| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic or Locally Advanced Unresectable Urothelial Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
Urothelial Cancer not possible of being surgically removed which has
grown outside the area it started in and has either spread or not yet
spread to distant parts of the body |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10077840 |
| E.1.2 | Term | Urothelial cancer of renal pelvis |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046714 |
| E.1.2 | Term | Urothelial carcinoma bladder |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046723 |
| E.1.2 | Term | Urothelial carcinoma ureter |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046728 |
| E.1.2 | Term | Urothelial carcinoma urethra |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective is to assess Overall Survival with sacituzumab govitecan in comparison with treatment of physician’s choice
(TPC) in subjects with metastatic or locally advanced unresectable UC. |
|
| E.2.2 | Secondary objectives of the trial |
1. To assess PFS of sacituzumab govitecan in comparison with TPC by investigator assessment and blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
2. To assess ORR, clinical benefit rate (CBR), and duration of objective tumor response (DOR) with sacituzumab govitecan in comparison with TPC by investigator assessment and BICR using RECIST v1.1
3. To assess safety and tolerability of sacituzumab govitecan in comparison with TPC
4. To assess Quality of Life (QOL) based on European Organisation for
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) with sacituzumab govitecan in comparison with TPC |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Female or male subjects, ≥ 18 years of age, able to understand and give written informed consent.
2) Subjects with histologically documented UC that is metastatic or locally advanced unresectable UC defined as:
• Tumor (T) 4b, any node (N) or
• Any T, N 2-3
3) Tumors of upper and lower urinary tract are permitted. Mixed histologic types are allowed if urothelial is the predominant histology.
4) ECOG PS score of 0 or 1.
5) Subjects with progression or recurrence following receipt of platinum-containing regimen and anti-PD-1/PD-L1 therapy for metastatic or locally advanced unresectable disease will be enrolled.
a) Subjects with recurrence or progression ≤ 12 months following completion of cisplatin-containing chemotherapy given in the neoadjuvant/ adjuvant setting may utilize that line of therapy to be eligible for the study. The 12-month period is counted from completion of surgical intervention or cisplatin therapy, respectively. These subjects must receive anti-PD-1/PD-L1 therapy in the metastatic or locally advanced unresectable setting to be eligible.
b) Subjects who received either carboplatin or anti-PD-1/PD-L1 therapy in the neoadjuvant/ adjuvant setting will not be able to count that line of therapy towards eligibility for the study.
c) Cisplatin-ineligible subjects who meet one of the below criteria and who were treated with carboplatin in the metastatic or locally advanced unresectable settings may count that line of therapy towards eligibility. They must then have received anti-PD-1/PDL1
therapy in metastatic or locally advanced unresectable setting to be eligible for the study.
Cisplatin ineligibility is defined as meeting one of the following criteria:
i) Creatinine Clearance <60 mL/min
ii) Grade ≥2 Audiometric Hearing Loss
iii) Grade ≥2 Peripheral Neuropathy
iv) New York Heart Association (NYHA) Class III heart failure
v) ECOG PS ≥2
d) Anti PD-1/PD-L1 therapy administered as part of maintenance therapy may be counted towards eligibility for the study
e) Subjects who have progressed after receiving enfortumab vedotin in prior lines of therapy, and subjects who are either ineligible or unable to tolerate enfortumab vedotin therapy, are eligible to enroll in the study.
f) Subjects who received only concurrent chemoradiation for bladder preservation without further systemic therapy are not eligible to enroll in the study. The substitution of carboplatin for cisplatin does not constitute a new regimen provided no new chemotherapeutic agents were added to the regimen and no progression was noted prior to the change in platinum.
6) Subjects with previously treated brain metastases may participate in the study provided they have stable CNS disease for at least 4 weeks prior to the first dose of study drug and stabilization of all neurologic symptoms, have no evidence of new or enlarging brain metastases, and are not using steroids > 20 mg of prednisone (or equivalent) daily for brain metastases for at least 7 days prior to first dose of the study drug.
7) Adequate hematologic counts without transfusion or growth factor support within 2 weeks of study drug initiation (hemoglobin ≥ 9 g/dL, absolute neutrophil count [ANC] ≥ 1,500/mm3, and platelets ≥ 100,000/μL).
