Study of Sacituzumab Govitecan in Participants With Urothelial Cancer That Cannot Be Removed or Has Spread

Study Overview
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Brief Summary
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The objective of this study is to evaluate the efficacy and safety of sacituzumab govitecan-hziy monotherapy and with novel combinations in participants with metastatic urothelial cancer (mUC).

Detailed Description
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Non-Randomized for Cohorts 1,2,3, and 4; Randomized for Cohorts 5 and 6. Cohort 5 has been cancelled, effective December 2023.

Official Title
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A Phase II Open-Label Study of Sacituzumab Govitecan in Unresectable Locally Advanced/Metastatic Urothelial Cancer

Conditions
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Metastatic Urothelial Cancer

Intervention / Treatment
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* Drug: Sacituzumab Govitecan-hziy
* Drug: Pembrolizumab
* Drug: Cisplatin
* Drug: Avelumab
* Drug: Zimberelimab
* Drug: Carboplatin
* Drug: Gemcitabine
* Drug: Domvanalimab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Female or male individuals, ≥ 18 years of age (19 Years old for South Korea). Individuals with histologically confirmed urothelial cancer (UC). Eastern Cooperative Oncology Group (ECOG) Performance status score of 0 or 1. Cohort 1: Have had progression or recurrence of urothelial cancer following receipt of platinum-containing regimen (cisplatin or carboplatin): Received a first-line platinum-containing regimen in the metastatic setting or for inoperable locally advanced disease; Or received neo/adjuvant platinum-containing therapy for localized muscle-invasive urothelial cancer, with recurrence/progression ≤12 months following completion of therapy. Cohort 1: In addition to above criterion, have had progression or recurrence of urothelial cancer following receipt of an Anti-programmed Cell Death Protein 1 (anti-PD-1)/ Anti-programmed Death Ligand 1 (PD-L1) therapy. Cohort 2: Were ineligible for platinum-based therapy for first line metastatic disease and have had progression or recurrence of urothelial cancer after a first-line therapy for metastatic disease with anti-PD-1/PD-L1 therapy. Individual may not have received any platinum for treatment of recurrent, metastatic or advanced disease. Cohort 3: Progression or recurrence of UC following a platinum containing regimen in the metastatic setting, or progression or recurrence of UC within 12 months of completion of platinum-based therapy as neoadjuvant or adjuvant therapy. Cohort 4: Individual has not received any platinum-based chemotherapy in the metastatic or unresectable locally advanced setting. Creatinine clearance of at least 50 mL/min calculated by Cockcroft-Gault formula or another validated tool. For individuals receiving cisplatin at 70 mg/m^2 on Day 1 of every 21-day cycle, a creatinine clearance of least 60 mL/min calculated by Cockcroft -Gault formula or another validated tool is required. Individuals with creatinine clearance between 50 to 59 mL/min are to receive a split dose of cisplatin (35 mg/m^2 Day 1 and Day 8 of every 21-day cycle). Cohorts 4, 5, 6: Archival tumor tissue comprising muscle-invasive or metastatic urothelial carcinoma, or a biopsy of metastatic urothelial carcinoma. Cohort 5: Individuals received at least 4 cycles and no more than 6 cycles of GEM + cisplatin. No other chemotherapy regimens are allowed in this cohort, with the exception of prior adjuvant or neoadjuvant systemic therapy with curative intent after > 12 months from completion of therapy. No evidence of progressive disease following completion of first-line chemotherapy (ie, CR, PR, or SD per RECIST v1.1 guidelines as per investigator). Treatment-free interval of 4 to 10 weeks since the last dose of chemotherapy. Cohort 6: Cis-ineligible and no prior therapy for metastatic disease or for unresectable locally advanced disease. Checkpoint inhibitor therapy naïve or >12 months from completion of adjuvant therapy are permitted. Cohorts 4 and 6: Have measurable disease by CT or MRI as per RECIST 1.1 criteria. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Cohorts 1, 2, 3 and 5: Creatinine clearance ≥ 30 mL/min as calculated by the Cockcroft-Gault formula unless otherwise specified Adequate renal and hepatic function. Adequate hematologic parameters without transfusional support. Individuals must have a 3-month life expectancy. Key Exclusion Criteria: Females who are pregnant or lactating. