SACITUZUMAB GOVITECAN for Locally advanced/metastatic urothelial cancer

Inclusion criteria

• {"criterion_text":"- Inclusion Criteria for Cohorts 1 to 6: Female or male individuals, ≥ 18 years of age (19 Years old for South Korea).\n- 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.\n- 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.\n- Cohorts 1, 2, 3 and 5: Creatinine clearance ≥ 30 mL/min as calculated by the Cockcroft-Gault formula unless otherwise specified\n- Cohort 6: cisplatin-ineligibility defined as meeting 1 of the following criteria: a) Creatinine clearance ≥ 30 mL/min to < 60 mL/min as assessed by the Cockcroft-Gault equation or other validated instruments (eg, Modification of Diet in Renal Disease equation) b) Grade ≥ 2 audiometric hearing loss c) Grade ≥ 2 peripheral neuropathy d) NYHA Class III heart failure\n- Cohort 6: checkpoint inhibitor therapy naive or > 12 months from completion of adjuvant therapy are permitted.\n- Cohorts 4, 5, and 6: adequate hematology without transfusion support or growth factor support within 2 weeks of study drug initiation ANC ≥ 1500 per mm3, platelets ≥ 100,000 per μL, and hemoglobin ≥ 9 g/dL).\n- Adequate hepatic function (bilirubin ≤ 1.5 ULN, AST and ALT ≤ 2.5  ULN or AST and ALT ≤ 5  ULN if known liver metastases).\n- Cohorts 1, 2, 3, and 5: creatinine clearance ≥ 30 mL/min as calculated by the Cockcroft-Gault formula unless otherwise specified.\n- Cohort 4: creatinine clearance of at least 50 mL/min calculated by Cockcroft-Gault formula or another validated tool. For subjects receiving cisplatin at 70 mg/m2 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. Subjects with creatinine clearance between 50 to 59 mL/min are to receive a split dose of cisplatin (35 mg/m2 Day 1 and Day 8 of every 21-day cycle).\n- Cohort 5: subjects 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. a) No evidence of progressive disease following completion of first-line chemotherapy (ie, CR, PR, or SD per RECIST 1.1 guidelines as per investigator). b) Treatment-free interval of 4 to 10 weeks since the last dose of chemotherapy.\n- Individuals with histologically confirmed urothelial cancer (UC).\n- Subjects must have a 3-month life expectancy.\n- Adequate coagulation (prothrombin time [PT]) or international normalized ratio [INR] and activated partial thromboplastin time [aPTT]) ≤ 1.5  ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants.\n- 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.\n- Male/assigned male at birth subjects and female/assigned female at birth subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception as described in Appendix 16.7.\n- Subject must be willing and able to comply with all protocol requirements.\n- Inclusion Criteria for Cohort 7: Female/assigned female at birth or male/assigned male at birth subjects, 18 years of age or older, able to understand and give written informed consent.\n- Subjects with histologically documented UC that is locally advanced (tumor [T] 4b, any node [N]; or any T, N 2-3) or metastatic (M1, Stage IV). Upper and lower tract tumors are permitted and mixed histologies are permitted if UC is the predominant histology.\n- Archival tumor tissue comprising primary or locally advanced or metastatic UC must be provided for biomarker testing including PD-L1 and Trop-2. If archival tumor tissue is not available, a fresh biopsy from locally advanced or metastatic UC must be provided for biomarker testing including PD-L1 and Trop-2.\n- No prior systemic therapy for locally advanced or metastatic UC. Therapy in the curative setting is allowed provided recurrence is > 12 months since the last dose of systemic therapy.\n- ECOG performance status 0-1.\n- Eastern Cooperative Oncology Group (ECOG) Performance status score of 0 or 1.\n- Adequate hematologic counts without transfusional or growth factor support within 2 weeks of study drug initiation (hemoglobin ≥ 9 g/dL, ANC ≥ 1500/mm3, and platelets ≥ 100,000/μL).\n- Adequate hepatic function (bilirubin ≤ 1.5 × ULN, AST and ALT ≤ 2.5 × ULN or AST and ALT ≤ 5 × ULN if known liver metastases).\n- Creatinine clearance ≥ 30 mL/min as assessed by the Cockcroft-Gault equation or other validated instruments (eg, Modification of Diet in Renal Disease equation).\n- Have measurable disease by computed tomography (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.\n- Subjects must have at least a 3-month life expectancy.\n- Male/assigned male at birth subjects and female/assigned female at birth subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocolspecified method(s) of contraception as described in Appendix 16.7.\n- Subject must be willing and able to comply with all protocol requirements.\n- 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.\n- 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.\n- 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.\n- 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.\n- 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/m2 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/m2 Day 1 and Day 8 of every 21-day cycle).\n- 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."}

