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 with 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) 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 metastatic or locally advanced unresectable UC defined as:
• Tumor (T) 4b, any node (N) or
• Any T, N 2-3
Tumors of upper and lower urinary tract are permitted. Mixed histologic types are allowed if urothelial is the predominant histology.
3) ECOG PS score of 0 or 1.
4) Subjects with progression or recurrence following receipt of platinumcontaining
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.
5) 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.
6) 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).
7) 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.
8) 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.
9) 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 known history of Human Immunodeficiency Virus (HIV)-1/2 with undetectable viral load and on 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. European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) score and European Quality of Life 5-dimensions 5-levels (EuroQOL EQ-5D-5L) 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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 120 |
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 | 9 |
E.8.9.1 | In the Member State concerned days | |
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 |