A Phase III Randomized Trial of Pembrolizumab in Combination With Sacituzumab Govitean-hziy vs Standard of Care in Anti-PD(L)1-Resistant Advanced Urothelial Cancer

Official Summary

This phase III trial compares the effectiveness of pembrolizumab and sacituzumab govitean-hziy to standard of care in treating patients with urothelial cancer that has spread to nearby tissue or lymph nodes (locally advanced) or that has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Sacituzumab govitean-hziy is a monoclonal antibody, called sacituzumab, linked to a chemotherapy drug called govitean-hziy. Sacituzumab attaches to TROP2 positive tumor cells in a targeted way and delivers govitean-hziy to kill them. The usual treatment approach is treatment with chemotherapy such as cisplatin, carboplatin, gemcitabine, docetaxel or paclitaxel. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of tumor cells. Gemcitabine is a chemotherapy drug that blocks the cells from making deoxyribonucleic acid and may kill tumor cells. Docetaxel is in a class of medications called taxanes. It stops tumor cells from growing and dividing and may kill them. Paclitaxel is in a class of medications called antimicrotubule agents. It stops tumor cells from growing and dividing and may kill them. Giving pembrolizumab and sacituzumab govitean-hziy may be more effective than usual care of carboplatin or cisplatin with gemcitabine, docetaxel or paclitaxel in treating patients with locally advanced or metastatic urothelial cancer.

Eligibility Requirements

• Minimum Age: 18 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 320 participants

Study Arms

• Arm I (TPC chemotherapy) (ACTIVE_COMPARATOR)
  Patients receive TPC with carboplatin or cisplatin 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 additional undergo blood sample collection, and C
• Arm II (pembrolizumab, sacituzumab govitean-hziy) (EXPERIMENTAL)
  Patients receive pembrolizumab IV over 30 minutes on day 1 and sacituzumab govitean-hziy IV over 1-3 hours on days 1 and 8 of each cycle. Cycles repeat 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.

Interventions

• PROCEDURE: Biospecimen Collection — Undergo blood sample collection
• DRUG: Carboplatin — Given IV
• DRUG: Cisplatin — Given IV
• PROCEDURE: Computed Tomography — Undergo CT
• DRUG: Docetaxel — Given IV

Primary Outcomes

• Overall survival (OS) (From randomization to death due to any cause, assessed up to 5 years)

Secondary Outcomes

• Progression-free survival (PFS) (From randomization to the earlier progression or death due to any cause, assessed up to 5 years)
• Overall response rate (ORR) (Up to 5 years)
• Clinical benefit rate (CBR) (Up to 5 years)
• Duration of response (DOR) (From the first occurrence of a documented objective response to disease progression or death, whichever occurs first, assessed up to 5 years)
• Incidence of adverse events (AEs) (Up to 30 days after last dose of study drug)

Eligibility 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 cont

Trial Locations

• Cancer Center at Saint Joseph's, Phoenix, Arizona, United States
• UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care, Irvine, California, United States
• UC Irvine Health/Chao Family Comprehensive Cancer Center, Orange, California, United States
• UF Health Cancer Institute - Gainesville, Gainesville, Florida, United States
• Emory University Hospital Midtown, Atlanta, Georgia, United States
• Emory University Hospital/Winship Cancer Institute, Atlanta, Georgia, United States
• Emory Saint Joseph's Hospital, Atlanta, Georgia, United States
• Kootenai Health - Coeur d'Alene, Coeur d'Alene, Idaho, United States
• Kootenai Clinic Cancer Services - Post Falls, Post Falls, Idaho, United States
• Kootenai Clinic Cancer Services - Sandpoint, Sandpoint, Idaho, United States
• ...and 10 more locations

Study Officials

• Monika Joshi — PRINCIPAL_INVESTIGATOR
  ECOG-ACRIN Cancer Research Group

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