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (ie, ≤Grade 1 from AEs due to a previously administered agent). For Cohort 5: Alopecia, sensory neuropathy Grade ≤2 is acceptable, or other Grade < 2 adverse events not constituting a safety risk based on the investigator's judgment are acceptable. Requires concomitant medication interfering with UGT1A1 with no alternate option available. Has an active second malignancy. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Has known active Hepatitis B or Hepatitis C. Has other concurrent medical or psychiatric conditions. Cohort 3: Has received anti-PD-1/PD-L1 therapy previously. Cohorts 3 to 5: Has an active autoimmune disease that required systemic treatment in past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. Cohorts 3 to 6: Has received a live vaccine within 30 days prior to the first dose of study drug(s), has history or evidence of interstitial lung disease (ILD) or non-infectious pneumonitis. Cohort 4: Refractory to platinum (i.e., relapsed ≤ 12 months after completion of chemotherapy) in the neoadjuvant/adjuvant setting. Cohorts 4, 5, and 6: For individuals who received prior CPI, a treatment-free interval >12 months between the last treatment administration and the date of recurrence is required. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Sacituzumab Govitecan-hziy<br>Participants with urothelial cancer (UC) previously treated with platinum-based and/or checkpoint inhibitors (CPIs) will receive sacituzumab govitecan-hziy 10 mg/kg intravenously on Days 1 and 8 of a 21-day cycle. | Drug: Sacituzumab Govitecan-hziy<br>* Administered intravenously.<br>* Other names: Trodelvy™;|
| Experimental: Cohort 2: Sacituzumab Govitecan-hziy<br>Participants with UC who are ineligible for platinum-based therapy and failed therapy with previous immune CPI therapy will receive sacituzumab govitecan-hziy 10 mg/kg intravenously on Days 1 and 8 of a 21-day cycle. | Drug: Sacituzumab Govitecan-hziy<br>* Administered intravenously.<br>* Other names: Trodelvy™;|
| Experimental: Cohort 3: Sacituzumab Govitecan-hziy + Pembrolizumab<br>Participants who have had progression or recurrence of UC following a platinum-containing regimen in the metastatic setting, or progression or recurrence of UC within 12 months of completion of platinum-based therapy as neoadjuvant or adjuvant therapy will receive sacituzumab govitecan-hziy 10 mg/kg intravenously on Days 1 and 8 of a 21-day cycle and pembrolizumab at the standard approved dose (200 mg) only on Day 1 of a 21-day cycle. Lower doses of sacituzumab govitecan-hziy may be tested based on dose-limiting toxicities (DLTs) observed to determine the Recommended Phase 2 Dose (RP2D) of sacituzumab govitecan-hziy in combination with pembrolizumab. | Drug: Sacituzumab Govitecan-hziy<br>* Administered intravenously.<br>* Other names: Trodelvy™;Drug: Pembrolizumab<br>* Administered per package insert<br>* Other names: KEYTRUDA®;|
| Experimental: Cohort 4: Sacituzumab Govitecan-hziy + Cisplatin + Avelumab (Dose Escalation Phase)<br>Participants with UC who have never received therapy with platinum in the metastatic setting or for unresectable locally advanced disease will first receive cisplatin (either at 70 mg/m^2 on Day 1 of a 21-day cycle or at a split dose of 35 mg/m^2 on Days 1 and 8 of a 21-day cycle with a maximum body surface area of 2) and sacituzumab govitecan-hziy with maximum dose of 10 mg/kg intravenously on Days 1 and 8 of a 21-day cycle for up to 6 cycles. Based on DLTs observed, two additional lower doses may be tested to determine RP2D of sacituzumab govitecan-hziy in combination with cisplatin. If premature termination of 1 agent occurs due to toxicity, the other agent may be continued to complete up to 6 cycles of therapy. For participants who have not progressed, maintenance therapy will begin with infusions of avelumab 800 mg every 2 weeks beginning on Cycle 1, Day 1 and every 2 weeks thereafter and sacituzumab govitecan-hziy 10 mg/kg on Days 1 and 8 every 21 days. | Drug: Sacituzumab Govitecan-hziy<br>* Administered intravenously.<br>* Other names: Trodelvy™;Drug: Cisplatin<br>* Administered per package insert<br>Drug: Avelumab<br>* Administered per package insert<br>* Other names: BAVENCIO®;|
