University of Kansas Medical Center

Conditions

• Locally Advanced Urothelial Carcinoma
• Metastatic Urothelial Carcinoma
• Unresectable Urothelial Carcinoma

Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- Patient must be ≥ 18 years of age

- Patient must have Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

- Patient must have locally advanced (unresectable and/or not amenable to curative
intent therapy) or metastatic urothelial cancer

- Patient must have histologically proven conventional urothelial carcinoma (UC) of
any urinary tract origin [any histologic subtype except neuroendocrine (small or
large cell)] are permitted so long as tumors include ≥ 1% conventional urothelial
histology). NOTE: Pure non-urothelial histology is excluded

- Patient must have measurable disease per Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1 criteria. Baseline imaging must be obtained ≤ 35 days prior to
randomization

- Patient must have the following prior treatment(s). Patient must have had
progression on or after the immediate prior anti-cancer therapy

- Patient must have had prior exposure to anti-PD(L)1 therapy [anti -PD(L)1
monotherapy or as a combination regimen in any disease/therapy setting for UC].
Patients must have received at least 1 dose of anti-PD(L)1 therapy

- NOTE: Anti-PD(L)1 therapy does not need to be the most recent therapy received
prior to enrollment on this protocol

- NOTE: Patient must not have had progression within 12 weeks of starting their
first anti-PD(L) 1 therapy, even if anti-PD-(L)1 treatment was given in more
than one lines of therapy

- Patient must have had ≥ 1 line of systemic therapy given in the advanced/metastatic
disease setting, except for patients who had received anti-PD(L)1 + enfortumab
vedotin in the localized disease setting (e.g., neoadjuvant and/or adjuvant) and had
cancer progression within 12 months from the last systemic therapy dose

- For tumors with known FGFR3+ susceptible alteration (for FGFR inhibitor), patients
must have received a prior FGFR inhibitor unless contraindicated per physician
discretion

- Patient must have received prior enfortumab vedotinor any other Nectin-4 directed
therapy or other MMAE-containing therapy in any disease/therapy setting unless
contraindicated per physician

- Patient must have had no prior exposure to Sacituzumab govitean-hziy or other TROP-2
directed therapies or antibody-drug conjugate that contains topo-isomerase I
inhibitor, e.g. trastuzumab deruxtecan

- Patient must have Bellmunt score of 0-2. The Bellmunt score assesses a patient's
risk and is calculated based on ECOG PS, hemogloblin level and presence of liver
metastases

- Patient must not have history of grade 3 or higher immune-related adverse events on
prior anti-PD1/L1, except for endocrinopathies on adequate hormone therapy repletion
and/or clinically insignificant laboratory abnormalities

- Patient must have recovered (i.e., ≤ grade 1) from clinically significant AEs due to
previously administered systemic therapy agent, except for endocrinopathies on
adequate hormone therapy repletion

- NOTE: Patients with ≤ grade 2 neuropathy, any grade of alopecia, or any grade
of non-clinically significant laboratory abnormality are exceptions to this
criterion and are allowed in this trial.

- Examples of non-clinically significant laboratory abnormalities include, but
are not limited to:

- Lymphopenia or monopenia

- Lymphocytosis or monocytosis

- Increase in amylase or lipase with no clinical correlation

- Any other abnormal laboratory findings that have no clinical relevance per
the treating investigator.

- NOTE: If patient has undergone major surgery, they must have recovered
adequately from the toxicity and/or complications from the intervention prior
to randomization

- Patient must not be pregnant or breast-feeding due to the potential harm to an
unborn fetus and possible risk for adverse events in nursing infants with the
treatment regimens being used. All patients of childbearing potential must have a
blood test or urine study within 14 days prior to randomization to rule out
pregnancy. A patient of childbearing potential is defined as anyone, regardless of
whether they have undergone tubal ligation, who meets the following criteria: 1) has
achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral
oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following
cancer therapy does not rule out childbearing potential) for at least 24 consecutive
months (i.e., has had menses at any time in the preceding 24 consecutive months).
Patient must not nurse infants while on protocol treatment and for 4 months after
the last dose of protocol treatment

- Patient must not expect to conceive or father children by using an accepted and
effective method(s) of contraception or by abstaining from sexual intercourse for
the duration of their participation in the study. Patients of childbearing potential
must continue contraceptive method(s) or abstain for 6 months after the last dose of
protocol treatment. Patients with partners who could become pregnant should use
effective contraception during therapy and for 3 months after the last dose of
protocol treatment

- Patient must have the ability to understand and the willingness to sign a written
informed consent document. Patients with impaired decision-making capacity (IDMC)
who have a legally authorized representative (LAR) or caregiver and/or family member
available will also be considered eligible

- Absolute neutrophil count (ANC) ≥ 1,500/uL (obtained ≤ 14 days prior to
randomization)

- Platelets ≥ 100,000/uL (obtained ≤ 14 days prior to randomization)

