An Open-Label, Randomized Phase 3 Study to Evaluate Enfortumab Vedotin vs Chemotherapy in Subjects with Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301)

According to the International Agency for Research on Cancer (IARC), urothelial
cancer kills
more than 165000 patients annually and is the ninth most common cancer overall
worldwide.
Approximately 151000 new cases of urothelial cancer are diagnosed annually in
Europe, with
52000 deaths per year. Over 22000 new cases are diagnosed annually in Japan,
with
7600 deaths per year [Cancer Fact Sheets, 2017]. According to National Cancer
Institute
estimates, over 79000 new cases of urothelial cancer were diagnosed in 2017,
and more than
16000 people died from the disease in the United States (US) [SEER Cancer Stat
Facts, 2017].
First-line therapy for metastatic urothelial cancer in patients with sufficient
renal function
consists of cisplatin-based combinations, like methotrexate, vinblastine,
doxorubicin, and
cisplatin (MVAC) and gemcitabine with cisplatin, which demonstrate overall
response rates
up to 50%, including approximately 10 * 15% complete responses (CRs) [Bellmunt
et al,
2011]. Despite initial chemosensitivity, patients are not cured and the outcome
of metastatic
urothelial cancer after these regimens is poor: median time to progression is
only 7 months
and median overall survival (OS) is 14 months. Approximately 15% of patients
survive at
least 5 years and the prognosis is particularly poor among patients with
visceral metastases
for whom the 5-year OS rate is 7% [von der Maase, 2005].
For second line treatment, the small-molecule tubulin inhibitor vinflunine
(Javlor®) is
approved only in Europe. The median OS is 6.9 months compared to a median OS of
4.6 months for best supportive care [Bellmunt et al, 2009]. For decades, there
were no major
changes to the treatment landscape with only cytotoxic chemotherapies
available, until the
recent approvals of immune check point inhibitors (CPI) targeting the
programmed death
1/programmed death-ligand 1 (PD-1/PD-L1). As of May 2016, starting with the
PD-L1
inhibitor atezolizumab, several CPIs have received FDA approval for urothelial
cancer for
platinum-pretreated patients in the United States. Most approvals have been
based on single
arm phase II data [Tecentriq Prescribing Information, Genentech, Apr 2017],
[Opdivo
Prescribing Information, Bristol-Myers Squibb, September 2017], [Imfinzi
Prescribing
Information, AstraZeneca, May 2017] and [Bavencio Prescribing Information, EMD
Serono,
Mar 2017]. However, in 2017, results from the phase III trial KEYNOTE-045
demonstrated
that patients treated with pembrolizumab had significantly longer survival when
compared
with the standard second-line chemotherapy [Bellmunt et al, 2017]. This led to
the regular
approval of pembrolizumab as second line treatment for patients with locally
advanced or
metastatic urothelial cancer (mUC; [Keytruda Prescribing Information, Merck,
Sep 2017]).
The approval was based on a median OS of 10.3 months for pembrolizumab compared
with
7.4 months with taxane chemotherapy or vinflunine [Bellmunt et al, 2017].
Marketing
approval of CPIs in Europe have followed and approvals in Asia are expected.
Other PD-1
and PD-L1 inhibitors are currently being evaluated in clinical trials for
urothelial cancer, as
first and second line therapy [Mullane & Bellmunt, 2016].
Currently, no therapies are approved for patients with locally advanced or mUC
previously
treated with a CPI.

Study Objective(s):
Primary
-To compare the overall survival (OS) of subjects with locally advanced or
metastatic urothelial
cancer treated with enfortumab vedotin (EV) to the OS of subjects treated with
chemotherapy

Secondary
-To compare progression-free survival on study therapy (PFS1) per Response
Evaluation Criteria
in Solid Tumors (RECIST) V1.1 of subjects treated with EV to subjects treated
with
chemotherapy
-To compare the overall response rate (ORR) per RECIST V1.1 of EV to
chemotherapy
-To evaluate the duration of response (DOR) per RECIST V1.1 of EV and
chemotherapy
-To compare the disease control rate (DCR) per RECIST V1.1 of EV to chemotherapy
-To assess the safety and tolerability of EV
-To assess quality of life (QOL) and Patient Reported Outcomes (PRO) parameters

