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 or non-urothelial carcinoma of the urinary tract predominant |
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E.1.1.1 | Medical condition in easily understood language |
Malignant urothelial cancer of renal pelvis, bladder, urethra or ureter |
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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 | 20.0 |
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 |
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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 |
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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 |
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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 |
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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 central review. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are Duration of Response (DOR) and Progression-Free Survival (PFS) both based on central review and Overall Survival (OS). |
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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 (M1, Stage IV) urothelial or non-urothelial carcinoma of the urinary tract predominant 3. ECOG Performance status score of 0 or 1. 4. Cohort 1: Have had progression or recurrence of urothelial cancer 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 adjuvant platinum-containing therapy following cystectomy for localized muscle-invasive urothelial cancer, with recurrence/progression ≤12 months following completion of therapy. 5. Cohort 1: In addition to criterion #4, have had progression or recurrence of urothelial cancer following receipt of an anti-PD-1 /PD-L1 therapy and have a creatinine clearance ≥ 60 ml/min. 6. Cohort 2: Were ineligible for cisplatin-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 and have a creatinine clearance between 30-60mL/min. * Cisplatin ineligible defined as meeting one of the following criteria: a. Creatinine Clearance <60 ml/min b. Grade >=2 audiometric hearing loss c. Grade >=2 peripheral neuropathy d. New York Heart Association Class III heart failure 7. Adequate hematology without transfusion support (Hemoglobin > 9 g/dL, Absolute Neutrophil Count > 1,500 per mm3, and Platelets > 100,000 per mcL). 8. Adequate hepatic function (Bilirubin ≤ 1.5 IULN, AST and ALT ≤ 2.5 x IULN or ≤ 5 x IULN if known liver metastases and serum albumin >3 g/dl)). 9. Subjects must have a 3-month life expectancy. 10. 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. 11. 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. 12. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 13. Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >2 years. 14. Male subjects must agree to use an adequate method of contraception starting with the first dose of study therapy through 6 months after the last dose of study therapy. |
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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 monoclonal antibody (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. Requires concomitant medication interfering with ABCA1 transporter or UGT1A1 7. Subjects with Gilbert’s disease. 8. Patients who previously received irinotecan. 9. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. A history of prostate cancer that was identified incidentally following cystoprostatectomy for bladder cancer is acceptable, provided that the following criteria are met: Stage T2N0M0 or lower; Gleason score ≤ 6, PSA undetectable. 10. 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 for at least 7 days prior to trial treatment. All patients with carcinomatous meningitis are excluded regardless of clinical stability. 11. Has active cardiac disease, defined as: o Myocardial infarction or unstable angina pectoris within 6 months of the first date of study therapy. o History of serious ventricular arrhythmia (i.e., 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 antiarrhythmic medication); history of QT interval prolongation. o New York Heart Association (NYHA) Class III or greater congestive heart failure or left ventricular ejection fraction of < 40%. 12. Has active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) and subjects with a history of bowel obstruction. 13. Has prior history of clinically significant bleeding, intestinal obstruction, or GI perforation within 6 months of enrollment. 14. 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). 15. Has an active infection requiring systemic therapy. 16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV -1/2 antibodies) 17. Has known active Hepatitis B or Hepatitis C (In patients with a history of HBV, hepatitis B core antibody (HBcAb) testing is required and if positive, then HB DNA testing will be performed and if positive the patient will be excluded). 18. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. The Objective Response Rate (ORR) is defined as the rate of the overall best response as CR or PR. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Duration of Response (DOR) 2. Progression-Free S (PFS) 3. Overall Survival (OS) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Date of the first progressive disease (PD) as assessed by central review and investigator assessment 2. Objective tumor progression as assessed by central review and investigator assessment or death, whichever comes first 3. Death from any cause |
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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 | No |
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.8.2.4 | 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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 |
Belgium |
Czech Republic |
France |
Italy |
United States |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |