| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced or metastatic, low PD-L1 expression 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 |
To The primary objective is:
•To evaluate the anti-tumor activity of 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 with low programmed cell death ligand 1 (PD-L1) expression
|
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
•To evaluate the efficacy of NKTR-214 in combination with nivolumab by assessing duration of response (DOR) by RECIST 1.1 per BICR
•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.
• Patients with mixed histologies are required to have a dominant transitional cell pattern.
• Sample of fresh baseline tumor biopsies (fresh baseline biopsy is defined as a biopsy specimen taken during screening) is required to document PD L1 status. Patients who cannot provide a fresh baseline tumor biopsy, must provide archival tissue either from a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue sections (minimum of 15 to 25 slides).
• Central laboratory must confirm receipt of evaluable tumor tissue prior to randomization. For those patients with no local PD-L1 testing, central laboratory testing must be completed and patient confirmed as low PD L1 prior to randomization.
• Tumor must be PD-L1 low (defined by a Combined Positive Score [CPS] of < 10 utilizing the Dako PD-L1 immunohistochemistry (IHC) 22C3 pharmDx assay). Patients with validated local testing confirming low PD L1 status by the 22C3 pharmDx assay may enroll and start treatment. They must, however, submit a fresh baseline or archival tumor biopsy for confirmation. If the central PD L1 testing returns high PD-L1 (i.e., CPS ≥ 10), these patients will continue to be treated, but will not be included in the efficacy evaluation and will be replaced.
• 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 8 weeks after treatment is complete (confirmed by the head imaging obtained within 28 days prior to randomization). There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to randomization. Stable dose of anticonvulsants is required within 14 days prior to randomization. Treatment for CNS metastases may include stereotactic radiosurgery (e.g. GammaKnife, CyberKnife, or equivalent) or neurosurgical resection. Patients who received whole brain radiation therapy are not eligible.
3. Prior active malignancy within the previous 3 years except for locally curable cancers that have been apparently cured, 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 the following criteria are met: Stage T2N0M0 or lower; Gleason score ≤ 6, and prostate specific antigen (PSA) below lower limit of normal by local laboratory.
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, or eczema.)
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 randomization. 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 a live / attenuated vaccine within 30 days before first treatment.
8. Prior treatment with an anti PD-1, anti PD-L1, or anti cytotoxic T lymphocyte associated protein 4 (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 transplant that requires use of immune suppressive agents.
12. Active infection requiring systemic therapy.
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. Treatment with botanical preparations (e.g., herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to randomization/treatment. Refer to Section 6.9.3 for prohibited therapies in the NKTR 214/nivolumab arm.
16. 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 (CVA)
c) Congestive heart failure (New York Heart Association [NYHA] Class III or IV)
d) Uncontrolled clinically significant arrhythmias
17. Patients with hypertension must be on a stable antihypertensive regimen for the 14 days prior to randomization
18. Known current drug or alcohol abuse.
19. Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of the Investigator, would preclude the patient from adhering to the protocol or would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
20. Vulnerable populations as described by local public health code, as applicable per country.
21. Legally protected majors or majors who are unable to express their consent as described by their local public health code, as applicable per country. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy measurement is:
•Objective Response Rate (ORR) by blinded independent central review (BICR)
|
|
| 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 efficacy outcome is:
•Duration of response (DOR) by BICR
|
|
| 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 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 programmed cell death ligand 1 (PD-L1) negative (PD-L1–) patients. |
|
| 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 93 |
| 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 |
| Austria |
| Belgium |
| Brazil |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Greece |
| Hong Kong |
| Ireland |
| Israel |
| Italy |
| Mexico |
| Netherlands |
| New Zealand |
| Norway |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Singapore |
| Spain |
| Sweden |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
|
| 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 shown for the last participant and is expected to occur approximately 12 months after the last patient enrolls in the study. 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 later. 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 | |
| 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 |
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