Exploratory
-Exploratory genomic and/or other biomarkers in tumor tissue and in peripheral
blood that may
correlate with treatment outcome, including Nectin-4 expression
-To assess the pharmacokinetics of EV
-To assess the incidence of antitherapeutic antibodies (ATA)
-To evaluate PFS in the next line of therapy (PFS2) of EV compared to
chemotherapy
-Healthcare resources utilization (HRU)

Study Design Overview:
This is a global, open-label, randomized Phase 3 study in adult subjects with
locally advanced or
metastatic urothelial cancer who have received a platinum-containing
chemotherapy and have
experienced disease progression or relapse during or following treatment with
an immune checkpoint
inhibitor. Approximately 550 subjects will be randomized to EV (Arm A) or
chemotherapy (Arm B)
in a 1:1 ratio. Subjects will be stratified according to the following: Eastern
Cooperative Oncology
Group Performance Status (ECOG PS), regions of the world and liver metastasis.
OS is the primary endpoint. OS is defined as the time from randomization to the
date of death.
Secondary endpoints include PFS1, ORR, DOR, DCR, safety and QOL/PRO.
Subjects in Arm A will receive EV on Days 1, 8 and 15 of each 28-day cycle.
Subjects in arm B will
receive either docetaxel, paclitaxel or vinflunine (as decided by the
investigator prior to
randomization: vinflunine is a choice of comparator only in countries where it
is approved for
urothelial cancer) on Day 1 of every 21-day cycle. Within the control arm, the
overall proportion of
subjects receiving vinflunine will be capped at approximately 35%. Subjects
will continue to receive
study treatment until radiological disease progression as determined per
Investigator assessment or
other treatment discontinuation criteria are met. No on-study crossover will be
allowed. This study
will consist of three phases: screening, treatment and follow-up.
Screening will take place up to 28 days prior to randomization. Subjects will
start with cycle 1 and
continue on to subsequent 21-day or 28-day cycles until one of the
discontinuation criteria are met. A
treatment cycle is defined as 28 days for Arm A and 21 days for Arm B. Subjects
randomized to Arm
A (EV) will receive treatment and evaluation on Days 1, 8 and 15 of all
treatment cycles. Subjects
randomized to Arm B (docetaxel, paclitaxel or vinflunine) will receive
treatment and evaluation on
Day 1 of all treatment cycles.
Subjects will be evaluated for response according to the RECIST V1.1. Imaging
for both arms will
be performed at baseline and every 56 days (± 7 days) from the first dose of
study treatment
throughout the study until PFS1 is documented by radiological disease
progression or the subject is
lost to follow-up, death, withdraws study consent or starts a subsequent
anti-cancer therapy. Baseline
imaging performed prior to informed consent as standard of care may be used so
long as it is
performed within 28 days prior to randomization. All subjects will have a bone
scan (scintigraphy)
performed at screening/baseline. Subjects with positive bone scans at baseline
will have a bone scan
performed every 56 days (± 7 days) throughout the study or more frequently if
clinically indicated.
Subjects should have a follow-up bone scan performed if clinically indicated
regardless of baseline
status. Brain scans (computed tomography with contrast/magnetic resonance
imaging [MRI]) will
only be performed if clinically indicated at screening/baseline and repeated as
clinically indicated or
per standard of care throughout the study.
QOL assessments and PRO will be collected at protocol-specified time points
from all randomized
subjects. The following validated tools will be used: European Organisation for
Research and
Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and EuroQOL
5-dimensions (EQ-5D-5L). Healthcare Resource Utilization (HRU) information will
be collected at
protocol-specified time points with particular focus on the number of subjects
who have an unplanned
use of healthcare resources related to clinical or AEs from subjects assigned
to treatment arms A
and B.
Blood samples for pharmacokinetics and ATA will be collected throughout the
study for subjects
randomized into Arm A. Validated assays will be used to measure the
concentrations of EV antibodydrug
conjugate (ADC) and monomethyl auristatin E (MMAE) in serum or plasma and to
assess ATA.
Pharmacokinetic samples will not be collected from subjects randomized into Arm
B. Samples for
exploratory biomarkers will be collected at protocol-specified timepoints.
Biomarker assessments
will not be used for subject selection.
Following discontinuation from study drug, subjects will have a follow-up visit
30 days (+ 7 days)
after their last dose of drug for safety assessments. If a subject discontinues
study drug prior to
radiographic disease progression (i.e., PFS1), the subject should enter the
post treatment follow-up
period and continue to undergo imaging assessments every 56 days (± 7 days)
until PFS1 is
documented or the subject starts another anticancer treatment, whichever occurs
earlier.
Following PFS1, subjects will enter the long-term follow-up period and be
followed per institutional
guidelines but not less than every 3 months from the date of the follow-up
visit for survival status and
progression status on subsequent therapy (i.e., PFS2).
Subjects will be followed until PFS2 is documented or the subject starts
another anticancer treatment,
whichever occurs earlier. All subsequent anticancer therapy including date and
site of progression for
PFS2 will be recorded on the case report form.
Following PFS2, subjects will enter the survival follow-up period and be
followed every 3 months for
survival status until death, lost to follow-up, withdrawal of study consent, or
study termination by
sponsor. This study is expected to end once final survival analysis is complete.
An Independent Data Monitoring Committee (IDMC) will be chartered to oversee
safety and the
planned interim efficacy analysis, which will occur after at least 250 OS
events (about 65% of the
total planned events) are observed. The primary analysis will occur at 384 OS
events. The IDMC may
recommend to the sponsor whether the trial should be terminated, modified or
continue unchanged
based on ongoing reviews of safety data and interim efficacy analysis. Further
details will be outlined
in the IDMC charter.