8) Adequate hepatic function (bilirubin ≤ 1.5x institutional upper limit of normal [IULN], aspartate aminotransferase [AST] and alanine aminotransferase [ALT] ≤ 2.5 x IULN or ≤ 5 x IULN if known liver metastases and serum albumin > 3 g/dL).
Docetaxel will only be an option in TPC arm for subjects with a total bilirubin ≤ 1 x IULN, and an AST and/or ALT ≤ 1.5x IULN if alkaline phosphatase is also > 2.5 x IULN.
9) Creatinine clearance ≥ 30 mL/min as assessed by the Cockcroft-Gault equation or other validated instruments (eg Modification of Diet in Renal Disease [MDRD] equation.
10) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception. |
|
| E.4 | Principal exclusion criteria |
1) Women who are pregnant or lactating.
2) Have had a prior anti-cancer mAb/ADC within 4 weeks prior to 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.
3) Have received prior chemotherapy for urothelial cancer with any available SOC therapies in the control arm (ie, either prior paclitaxel and docetaxel in countries where vinflunine is not an approved therapy, or either paclitaxel, docetaxel and vinflunine in countries where vinflunine is approved and is commercially available).
4) Have not recovered (ie, ≤ Grade 1) from AEs due to previously administered chemotherapeutic agent.
• Note: Subjects with ≤ Grade 2 neuropathy or any grade of alopecia are an exception to this criterion and will qualify for the study.
• Note: If subjects received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study therapy.
5) Have previously received topoisomerase 1 inhibitors.
6) Have an active second malignancy.
• Note: Subjects with a history of malignancy that have been completely treated and 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 in the study after discussion with the medical monitor.
7) Have active cardiac disease, defined as:
a) Myocardial infarction or unstable angina pectoris within 6 months of C1D1
b) History of serious ventricular arrhythmia (ie, 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 anti-arrhythmic medication); history of QT interval prolongation.
c) NYHA Class III or greater congestive heart failure or left ventricular ejection fraction of <40%.
8) Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or GI perforation within 6 months of enrollment.
9) Have an active serious infection requiring anti-infective therapy (Contact medical monitor for clarification).
10) Have uncontrolled (HIV)-1/2 viral load (ie, = 200 copies/mL and/or CD4+ count < 350 cells/mm3) and/or medications that may interfere with SN-38 metabolism.
11) Have active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV). In subjects with a history of HBV or HCV, subjects with a detectable viral load will be excluded.
12) 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.
13) Have inability to tolerate or are allergic to any potential TPC agent or sacituzumab govitecan or unable or unwilling to receive the doses specified in the protocol.
14) Have inability to complete all specified study procedures for any reason.
15) History of active interstitial lung disease or noninfectious pneumonitis. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall Survival (OS):
OS is defined as the time from the date of randomization to the date of death, regardless of cause. If a subject is not known to have died, OS will be censored at the date the subject is last known to be alive. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Monitored throughout the study and OS will be captured q8 weeks once patients discontinue treatment |
|
| E.5.2 | Secondary end point(s) |
1. Progression-free Survival (PFS) by investigator assessment and Blinded Independent Central Review (BICR) using RECIST v1.1
2. Objective Response Rate (ORR), Clinical Benefit Rate (CBR) and Duration of Objective Tumor Response (DOR) by investigator assessment and BICR using RECIST v1.1
3. Safety and tolerability evaluated by AEs, SAEs, and laboratory changes
4. Change from baseline in the physical functioning, global health status, pain, and fatigue scales of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) score |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Monitored throughout the study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 127 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| China |
| Hong Kong |
| Israel |
| Korea, Republic of |
| United States |
| Austria |
| France |
| Sweden |
| Bulgaria |
| Spain |
| Switzerland |
| Czechia |
| Germany |
| Greece |
| Italy |
| Belgium |
| Croatia |
| Georgia |
| Hungary |
| Ireland |
| Portugal |
| Russian Federation |
| Turkey |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study will be the date of the last visit/contact/survival follow-up in the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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