Exclusion criteria

• {"criterion_text":"- Exclusion Criteria for Cohorts 1 to 6: Females who are pregnant or lactating.\n- Has an active second malignancy. Note: subjects with a history of malignancy that has been completely treated, with no evidence of active cancer for 3 years prior to enrollment, or subjects with surgically cured tumors with low risk of recurrence are allowed to enroll.\n- Has 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 not using steroids ≥ 10 mg of prednisone (or equivalent) daily for brain metastases for at least 7 days prior to study treatment. All subjects with carcinomatous meningitis are excluded regardless of clinical stability.\n- Has active cardiac disease, defined as: a) Myocardial infarction or unstable angina pectoris within 6 months of the first date of study therapy. b) History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring antiarrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication); history of QT interval prolongation. c) NYHA Class III or greater congestive heart failure or left ventricular ejection fraction of < 40%.\n- Has active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) and subjects with a history of bowel obstruction.\n- Has prior history of clinically significant bleeding, intestinal obstruction, or GI perforation within 6 months of enrollment.\n- Must be at least 2 weeks beyond high-dose systemic corticosteroids (however, low-dose corticosteroids < 10 mg prednisone or equivalent daily are permitted for reasons outside of CNS disease provided the dose is stable for 4 weeks).\n- Has an active infection requiring systemic therapy.\n- Have known history of HIV-1 or -2 with uncontrolled viral load (ie, ≥ 200 copies/mL or CD4+ T-cell count < 350 cells/μL) or taking medications that may interfere with metabolism of study drugs. No HIV testing is required unless mandated by local health authority.\n- Has active hepatitis B virus or hepatitis C virus defined as those with a detectable viral load.\n- Has 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.\n- Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to the first dose of study treatment.\n- Use of live attenuated vaccine(s) within 30 days before start of study drug.\n- Cohorts 3, 4, 5, and 6: 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.\n- Cohorts 3, 4, 5, and 6: has received a live vaccine including COVID-19 vaccines within 30 days prior to the first dose of study drug(s). Seasonal flu and COVID-19 vaccines that do not contain live virus are permitted.\n- Cohorts 3, 4, 5, and 6: has received immunosuppressive therapy within 3 years prior to Cycle 1 Day 1 (C1D1).\n- Cohorts 3, 4, 5, and 6: has history or evidence of interstitial lung disease or noninfectious pneumonitis.\n- Cohort 3: has received anti–PD-1– or anti–PD-L1–based therapy previously. Cohorts 4, 5, and 6: for subjects who received prior CPI, a treatment-free interval > 12 months between the last treatment administration and the date of recurrence is required.\n- Cohort 4 and Cohort 6: hypersensitivity or anaphylaxis to cisplatin, CARBO, or GEM.\n- Cohorts 1 to 6: have inability to tolerate or are allergic to SG, or CPIs, or are unable or unwilling to receive the doses specified in the protocol.\n- Cohort 4: Grade ≥ 2 hearing loss.\n- Cohort 4: Grade ≥ 2 peripheral neuropathy.\n- Has a diagnosis of immunodeficiency.\n- Cohort 5: subjects whose disease progressed by RECIST 1.1 on or after first-line chemotherapy for UC.\n- Exclusion Criteria for Cohort 7\n- Has had a prior anticancer mAb within 4 weeks prior to study Day 1 or who has not recovered (ie, Grade ≤ 1) from AEs due to agents administered more than 4 weeks earlier.\n- 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). However, 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. Note: subjects with Grade ≤ 2 neuropathy or Grade ≤ 2 alopecia are an exception to this criterion and may qualify for the study. Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.\n- Cohort 4: refractory to platinum (ie, relapsed ≤ 12 months after completion of chemotherapy) in the neoadjuvant/adjuvant setting.\n- Criterion removed: requires concomitant medications that significantly interfere with UGT1A1 with no alternate option available.\n- Subjects with Gilbert’s disease.\n- Subjects who previously received irinotecan."}