| Experimental: Cohort 4: Sacituzumab Govitecan-hziy + Cisplatin + Zimberelimab (Dose Expansion Phase)<br>Participants with UC who have never received therapy with platinum in the metastatic setting or for unresectable locally advanced disease will first receive cisplatin (either at 70 mg/m^2 on Day 1 of a 21-day cycle or at a split dose of 35 mg/m^2 on Days 1 and 8 of a 21-day cycle with a maximum body surface area of 2) and sacituzumab govitecan-hziy with maximum dose of 10 mg/kg intravenously on Days 1 and 8 of a 21-day cycle for up to 6 cycles. If premature termination of 1 agent occurs due to toxicity, the other agent may be continued to complete up to 6 cycles of therapy. For participants who have not progressed, maintenance therapy will begin with infusions of sacituzumab govitecan-hziy 10 mg/kg on Days 1 and 8 every 21 days and zimberelimab 360 mg every 3 weeks (Day 1 of a 21-day cycle). | Drug: Sacituzumab Govitecan-hziy<br>* Administered intravenously.<br>* Other names: Trodelvy™;Drug: Cisplatin<br>* Administered per package insert<br>Drug: Zimberelimab<br>* Administered intravenously<br>|
| Experimental: Cohort 5 (Arm 1): Sacituzumab Govitecan-hziy + ZIM<br>Participants in Cohort 5 will have completed 4 to 6 cycles of gemcitabine (GEM) + cisplatin therapy without PD prior to study entry. The safety lead-in will be conducted, in 6 to 8 participants (treated with SG 10 mg/kg IV on Day 1 and Day 8 of a 21-day cycle + ZIM 360 mg IV every 3 weeks on a 21-day cycle). Upon completion of the safety lead-in, participants will receive SG 10 mg/kg IV on Days 1 and 8 of a 21-day cycle followed by ZIM 360 mg IV, Q3W (Day 1 of a 21-day cycle) until PD, unacceptable toxicity, or loss of clinical benefit. participants who must discontinue 1 agent may continue the other until PD, unacceptable toxicity, or loss of clinical benefit. | Drug: Sacituzumab Govitecan-hziy<br>* Administered intravenously.<br>* Other names: Trodelvy™;Drug: Zimberelimab<br>* Administered intravenously<br>|
| Experimental: Cohort 5 (Arm 2): Avelumab<br>Participants in Cohort 5 will have completed 4 to 6 cycles of gemcitabine (GEM) + cisplatin therapy without PD prior to study entry. The safety lead-in will be conducted, in 6 to 8 participants (treated with SG 10 mg/kg IV on Day 1 and Day 8 of a 21-day cycle + ZIM 360 mg IV every 3 weeks on a 21-day cycle). Upon completion of the safety lead-in, participants will be randomized to receive avelumab 800 mg IV Q2W until PD, unacceptable toxicity, or loss of clinical benefit. | Drug: Avelumab<br>* Administered per package insert<br>* Other names: BAVENCIO®;|
| Experimental: Cohort 5 (Arm 3): ZIM<br>Participants in Cohort 5 will have completed 4 to 6 cycles of gemcitabine (GEM) + cisplatin therapy without PD prior to study entry. The safety lead-in will be conducted, in 6 to 8 participants (treated with SG 10 mg/kg IV on Day 1 and Day 8 of a 21-day cycle + ZIM 360 mg IV every 3 weeks on a 21-day cycle). Upon completion of the safety lead-in, participants will be randomized to receive ZIM 360 mg IV Q3W (Day 1 of a 21-day cycle) until PD, unacceptable toxicity, or loss of clinical benefit. | Drug: Zimberelimab<br>* Administered intravenously<br>|
| Experimental: Cohort 6 (Arm 1): Sacituzumab Govitecan-hziy<br>Upon completion of the safety lead-in, participants in Cohort 6 will be randomized and SG will be administered in cisplatin-ineligible participants who have never received therapy in the metastatic setting or for unresectable locally advanced disease. Treatment may be discontinued at any time, but participants will continue to be followed for tumor response until progression is documented, and alternate therapy is initiated. If participants discontinue therapy before evidence of radiologic progression, imaging should continue until radiologic progression is documented, if feasible. | Drug: Sacituzumab Govitecan-hziy<br>* Administered intravenously.<br>* Other names: Trodelvy™;|
| Experimental: Cohort 6 (Arm 2): Sacituzumab Govitecan-hziy + ZIM<br>Upon completion of the safety lead-in, participants in Cohort 6 will be randomized and SG in combination with ZIM will be administered in cisplatin-ineligible participants who have never received therapy in the metastatic setting or for unresectable locally advanced disease. The standard approved dose of SG will be used in combination with ZIM. Treatment may be discontinued at any time, but participants will continue to be followed for tumor response until progression is documented or alternate therapy is initiated. If participants discontinue therapy before evidence of radiologic progression, imaging should continue until radiologic progression is documented, if feasible. | Drug: Sacituzumab Govitecan-hziy<br>* Administered intravenously.<br>* Other names: Trodelvy™;Drug: Zimberelimab<br>* Administered intravenously<br>|
