E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced or metastatic urothelial bladder cancer |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 10064467 |
E.1.2 | Term | Urothelial carcinoma |
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 evaluate the anti-tumor activity of bempegaldesleukin (NKTR-214) in combination with nivolumab by assessing the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) per blinded independent central review (BICR) in patients whose tumors have low programmed cell death ligand 1 (PD-L1) expression
|
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives are: •To evaluate the effect of NKTR-214 in combination with nivolumab by assessing the ORR by RECIST 1.1 per BICR in all treated patients •To evaluate the effect of NKTR-214 in combination with nivolumab by assessing DOR by RECIST 1.1 per BICR in all treated patients and patients whose tumors have low PD-L1 expression •To evaluate the effect of NKTR-214 in combination with nivolumab by assessing the ORR and DOR by RECIST 1.1 per Investigator assessment in all treated patients and patients whose tumors have low PD-L1 expression •To evaluate the safety and tolerability of NKTR-214 in combination with nivolumab
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Each patient will be entered into this study only if he/she meets all of the following criteria: • Male or female patients, age 18 years or older at the time of signing the informed consent form (ICF). • Patients must have histologically or cytologically documented inoperable, locally advanced (T4b, any N; or any T, N2-3) or metastatic (M1, Stage IV) urothelial cell carcinoma (also termed transitional cell carcinoma) including renal pelvis, ureters, urinary bladder and urethra. • Histologically or cytologically confirmed locally advanced and unresectable or metastatic urothelial cancer, including mixed urothelial cell and non-urothelial cell histologies. If the histology is mixed with non-urothelial carcinoma (e.g., squamous cell carcinoma), the urothelial cell component must be dominant (> 50% of the total histology). • Tumor tissue is required to be analyzed by the central laboratory to document PD L1 status. Tissue can be provided in one of 2 ways: 1) A new biopsy taken during screening 2) Archival tissue from either a formalin - fixed, paraffin - embedded (FFPE) tissue block or unstained tumor tissue sections (see Section 7.5). Archival tissue must be within 12 months prior to enrollment and with no intervening treatment. 3) A tracking number confirming shipment of the sample to the central laboratory supplied prior to Cycle 1 Day 1. • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. • Patients must have measurable disease per RECIST 1.1 criteria, and have adequate organ function. • Patients must be able and willing to comply with the study visit schedule and study procedures. |
|
E.4 | Principal exclusion criteria |
A patient will be excluded from this study if he/she meets any of the following criteria: 1. Female patients who are pregnant or lactating, who plan to get pregnant, or who have a positive serum or urine pregnancy test. 2. Active brain metastases or leptomeningeal metastases. Patients with brain metastases are eligible if these have been treated and there is no radiographic evidence of progression for at least 4 weeks after treatment is complete (confirmed by the head imaging obtained within 28 days prior to Cycle 1 Day 1). There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to Cycle 1 Day 1. Stable dose of anticonvulsants is allowed. Treatment for CNS metastases may include whole brain radiation, stereotactic radiosurgery (e.g. GammaKnife, CyberKnife, or equivalent) or neurosurgical resection. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 28 days prior to Cycle 1 Day 1 are not eligible. 3. Prior active malignancy within the previous 3 years except for locally curable cancers with negligible risk of metastases or death that have been treated with expected curative outcome, such as basal or squamous cell skin cancer, carcinoma in situ of the prostate, cervix, or breast. An incidental finding of prostate cancer (identified upon resection of the prostate) is acceptable, provided that one of the following criteria is met: T2N0M0 or Gleason score ≤ 3+4, or prostate - specific antigen (PSA) below upper limit of normal by local laboratory and not requiring active treatment. 4. Patients who have an active, known or suspected autoimmune disease. Patients requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease that requires systemic steroids or immunosuppressive agents. (Exceptions include any patient on 10 mg or less of prednisone or equivalent, patients with vitiligo, hypothyroidism stable on hormone replacement, Type I diabetes, Graves' disease, Hashimoto's disease, alopecia areata, eczema, or psoriasis.) 5. Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of Cycle 1 Day 1. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. 6. Patients must not have received prior IL-2 therapy. 7. Patients who have received any live/ attenuated vaccine within 30 days before Cycle 1 Day 1. 8. Prior treatment with an anti PD-1, anti PD-L1,anti-PD-L2, or anti CTLA-4 antibody, agents that target IL-2 pathway, or any other antibody or drug specifically targeting T- cell costimulation or immune checkpoint pathways. 9. History of allergy to study drug components. 10. History of severe hypersensitivity reaction to any monoclonal antibody. 11. History of organ, hematopoetic, or tissue tranasplant that requires the systemic use of immunosuppressive agents. 12. Active infection requiring systemic therapy within 14 days prior to Cycle 1 Day 1. 13. Any positive test result for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating presence of virus, e.g. hepatitis B surface antigen (HBsAg) positive, or hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative). 14. Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated locally. 15. Known cardiovascular history including unstable or deteriorating cardiac disease within the previous 12 months prior to screening including but not limited to the following: a) Unstable angina or myocardial infarction b) Transient ischemic attack (TIA)/ cerebrovascular accident c) Congestive heart failure NYHA Class III or IV) d) Uncontrolled clinically significant arrhythmias 16. History of pulmonary embolism (PE), deep vein thrombosis (DVT), or prior clinically significant venous or non-CVA/TIA arterial thromboembolic event (e.g., internal jugular vein thrombosis) within 3 months prior to enrollment. - Patients with a history of a venous or arterial thromboembolic event must be asymptomatic for at least 2 weeks prior to enrollment and must be receiving a stable regimen of therapeutic anticoagulation (preferably low molecular weight heparin [LMWH] or direct oral anticoagulation [DOAC]; see Section 6.7.2.1 for further guidance). - Unless there is a new medical contraindication observed after Cycle 1 Day 1, a patient with a history of venous or arterial thromboembolic event must be maintained on therapeutic anticoagulation throughout the patient's participation in the study (i.e., through the end-of-treatment [EOT] visit). Please refer to protocol for the complete list of exclusion criteria |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is: •Objective Response Rate (ORR) by blinded independent central review (BICR) in patients whose tumors have low PD-L1 expression |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Tumor measurements will be performed every 9 weeks ± 7 days |
|
E.5.2 | Secondary end point(s) |
The secondary endpoints are: • ORR per BICR in all treated patients • DOR by BICR in all treated patients and patients whose tumors have low PD-L1 expression • ORR and DOR by Investigator assessment in all treated patients and patients whose tumors have low PD-L1 expression
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Every 9 weeks until after 12 months then the evaluation period changes to every 12 weeks. (± 7 days). |
|
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 | No |
E.6.4 | Safety | No |
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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
To evaluate the anti-tumor activity of bempegaldesleukin (NKTR--214) in combination with nivolumab by assessing the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) per blinded independent central review (BICR) in patients whose tumors have low programmed cell death ligand 1 (PD--L1) expression |
|
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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 80 |
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 |
Argentina |
Australia |
Canada |
Israel |
Mexico |
Russian Federation |
Turkey |
United States |
Austria |
Belgium |
Finland |
France |
Germany |
Greece |
Italy |
Poland |
Portugal |
United Kingdom |
Netherlands |
Spain |
|
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
|
End of study is defined as the last visit or scheduled procedure for the last participant. Total duration of the study is up to 5 years from enrollment of the last participant, or until the time of OS analysis, whichever occurs earlier. Maximum duration of treatment with NKTR- 214 and nivolumab for any patient is 2 years . |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 1 |