Investigational Product:
Enfortumab Vedotin
Dose, Mode of Administration and Dose Modification:
EV 1.25 mg/kg will be administered on Days 1, 8, and 15 of every 28-day cycle.
The investigational
product will be administered intravenously over a 30-minute period.
EV will be administered based on the subject*s actual body weight on Day 1 of
every cycle except for
subjects weighing greater than 100 kg; in such cases, the dose will be
calculated based on a maximum weight of 100 kg.
The dose does not need to be re-calculated based on actual weight on Day 8 and
15 of each cycle for Arm A unless it is required by institutional standards.
Dose reduction to 1 mg/kg (dose level - 1) and to 0.75 mg/kg (dose level - 2)
will be allowed
depending on the type and severity of toxicity. Subjects requiring a dose
reduction may be reescalated
by 1 dose level (i.e., subjects reduced to 0.75 mg/kg may only be re-escalated
to 1 mg/kg)
provided the toxicity does not require study drug discontinuation and has
returned to baseline or *
Grade 1. If the toxicity recurs, re-escalation will not be permitted. Subjects
with * Grade 2 corneal
AEs will not be permitted to dose re-escalate. EV should not be administered to
subjects with CrCl <
30 mL/min. Dose modification recommendations for EV associated toxicity are
presented in [Table
A] and [Table B] (please refer to the protocol synopsis for the tables).
Dose interruptions for other EV associated toxicity is permitted at the
discretion of the site
investigator. Dose interruptions may last up to 8 weeks (2 cycles). Dose
interruptions for subjects who
are deriving clinical benefit from treatment may be extended beyond 8 weeks, if
the subject*s toxicity
does not otherwise require permanent discontinuation. Subjects may not receive
other investigational
drugs, radiotherapy or systemic anti-neoplastic therapy during dose delays. If
a subject is dose
reduced due to toxicity that subsequently resolves (returns to baseline or *
Grade 1) the subject may
resume treatment at the original dose at the discretion of the site
investigator. If there is a dose
interruption, the schedule for response assessments will not be adjusted.


Comparative Drug(s):
Docetaxel

Dose, Mode of Administration and Dose Modification:
Docetaxel will be administered intravenously on Day 1 of every21-day cycle.
The starting dose of docetaxel 75 mg/m2 will be administered over
60-minute period or per local requirement. Refer to local product label or SmPC
and
institution guidelines for docetaxel for further guidance on docetaxel dosing.

Docetaxel should not be given to subjects with total bilirubin > ULN, or to
subjects with AST and/or
ALT > 1.5 x ULN with concomitant alkaline phosphatase > 2.5 x ULN. Subjects
with elevations of
bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase
are at increased risk
for the development of Grade 4 neutropenia, febrile neutropenia, infections,
severe thrombocytopenia,
severe stomatitis, severe skin toxicity, and toxic death. Docetaxel should also
not be given to subjects
with a neutrophil count of < 1500 cells/mm3 . Severe fluid retention has been
reported following docetaxel therapy.

