| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Histologically documented locally advanced (tumor [T] 4b, any node [N]; or any T, N 2-3) or metastatic (M1, Stage IV) urothelial carcinoma of the urinary tract predominant |
|
| E.1.1.1 | Medical condition in easily understood language |
| Malignant urothelial cancer (UC) of renal pelvis, bladder, urethra or ureter |
|
| 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 Objective Response Rate (ORR) based on BICR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria (Cohorts 3, 4 and 6; Cohorts 1 and 2 by central review)
- PFS based on central review by RECIST 1.1 criteria (Cohort 5 only) |
|
| E.2.2 | Secondary objectives of the trial |
• Cohort 1 and 2
- DOR based on central review by RECIST 1.1
- PFS based on central review by RECIST 1.1
- OS
• Cohort 3
- DOR, CBR, and PFS based on BICR by RECIST 1.1
- ORR, DOR, CBR, and PFS based on investigator review by RECIST 1.1
- OS
- Safety and tolerability of SG in combination with pembrolizumab
• Cohort 4
- DOR, CBR, and PFS based on BICR by RECIST 1.1
- ORR, DOR, CBR, and PFS based on investigator review by RECIST 1.1 and iRECIST
- OS
- Safety and tolerability of SG in combination with cisplatin
• Cohort 5
- OS
- Safety and tolerability of SG in combination with ZIM (Cohort 5 Arm 1)
• Cohort 6
- DOR, CBR, and PFS based on BICR by RECIST 1.1
- ORR, DOR, CBR, and PFS based on investigator review by RECIST 1.1 and iRECIST
- OS
- Safety and tolerability of SG monotherapy (Cohort 6 Arm 1)
- Safety and tolerability of SG in combination with ZIM (Cohort 6 Arm 2)
- Safety and tolerability of SG in combination with ZIM and DOM (Cohort 6 Arm 3)
|
|
| 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 locally advanced (tumor [T] 4b, any node [N]; or any T, N 2-3) or metastatic UC.
Upper and lower tract tumors are permitted and mixed histologies are permitted if UC is the predominant histology.
3. Cohorts 4, 5 and 6: Archival tumor tissue comprising muscle-invasive or metastatic urothelial carcinoma, or a biopsy of metastatic urothelial carcinoma must be provided for biomarker testing including PD-L1 and Trop-2.
4. ECOG Performance status score of 0 or 1.
5. Cohort 1: Have had progression or recurrence of UC following receipt of platinum-containing regimen (cisplatin or carboplatin):
a) Received a first-line platinum-containing regimen in the metastatic setting or for inoperable locally advanced disease;
b) Or received neo/adjuvant platinum-containing therapy for localized muscle-invasive urothelial cancer, with ecurrence/progression ≤12 months following completion of therapy.
6. Cohort 1: In addition to #5, have had progression or recurrence of UC following receipt of an anti-PD-1/PD-L1 therapy and
have a creatinine clearance ≥60 ml/min.
7. Cohort 2: Were ineligible for platinum-based therapy* and have had progression or recurrence of UC therapy for metastatic disease with antiPD1/PD-L1 therapy. Subject may not have received any platinum for treatment of recurrent, metastatic or advanced disease.
8. *Cisplatin-ineligible
9. 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
10. Cohort 4: Cisplatin-eligible subject who has not received any therapy, specifically platinum-based chemotherapy in the metastatic or unresectable locally advanced setting.
11. Cohort 1, 2, 3: Adequate hematology without transfusion support or growth factor support within 2 weeks of study drug initiation (hemoglobin >9 g/dL, absolute neutrophil count (ANC) >1,500 per mm3, and Platelets >100,000 per μL).
12. Cohort 6: Subject with no prior therapy for metastatic disease or for unresectable locally advanced disease with the following exceptions:
a) Subjects who received neoadjuvant chemotherapy with curative intent with recurrence >12 months from completion of therapy are permitted.
b) Subjects who received adjuvant chemotherapy following cystectomy with curative intent with recurrence >12 months from completion of therapy are permitted.
13. Cohort 6: Cisplatin-ineligible
14. Cohort 6: Checkpoint inhibitor therapy naïve or >12 months from completion of for adjuvant therapy are permitted.
15. 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).