| Experimental: Cohort 6 (Arm 3): Sacituzumab Govitecan-hziy + ZIM + Domvanalimab<br>Upon completion of the safety lead-in, participants in Cohort 6 will be randomized and SG in combination with ZIM and DOM will be administered in cisplatin-ineligible participants who have never received therapy in the metastatic setting or for unresectable locally advanced disease. | Drug: Sacituzumab Govitecan-hziy<br>* Administered intravenously.<br>* Other names: Trodelvy™;Drug: Zimberelimab<br>* Administered intravenously<br>Drug: Domvanalimab<br>* Administered intravenously<br>|
| Experimental: Cohort 6 (Arm 4): Carboplatin + Gemcitabine<br>Upon completion of the safety lead-in, participants in Cohort 6 will be randomized and CARBO in combination with GEM will be administered in cisplatin-ineligible participants who have never received therapy in the metastatic setting or for unresectable locally advanced disease. Participants without disease progression as assessed by the investigator after completion of 4 to 6 cycles of therapy may continue with maintenance therapy (avelumab 800 mg every 2 weeks) until loss of clinical benefit. | Drug: Avelumab<br>* Administered per package insert<br>* Other names: BAVENCIO®;Drug: Carboplatin<br>* Administered per package insert<br>Drug: Gemcitabine<br>* Administered per package insert<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) Based on Central Review by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Criteria (Cohorts 1 to 4 and 6) | ORR will be defined as the rate of the best overall response as Complete Remission (CR) or Partial Response (PR) and based on central review by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) criteria. | Up to Survival Follow-up Visit (maximum of 2 years after Safety Follow-up Visit (30 days after last dose date)) | 
| Progression free survival (PFS) based on central review by RECIST 1.1 criteria (Cohort 5 only) | PFS will be defined as the time from first dose until objective tumor progression, as assessed based on central review, or death, whichever comes first. | Up to Survival Follow-up Visit (maximum of 2 years after Safety Follow-up Visit (30 days after last dose date)) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR will be defined as the rate of the best overall response as CR or PR and based on investigator review by RECIST 1.1 criteria for cohorts 3, 4, and 5. ORR will also be evaluated based on investigator review by Modified RECIST 1.1 for Immune-Based Therapeutics (iRECIST 1.1) for Cohort 3 only. | Up to Survival Follow-up Visit (maximum of 2 years after Safety Follow-up Visit (30 days after last dose date)) | 
| Duration of Response (DOR) | DOR will be calculated from the date of the first evaluation showing documented response, PR, or CR, to the date of the first disease progression or death and based on central and investigator review by RECIST 1.1 criteria for all cohorts. DOR will also be evaluated based on investigator review by iRECIST 1.1 for Cohort 3 only. | Up to Survival Follow-up Visit (maximum of 2 years after Safety Follow-up Visit (30 days after last dose date)) | 
| Progression-Free Survival (PFS) | PFS is defined as the time from the first dose until objective tumor progression,or death, whichever comes first and based on central and investigator review by RECIST 1.1 criteria for all cohorts. PFS will also be evaluated based on investigator review by iRECIST 1.1 for Cohort 3 only. | Up to Survival Follow-up Visit (maximum of 2 years after Safety Follow-up Visit (30 days after last dose date)) | 
| Overall Survival (OS) | OS will be measured from the date of first dose to death from any cause. | Up to Survival Follow-up Visit (maximum of 2 years after Safety Follow-up Visit (30 days after last dose date)) | 
| Clinical Benefit Rate (CBR) | CBR is defined as CR + PR + Stable Disease (SD) for at least 6 months and based on central and investigator review by RECIST 1.1 criteria for cohorts 3, 4, and 5. CBR will also be evaluated based on investigator review by iRECIST 1.1 for Cohort 3 only. | Up to Survival Follow-up Visit (maximum of 2 years after Safety Follow-up Visit (30 days after last dose date)) | 
| Cohorts 3, 4, and 5: Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) |  | First dose date up to last dose date plus 30 days (approximately 3 years) | 
| Cohorts 3, 4, and 5: Percentage of Participants Experiencing any Clinically Significant Laboratory Abnormalities |  | First dose date up to last dose date plus 30 days (approximately 3 years) |