Subjects should be premedicated with oral corticosteroids per institutional
guidelines prior to each docetaxel administration. Subjects with pre-existing
effusions should be
closely monitored from the first dose for the possible exacerbation of the
effusions. Subjects
developing peripheral edema may be treated with standard measures, e.g., salt
restriction, oral
diuretic(s). Dose interruptions may last up to 6 weeks (2 cycles). Dose
interruptions for subjects who
are deriving clinical benefit from treatment may be extended beyond 6 weeks, if
the subject*s toxicity
does not otherwise require permanent discontinuation.

Please refer to the Protocol Synopsis for the recommended dose modification
guidelines.


Comparative Drug(s):
Vinflunine
Dose, Mode of Administration and Dose Modification:
Vinflunine will be administered intravenously on Day 1 of every 21-day cycle.

Vinflunine will beadministered intravenously over a 20-minute period. For
subsequent administrations, vinflunine is
contraindicated in subjects with baseline ANC < 1,000/mm3 or platelets <
100,000/mm3 .
The starting dose of vinflunine 320 mg/m2 will be administered over a 20 minute
period
(or per local requirement) unless otherwise specified below.

In case of WHO/ECOG PS of * 1 or ECOG PS of 0 and prior pelvic irradiation,
vinflunine treatment should be
started at the dose of 280 mg/m². In the absence of any hematological toxicity
during the first cycle
causing treatment delay or dose reduction, the dose may be increased to 320
mg/m² every 21-days for
the subsequent cycles.
In subjects with moderate renal impairment (40 mL/min * CrCl * 60 mL/min), the
recommended
dose is 280 mg/m² given once every 21-day cycle. In subjects with renal
impairment
(30 mL/min * CrCl < 40 mL/min), the recommended dose is 250 mg/m² given once
every 21-day
cycle. The recommended dose of vinflunine is 250 mg/m² given once every 21-day
cycle in subjects
with mild liver impairment (Child-Pugh grade A).
The doses recommended in subjects * 75 years old are as follows:
-in subjects at least 75 years old but less than 80 years, the dose of
vinflunine to be given is
280 mg/m² every 21-day cycle.
-in subjects 80 years old and beyond, the dose of vinflunine to be given is 250
mg/m² every
21-day cycle.
Dose interruptions may last up to 6 weeks (2 cycles). Dose interruptions for
subjects who are deriving
clinical benefit from treatment may be extended beyond 6 weeks, if the
subject*s toxicity does not
otherwise require permanent discontinuation. Please refer to the approved
product label for specific
dose modifications for subjects receiving vinflunine.

Comparative Drug(s):
Paclitaxel
Dose, Mode of Administration and Dose Modification:
Study treatment of paclitaxel should be administered on Day 1 of every 21 day
cycle after all
procedures/assessments have been completed. The starting dose of paclitaxel 175
mg/m2 will be administered as an IV
infusion administered over 3 hours or per local requirement. See guidelines on
adjustment of initial dose. Refer to local product label or
SmPC and institution guidelines for paclitaxel for further guidance on
paclitaxel dosing.

All subjects should be premedicated prior to paclitaxel administration per
institutional guidelines in
order to prevent severe hypersensitivity reactions. Such premedication may
consist of dexamethasone
20 mg orally administered approximately 12 and 6 hours before paclitaxel,
diphenhydramine (or its
equivalent) 50 mg IV 30 to 60 minutes prior to paclitaxel, and cimetidine (300
mg) or ranitidine (50
mg) IV 30 to 60 minutes before paclitaxel. The appropriate premedication
regimen may be
determined by the investigator.

