced or metastatic disease,
and has not received > 2 prior lines of cytotoxic anticancer therapy in the locally
advanced or metastatic setting.
- Subjects with locally advanced disease who previously received curative intent
treatment with platinum-based standard of care regimen in the adjuvant or
neoadjuvant setting or as part of concomitant chemoradiation therapy are eligible
if they have progressed or relapsed within 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.
Cohorts 6, 7 and 8: gastric or gastroesophageal junction (GEJ) or esophageal adenocarcinoma
- Subject has evidence of radiographic progression on or after the last regimen
received.
- Subject has histologically- or cytologically-confirmed gastric, GEJ, or esophageal
cancer.
- Subject has locally advanced or metastatic disease that is not amenable to curative
intent treatment.
- Subject has progressed, relapsed, or discontinued due to toxicity after 1
platinum-based standard of care regimen for locally advanced or metastatic disease,
and has not received > 2 prior lines of cytotoxic anticancer therapy in the locally
advanced or metastatic setting.
- Neoadjuvant or adjuvant cytotoxic 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.
- 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 9: 1L HNSCC
- Subject has histologically- or cytologically-confirmed head and neck squamous cell
carcinoma.
a. Primary tumor site must arise from the oral cavity, oropharynx, hypopharynx, and
larynx; tumors arising from the nasopharynx are excluded. Salivary gland tumors and/or
parotid gland tumors are not eligible for Cohort 9.
- Subject has recurrent or metastatic disease that is incurable by local therapies.
- Subject's tumor sample has PD-L1 combined positive score (CPS) of ≥ 1 as determined by
local or central IHC testing.
- Subject has had no prior systemic therapy administered with the exception of systemic
therapy completed > 6 months prior if given as part of multimodal treatment for
locally advanced disease. Subjects who have received a PD-1 or PD-L1 inhibitor in the
curative setting are eligible if it has been at least 12 months since last dose of the
anti PD-L1 agent.
- Subject has ANC ≥ 1.5 × 10^9/L.
- International normalized ratio (INR) OR prothrombin time (PT) and activated partial
thromboplastin (aPTT) both ≤ 1.5 × ULN unless subject is receiving anticoagulant
therapy as long as PT or aPTT is within the therapeutic range of intended use of
anticoagulants. PTT may be used if local lab is unable to perform aPTT.
- For subjects with oropharynx tumors, subject has results from testing of HPV status by
p16 testing.
Exclusion Criteria
For All Cohorts:
- 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 (within 3 months before first
dose) 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. The lowest HbA1c during the screening period will be used to determine
eligibility.
- 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.
Cohort 9: 1L HNSCC
- Had PD within 6 months of completion of curatively intended systemic treatment for
locoregionally advanced HNSCC.
- Has had an allogeneic tissue/solid organ transplant. Has severe hypersensitivity
(≥grade 3) to pembrolizumab and/or any of its excipients.
- Has a history of (non-infectious) pneumonitis / interstitial lung disease that
required steroids or has current pneumonitis / interstitial lung disease.
- Has a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening
chest CT scan.
- Has a life expectancy of less than 3 months and/or has rapidly progressing disease
(e.g. tumor bleeding, uncontrolled tumor pain) in the opinion of the treating
investigator.
- Active autoimmune disease that has required systemic treatment in past 2 years (i.e.
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
1. Replacement therapy (e.g., thyroxine, insulin, physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is not considered a
form of systemic treatment and is allowed.
2. Brief (<7 days) use of systemic corticosteroids is allowed when use is considered
standard of care.
3. Subjects with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or
resolved childhood asthma/atopy will not be excluded.
4. Subjects requiring intermittent use of bronchodilators, inhaled steroids, or
local steroid injections will not be excluded.
5. Subjects with hypothyroidism that is stable with hormone replacement or Sjögren's
syndrome will not be excluded.
- Has an active infection requiring systemic therapy.
- Has received prior therapy with an anti-PD-1 or anti-PD-L1 agent in the
recurrent/metastatic setting. If anti-PD-1 or anti-PD-L1 agent was given as part of
curative intent therapy, it must be at least 1 year since last dose.
- Has received a live vaccine within 30 days of planned start of study therapy. Examples
of live vaccines include, but are not limited to, the following: measles, mumps,
rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette
Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally
killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g.,
FluMist®) are live attenuated vaccines and are not allowed.
- Subject has active tuberculosis
Please note that we have obtained the inclusion and exclusion criteria information from the National Institutes of Health’s clinical trials web site ClinicalTrials.gov. The listed criteria may not necessarily reflect recent amendments to the protocol and the current criteria.
For further information about clinical trials, please contact us at 732-235-7356.