Primary endpoints

• {"endpoint_text":"- The primary endpoint in Cohorts 1 to 4 is ORR based on central review (Cohorts 1 and 2) or BICR (Cohorts 3 and 4) as assessed by RECIST 1.1 criteria. In Cohort 5, the primary endpoint is PFS based on BICR as assessed by RECIST 1.1 criteria.","definition_or_measurement_approach":"ORR = objective response rate assessed by central review or blinded independent central review (BICR) according to RECIST 1.1 criteria. PFS = progression-free survival assessed by BICR per RECIST 1.1."}
• {"endpoint_text":"- In Cohort 6, the primary endpoint is ORR based on BICR as assessed by RECIST 1.1 criteria.","definition_or_measurement_approach":"ORR assessed by blinded independent central review (BICR) using RECIST 1.1 criteria."}
• {"endpoint_text":"- In Cohort 7, the primary efficacy endpoint is confirmed ORR based on investigator review as assessed by RECIST 1.1 criteria.","definition_or_measurement_approach":"Confirmed ORR assessed by investigator review using RECIST 1.1 criteria."}

Secondary endpoints

• {"endpoint_text":"- Secondary efficacy endpoints for Cohorts 1 and 2 are DOR and PFS based on central review as assessed by RECIST 1.1 criteria and OS. Secondary efficacy endpoints for Cohorts 3 and 4 are DOR, CBR, and PFS based on BICR as assessed by RECIST 1.1 criteria; ORR, DOR, CBR, and PFS based on investigator assessment by RECIST 1.1 criteria; and OS. In Cohorts 3 and 4, ORR, DOR, CBR, and PFS will also be evaluated by the investigator according to iRECIST criteria.","definition_or_measurement_approach":"DOR = duration of response; PFS = progression-free survival; OS = overall survival; CBR = clinical benefit rate. Measurements by central review, BICR or investigator assessment per RECIST 1.1 and where specified iRECIST."}
• {"endpoint_text":"- In Cohort 5, the secondary efficacy endpoint is OS. In Cohort 6, secondary efficacy endpoints are DOR, CBR, and PFS based on BICR as assessed by RECIST 1.1 criteria; ORR, DOR, CBR, and PFS based on investigator assessment by RECIST 1.1 criteria; and OS. In Cohort 6, ORR, DOR, CBR, and PFS will also be evaluated by the investigator according to iRECIST criteria.","definition_or_measurement_approach":"OS = overall survival; DOR, CBR, PFS, ORR as defined above using BICR/RECIST 1.1 and investigator assessment; iRECIST used where specified."}
• {"endpoint_text":"- In Cohort 7, secondary efficacy endpoints are ORR based on BICR by RECIST 1.1 criteria; DOR, CBR, and PFS based on investigator review and BICR by RECIST 1.1 criteria; and OS. Additionally, ORR, DOR, CBR, and PFS will be evaluated by the investigator according to iRECIST criteria.","definition_or_measurement_approach":"ORR, DOR, CBR, PFS measured by BICR and investigator review per RECIST 1.1 and iRECIST where specified; OS = overall survival."}

France

Earliest CTIS Part Ii Submission Date

07-05-2019

Latest Decision Or Authorization Date

13-04-2026

Processing Time Days

2533

Number Of Participants

65

Germany

Earliest CTIS Part Ii Submission Date

15-02-2023

Latest Decision Or Authorization Date

09-04-2026

Processing Time Days

1149

Number Of Participants

2

Greece

Earliest CTIS Part Ii Submission Date

27-04-2023

Latest Decision Or Authorization Date

08-04-2026

Processing Time Days

1077

Number Of Participants

3

Italy

Earliest CTIS Part Ii Submission Date

27-10-2023

Latest Decision Or Authorization Date

07-04-2026

Processing Time Days

893

Number Of Participants

30

Spain

Earliest CTIS Part Ii Submission Date

03-02-2023

Latest Decision Or Authorization Date

10-04-2026

Processing Time Days

1162

Number Of Participants

16

Primary sponsor

Full Name

Gilead Sciences Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

CRO – Site Management

Third parties

• {"country":"United States","full_name":"Kcas LLC","duties_or_roles":"Lab services for PK &A DA samples","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Reify Health Inc.","duties_or_roles":"Pre-screening/enrolment","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"CRO – Site Management","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"EndPoint Clinical","duties_or_roles":"IXRS - Endpoint performs IXRS services for central randomization.","organisation_type":"Industry"}
• {"country":"United States","full_name":"Ventana Medical Systems Inc.","duties_or_roles":"Performing specialized testing (Trop-2), coordinated through LabCorp.","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"Drug Supply - Almac performs IP packaging, labeling and supply management to sites globally.","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Teckro Limited","duties_or_roles":"Digital clinical trial hub for content, communication and insights.","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Veeva Systems Inc.","duties_or_roles":"eTMF","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services S.a.r.l.","duties_or_roles":"Sample Management including lab coordination, lab kit build and distribution and lab manual services.","organisation_type":"Pharmaceutical company"}