Paclitaxel should not be administered to subjects with baseline neutrophil
counts of less than
1500 cells/mm3 . Subjects should not be re-treated with subsequent cycles of
paclitaxel until
neutrophils recover to a level > 1500 cells/mm3 and platelets recover to a level
> 100000/mm3. Severe conduction abnormalities have been
documented in < 1% of subjects during paclitaxel therapy and in some cases
requiring pacemaker
placement. If subjects develop significant conduction abnormalities during
paclitaxel infusion,
appropriate therapy should be administered and continuous cardiac monitoring
should be performed
during subsequent therapy with paclitaxel.
In case of mild hepatic impairment (total bilirubin * 1.25 ULN), paclitaxel
should be started at a dose
of 135 mg/m2 .
Recommended dose modification guidelines specific for subjects receiving
paclitaxel are
detailed below. Dose modifications should also be considered according to local
product
label or SmPC and institutional guidelines. Dose interruptions may last up to 6
weeks (2 cycles). Dose interruptions for subjects
who are deriving clinical benefit from treatment may be extended beyond 6
weeks, if the subject*s
toxicity does not otherwise require permanent discontinuation.

Please refer to the protocol synopsis for the recommended dose modifications
for subjects receiving paclitaxel.

- Blood draws
- Study visits
- Questionnaires: Quality of Life and Healthcare Resource Utilization
- Scans: Chest, Abdomen and Pelvis scan at baseline and repeated every 56 days.
- Side effects (see question E9)
- Risks related to study procedures:
Blood Samples:
Blood draws may cause pain, bleeding, and/or bruising. You may faint and/or get
an infection with redness and irritation at the place where the needle enters
your vein.

Electrocardiogram (ECG):
The ECG test is a painless recording of the electrical activity of your heart.
The sticky pads used may be cold when applied and sometimes cause some
discomfort such as redness or itching. If the hair under the patches needs to
be shaved, irritation from shaving also could occur.

CT Scan:
Computed tomography (CT) scans send x-rays through the body at different
angles. You will be exposed to small doses of radiation. This dose of
radiation could be potentially harmful, but the risks are so small that they
are difficult to measure. The amount of radiation is the equivalent of about 3
extra years' worth of natural background radiation, which is radiation that
naturally occurs in the atmosphere and rocks in the soil. All radiation adds up
over a lifetime. Some people may feel *closed in* while lying in the scanner.
However, the scanner is open at both ends and an intercom allows you to talk
with the doctors and staff. If you feel anxious during the scan, medical staff
may provide comfort or the scan may be stopped. If a CT scan is being done of
the abdomen, you usually drink a liquid contrast agent to help define various
abdominal organs. This liquid may cause hives, itching, or other allergic
symptoms, nausea and/or vomiting and/or diarrhea. You may also receive an IV
contrast to make the x-ray pictures more accurate. This IV solution may cause
flushing, nausea, and/or very infrequent severe allergic reactions which rarely
lead to death. Please inform the study doctor if you have a history of allergic
reactions while getting ready for a CT scan.

Bone Scan:
A radioactive dye will be injected into your vein to see if any cancer has
spread to your bones. A tiny amount of radiation is used in the dye, and nearly
all of it is released from your body within two or three days.

Magnetic Resonance Imaging (MRI):
An MRI scan cannot be performed on certain individuals, such as those who have
cardiac pacemakers or certain other metal implants. If you have any metallic
objects in your body, the magnetic field can cause dangerous interactions. It
is very important you tell the doctor or clinic staff about any previous
surgery, implanted devices such as pacemakers, bullets or shrapnel wounds. You
will have to lie flat within a relatively small space for as long as 1 hour.
There may be some anxiety and claustrophobia (fear of closed spaces) associated
with the scanner. If you think this might be a problem for you, please discuss
it with the doctor before scheduling the test. Some sedation may be needed for
participants who feel too anxious about the MRI. The risks with sedation are:
irritation or inflammation of veins; drowsiness; a decrease in breathing,
airway obstruction, high or low blood pressure, abnormal heart rhythms, nausea,
vomiting and shivering.

Tumor Biopsy for Biomarker Studies:
If you do not have a tumor tissue sample available for central laboratory
confirmation, this sample will be obtained by a biopsy.
Risks related to tumor biopsies include bleeding from the biopsy site, pain,
local reaction to the anesthesia, infection, and scarring. Your study doctor
will further discuss the risks involved with these biopsies if you are
providing a sample of your tumor tissue.

Eye Exam:
An eye doctor will do an eye exam if you have had problems with your eyes and
vision within the three months prior to the screening period or during the
study. For this eye exam, the eye doctor will dilate your pupils, which will
make your vision blurry for a short period of time. You may not be able to
drive right after the exam.