16. Adequate hepatic function (Bilirubin ≤1.5 ULN, AST and ALT ≤2.5 xULN or ≤5 x ULN if known liver metastases and serum albumin >/=3 g/dl)).
17. Cohorts 1, 2, 3 and 5: Creatinine clearance >/= 30mL/min as calculated by the Cockroft-Gault formula unless otherwise specified.
18. 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.
19. Cohort 5: Subjects received at least 4 cycles and no more than 6 cycles of GEM+CIS. 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 v1.1 guidelines as per investigator)
b) Treatment-free interval of 4 to 10 weeks since the last dose of chemotherapy.
20. Subjects must have a 3-month life expectancy.
21. Adequate coagulation (Prothrombin Time (PT) or INR and Activated Partial Thromboplastin Time (aPTT) ≤1.5xULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of
intended use of anticoagulants.
22. Cohorts 4 & 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.
23. Male subjects and female 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.
24. Subject must be willing and able to comply with all protocol requirements. |
|
| E.4 | Principal exclusion criteria |
1. Women who are pregnant or lactating.
2. 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 trial treatment.
3. Has a diagnosis of immunodeficiency.
4. Has had a prior anti-cancer mAb within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1) from adverse events due to agents administered more than 4 weeks earlier.
5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 from adverse events due to a previously administered agent.
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.
6. Cohorts 4 and 5: Refractory to platinum ( in the neoadjuvant/adjuvant setting.
7. Requires concomitant medications that significantly interfere with
UGT1A1 with no alternate option available.
8. Subjects with Gilbert’s disease.
9. Subjects who previously received irinotecan.
10. Has an active second malignancy.
11. 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 greater than 20 mg of prednisone daily for brain metastases for at least 7 days prior to trial treatment. All subjects with carcinomatous meningitis are excluded regardless of clinical stability.
12. 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 , 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. New York Heart Association Class III or greater congestive heart failure or left ventricular ejection fraction of < 40%.
13. Has active chronic inflammatory bowel disease and subjects with a history of bowel obstruction.
14. Has prior history of clinically significant bleeding, intestinal obstruction, or GI perforation within 6 months of enrollment.
15. Must be at least 2 weeks beyond high dose systemic corticosteroids (however, low dose corticosteroids ≤ 20 mg prednisone or equivalent daily are permitted for reasons outside of CNS disease provided the dose is stable for 4 weeks).
16. Has an active infection requiring systemic therapy.
17. 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.
18. Has active hepatitis B virus or hepatitis C virus defined as those with a detectable viral load.
19. 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.
20. Use of live attenuated vaccine(s) 30 days before start of study drug.
21. 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.
22. 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.
23. Cohorts 3, 4, 5, and 6: Has received immunosuppressive therapy within 3 years prior to C1D1.
24. Cohorts 3, 4, 5, and 6: Has history or evidence of interstitial lung disease or non-infectious pneumonitis.
25. Cohort 3: Has received anti-PD-1/PD-L1 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.
26. Cohort 4 and Cohort 6: Hypersensitivity or anaphylaxis to cisplatin, CARBO, or GEM.
27. 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.
28. Cohort 4: ≥Grade 2 hearing loss. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| In Cohorts 3, 4 and 6, the primary endpoint is ORR based on BICR by RECIST 1.1 criteria; In Cohort 5, the primary endpoint is PFS as assessed based on BICR by RECIST 1.1 criteria (Cohorts 1 and 2 by central review). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints include DOR, CBR, and PFS based on central review by RECIST 1.1 criteria and ORR, DOR, CBR, and PFS based
on investigator assessment by RECIST 1.1 criteria. In Cohort 3, 4 and 6, these secondary endpoints (ORR, DOR, CBR, and PFS) will also be evaluated by the investigator according to iRECIST 1.1 criteria |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The ORR is defined as the rate of the best overall response as CR or partial response (PR).
The DOR will be calculated as the date of the first evaluation showing documented response, PR, or CR, to the date of the first PD or death.
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.
CBR is defined as CR + PR + stable disease (SD) for at least 6 months.
OS will be measured from the date of first dose to death from any cause. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 57 |
| 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 |
| France |
| Germany |
| Greece |
| Italy |
| Korea, Republic of |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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