Combinatons of Sacituzumab govitecan plus enfortumab vedotin and pembrolizumab for metastatic urothelial carcinoma: the Double Antibody Drug conjugate (DAD) and Double Antibody Drug Conjugate with Immunotherapy (DAD-IO) Phase I/II trial

This research study will assess what doses of Sacituzumab Govitecan and Enfortumab Vedotin
can be safely combined in the treatment of metastatic urothelial carcinoma (mUC).

The names of the study drugs in this investigational combination are:

- Enfortumab Vedotin

- Sacituzumab Govitecan

Inclusion Criteria:

- Participants must have histologically documented confirmed predominant urothelial
carcinoma (i.e. of the bladder, renal pelvis, ureter or urethra). Patients with
squamous differentiation or mixed cell types are eligible; small-cell carcinoma is not
allowed.

Patients with locally advanced unresectable disease are eligible.

- Patient must have received prior treatment with a checkpoint inhibitor (CPI) in
locally advanced or metastatic urothelial cancer setting. Patients who received CPI
therapy in the neoadjuvant/adjuvant setting and had recurrent or progressive disease
either during or within 3 months of therapy completion are eligible. A CPI is defined
as a PD-1 or PD-L1 inhibitor.

- Patients must have received prior treatment with platinum containing therapy defined
as within the adjuvant/neoadjuvant setting with recurrent or progressive disease
within 12 months or receiving treatment with platinum in locally advanced or
metastatic setting.

- Age ≥18 years. Because no dosing or adverse event data are currently available on the
use of EV in combination with SG in participants <18 years of age, children are
excluded from this study, but will be eligible for future pediatric trials.

- ECOG performance status 0-1.

- Participants must have adequate organ and marrow function as defined below:

- Leukocytes ≥3,000/mcL

- Absolute neutrophil count ≥1,500/mcL

- Platelets ≥100,000/mcL

- Total bilirubin ≤ institutional upper limit of normal (ULN)

- AST(SGOT)/ALT(SGPT) ≤2.5x institutional ULN OR

≤5x ULN with liver metastases and serum albumin > 3 g/dL

- Glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 (by Cockcroft Gault formula)

- Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial.

- For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated.

- Participants with a history of hepatitis C virus (HCV) infection must have been
treated and cured. For participants with HCV infection who are currently on treatment,
they are eligible if they have an undetectable HCV viral load.

- Participants with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, participants should be class 2B or better.

- Have measurable disease by computed tomography (CT) or magnetic resonance imaging
(MRI) as per response evaluation criteria in solid tumors version 1.1 (RECIST 1.1
criteria). Tumor lesions situated in a previously irradiated area are considered
measurable if progression has been demonstrated in such lesions

- Female subjects of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study medication.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required

- Female subjects of childbearing potential must be willing to use 2 methods of birth
control or be surgically sterile or abstain from heterosexual activity for the course
of the study through 6 months after the last dose of study medication. Subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for >2 years

- The effects of SG and EV on the developing human fetus are unknown. Women of
child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration
of study participation. Should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, she should inform her
treating physician immediately. Men treated or enrolled on this protocol must also
agree to use adequate contraception prior to the study, for the duration of study
participation, and 4 months after completion of SG administration.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

Subjects meeting any of the following exclusion criteria at Screening/Day 1 of treatment
will not be enrolled in the study.

- Women who are pregnant or lactating. Pregnant women are excluded from this study
because SG and EV have potential for teratogenic or abortifacient effects. Because
there is an unknown but potential risk for adverse events in nursing infants secondary
to treatment of the mother with EV or SG, breastfeeding should be discontinued if the
mother is treated on protocol.

- Have had a prior anti-cancer biologic agent within 4 weeks prior to Cycle 1 Day 1
(C1D1) or have had prior chemotherapy, targeted small molecule therapy, or radiation
therapy within 2 weeks prior to C1D1. Subjects participating in observational studies
are eligible.

- Presence of any toxicities attributed to prior anti-cancer therapy that are not
resolved to Grade 1 or baseline that could impose serious risk for complications
before administration of study drug agent

- Note: If subjects received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy.

- Have previously received topoisomerase 1 inhibitors, SG or EV

- Have an active second malignancy. Subjects with a history of malignancy that have been
completely treated, with no evidence of active cancer for 3 years prior to start of
therapy on trial (Cycle 1 Day 1 [C1D1]), or subjects with surgically-cured tumors with
low risk of recurrence are allowed to enroll.

- Have known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they have stable CNS disease for at least 4 weeks prior to the first dose of study
drug and all neurologic symptoms have returned to baseline, have no evidence of new or
enlarging brain metastases, and are taking ≤20 mg/day of prednisone or its equivalent.

All subjects with carcinomatous meningitis are excluded regardless of clinical stability.

- Have active cardiac disease, defined as:

- Myocardial infarction or unstable angina pectoris within 6 months prior to C1D1

- History of serious ventricular arrhythmia (i.e., ventricular tachycardia or
ventricular fibrillation), high-grade atrioventricular block, or other cardiac
arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation
that is well controlled with antiarrhythmic medication); history of QT interval
prolongation

- New York Heart Association (NYHA) Class III or greater congestive heart failure
or left ventricular ejection fraction of < 40%

- Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease)
or gastrointestinal (GI) perforation within 6 months of C1D1

- Have active serious infection requiring antibiotics (Contact medical monitor for
clarification)

- Have other concurrent medical or psychiatric conditions that, in the Investigator's
opinion, may be likely to confound study interpretation or prevent completion of study
procedures and follow-up examinations.

- High dose systemic corticosteroids (≥20 mg of prednisone or its equivalent) are not
allowed within 2 weeks prior to C1D1.

- Participants who are receiving any other investigational agents.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to EV or SG or any excipient contained in the drug formulations (including
2-(N-morpholino) ethane sulfonic acid (MES), histidine, treahalose dihydrate
polysorbate 80 and polysorbate 20).

- Participants with uncontrolled intercurrent illness.

- Participants with psychiatric illness/social situations that would limit compliance
with study requirements.

- Patients with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin
A1C >8% or 7-8% with associated diabetes symptoms that are otherwise not explained

- Uncontrolled tumor related bone pain or impending spinal cord compression.