- Albumin ≥ 3 g/dL (obtained ≤ 14 days prior to randomization)

- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (obtained ≤ 14
days prior to randomization)

- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 3 ×
institutional ULN or ≤ 5.0 x institutional ULN if known liver metastases (obtained ≤
14 days prior to randomization)

- Creatinine clearance (CrCl) ≥ 30 mL/min (obtained ≤ 14 days prior to randomization)
NOTE: CrCl is estimated using the Cockcroft-Gault formula (or can be measured by
24-hour urine collection if needed)

- Hemoglobin (Hb) ≥ 8.5 mg/dl (obtained ≤ 14 days prior to randomization)

- Patient must not have a known genetic UGT1A1 deficiency (Gilbert's syndrome).
Patients with variant type UGT1A1*28 allele may have increased levels of SN-38
metabolite (due to reduced SN-38 metabolism and clearance) and are at higher risk
for severe adverse events when compared to wild-type.

- NOTE: If a patient's UGT1A1 status is unknown, they are eligible to enroll (the
study does not require this test as part of screening)

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months of randomization are eligible

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

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

- Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression and
are not using steroids > 10 mg of prednisone (or equivalent) daily for brain
metastases for at least 7 days prior to randomization

- Patients with prior or concurrent malignancy that is not considered clinically
significant and whose natural history or treatment does not have the potential to
interfere with the safety or efficacy assessment of the investigational regimen (at
the discretion of the treating physician) are eligible

- Patient must not be on systemic immunosuppressive medication, including steroids (if
doses exceed the equivalent of prednisone 10 mg daily). Short courses of steroids,
e.g. "burst", which are discontinued prior to randomization are acceptable. Patients
on inhaled, intranasal, intra-articular and/or topical steroids are eligible

- Patient must be English or Spanish speaking to be eligible for the HRQOL component
of the study.

- NOTE: Sites cannot translate the associated HRQOL forms

Recruiting Locations

Study Contact

Detailed Description

PRIMARY OBJECTIVE: I. To compare overall survival (OS) between the therapy of physician choice (TPC) arm and the Sacituzumab govitean-hziy + pembrolizumab arm. SECONDARY OBJECTIVES: I. To compare the progression free survival (PFS) between the TPC arm and the Sacituzumab govitean-hziy + pembrolizumab arm. II. To evaluate overall response rate (ORR) between the TPC arm and the Sacituzumab govitean-hziy + pembrolizumab arm. III. To evaluate clinical benefit rate (complete response [CR]/partial response [PR] /stable disease [SD]) between the TPC arm and the Sacituzumab govitean-hziy + pembrolizumab arm. IV. To evaluate duration of response (DoR) between the TPC arm and the Sacituzumab govitean-hziy + pembrolizumab arm. V. To evaluate toxicity of the Sacituzumab govitean-hziy + pembrolizumab arm using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). EXPLORATORY HEALTH RELATED QUALITY OF LIFE (HRQOL) OBJECTIVES: I. To compare HRQOL, as assessed by the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Bladder Symptom Index-18 (FBISI-18) summary score between patients on the TPC arm versus the Sacituzumab govitean-hziy + pembrolizumab arm at 6 months. II. To compare HRQOL change from baseline, as assessed by the FBISI-18 summary score, for patients on the TPC arm versus theSacituzumab govitean-hziy + pembrolizumab arm at baseline, 3, 6, and 12 months. III. To compare the change in patient-reported fatigue from baseline and across 3, 6, and 12 months as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) summary score; change from baseline will be compared between patients on the TPC arm versus the Sacituzumab govitean-hziy + pembrolizumab arm. IV. To compare quality-adjusted survival (overall survival x health utility score assessed by the European Quality of Life Five Dimension Five Level [EQ-5D-5L]) between patients on the TPC arm versus the Sacituzumab govitean-hziy + pembrolizumab arm. V. To compare time to HRQOL deterioration in global HRQOL, as measured by the FBISI-18 disease-related physical symptom subscale (FBISI-18 disease-related symptoms (DRS) in the physical emotional domains [DRS-P]), between patients on the TPC arm versus the Sacituzumab govitean-hziy + pembrolizumab arm. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive TPC with carboplatin or cisplatin intravenously (IV) on day 1 and gemcitabine IV on days 1 and 8 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may alternately receive TPC with docetaxel IV on day 1 of each cycle or paclitaxel IV on days 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients additionally undergo blood sample collection and computed tomography (CT) or magnetic resonance imaging (MRI) throughout the study. ARM B: Patients receive Sacituzumab govitean-hziy IV over 1-3 hours on days 1 and 8 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 35 cycles or for 2 years of pembrolizumab in the absence of disease progression or unacceptable toxicity. Cycles of sacituzumab govitean-hziy repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients additional undergo blood sample collection, and CT or MRI throughout the study. After completion of study treatment, patients are followed up at 30 days then once a year for 5 years from the date of randomization.