|E.1 Medical condition or disease under investigation |
|E.1.1||Medical condition(s) being investigated || |
|Advanced or metastatic urothelial carcinoma whose disease did not progress with 1L platinum-containing chemotherapy. |
|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 ||PT |
|E.1.2||Classification code ||10005003 |
|E.1.2||Term ||Bladder cancer |
|E.1.2||System Organ Class ||10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|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 evaluate PFS of maintenance treatment with avelumab treatment combination regimens compared to maintenance avelumab monotherapy. |
-To evaluate the safety and tolerability of avelumab combination regimens.
|E.2.2||Secondary objectives of the trial || |
|-To evaluate OS of maintenance treatment with avelumab combination regimens compared to maintenance avelumab monotherapy followed by subsequent anticancer treatment. |
-To evaluate OR of maintenance treatment with avelumab combination regimens compared to maintenance avelumab monotherapy.
-To evaluate DoR of maintenance treatment with avelumab combination regimens compared to maintenance avelumab monotherapy.
-To collect PK concentration data of avelumab, M6223, SG (derived from total SN-38 and unconjugated SN-38), and NKTR-255 to contribute to respective PopPK analyses and exposure-response analyses.
-To characterize the immunogenicity of avelumab administered alone or in combination with SG, NKTR-255 or M6223.
To characterize the immunogenicity of M6223, SG or NKTR-255 in combination with avelumab.
-To evaluate the effect of maintenance treatment with avelumab combination regimens compared to maintenance avelumab monotherapy on disease related physical symptoms.
|E.2.3||Trial contains a sub-study || No |
|E.3||Principal inclusion criteria || |
|1.Are ≥ 18 years of age at the time of signing the informed consent. |
a.Histologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma. Both transitional cell and mixed transitional/non- transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology.
b.Documented Stage IIIA/IIIB with N1-N3, or Stage IV disease (per American Joint Committee on Cancer/International Union for Cancer Control Tumor Node Metastasis system, 8th edition) at the start of first line chemotherapy.
3. Prior 1L chemotherapy must have consisted of at least 4 cycles and no more than 6 cycles of gemcitabine + cisplatin and/or gemcitabine + carboplatin. No other chemotherapy regimens are allowed in this study. (Note: Switch between platinum agents due for toxicity to complete a total of - 4 to 6 cycles first line platinum-based chemotherapy is acceptable).
4.The last dose of first line chemotherapy must have been received no less than 4 weeks, and no more than 10 weeks, prior to randomization in the present study.
5.Participants without progressive disease as per RECIST v1.1 guidelines (i.e., with an ongoing CR, PR, or SD) following completion of 4 to 6 cycles of 1L chemotherapy.
Eligibility based on this criterion will be determined by Investigator review of pre chemotherapy and post chemotherapy radiological assessments (CT/MRI scans).
6.All participants must provide archival formalin-fixed paraffin embedded (FFPE) tumor tissues (ideally < 6 months old prior to participant enrollment) from most recent primary or metastatic tumor biopsy or resection obtained prior to treatment with first line chemotherapy but within 24 months prior to randomization, with no intervening systemic anticancer therapy between the time the tissue was obtained and initiation of first line chemotherapy. If an archival FFPE tissue block cannot be provided, 15 or more unstained slides (15 slides minimum) will be acceptable. In addition, fresh baseline tumor samples (collected within 28 days before first dose) may be collected at Screening if archival tissue biopsy is not available. Provision of a tumor biospecimen is required for randomization into the study. The sample must be submitted to the Central Laboratory prior to randomization and deemed acceptable to allow the patient to randomize. Refer to the Central Laboratory Manual for additional specifications.
7.Participants who are willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
8.Estimated life expectancy of at least 3 months.
9.Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
10.Adequate bone marrow function, including:
a.Absolute neutrophil count (ANC) ≥ 1,500/mm3 or ≥ 1.5 × 109/L;
b.Platelets ≥ 100,000/mm3 or ≥ 100 × 109/L;
c.Hemoglobin ≥ 9 g/dL (may have been transfused).
11.Adequate renal function, defined as estimated creatinine clearance ≥ 30 mL/min as calculated using the Cockcroft-Gault equation or by 24-hour urine collection for creatinine clearance or according to the local institutional standard method.
12.Adequate liver function, including:
a.Total serum bilirubin ≤ 1.5 × upper limit of normal (ULN);
b.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN, or, for participants with documented metastatic disease to the liver, AST and ALT levels ≤ 5 × ULN.
13.All sexes allowed. The Investigator confirms that each participant agrees to use appropriate contraception and barriers, if applicable. The contraception, barrier, and pregnancy testing requirements are below.
Please see Protocol for more details about this inclusion criteria.
14.Capable of giving signed informed consent, as indicated in Appendix 2, which includes compliance with the requirements and restrictions listed in the ICF and this protocol.
15.Participants with known human immunodeficiency virus (HIV) infections are eligible if the following criteria are met:
16.Participants with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections are eligible if the following criteria are met:
Please see Protocol for more details about inclusion criteria 15 and 16.
|E.4||Principal exclusion criteria|| |
|1.Participants with symptomatic central nervous system (CNS) metastases requiring steroids. Participants with diagnosed CNS metastases are eligible if they have completed treatment, recovered from the acute effects of radiation therapy or surgery prior to randomization and off steroid treatment 7 days before randomization, have discontinued corticosteroid treatment for these metastases for at least 4 weeks, and are neurologically stable. |
2.Persisting toxicity related to prior therapy NCI-CTCAE v5.0 Grade > 1; however, alopecia, sensory neuropathy Grade ≤ 2 is acceptable, or other Grade ≤ 2 adverse events not constituting a safety risk based on the Investigator’s judgment are acceptable.
3.Diagnosis of any other malignancy unless a complete remission without further recurrence was achieved and the participant was deemed to have been cured with no additional therapy required or anticipated to be required. The exceptions to this criterion may include carcinoma in situ of cervical, colorectal, breast, or all localized prostate cancer that is not being treated. Possible exceptions to this criterion will be discussed on a by participant basis according to medical need.
4.Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Participants with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
5.Current significant cardiac conduction abnormalities, including corrected QT interval (QTcF, corrected with Fridericia formula) prolongation of > 450 ms on triplicate 12-lead ECG or impaired cardiovascular function.
6.Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication (except for atrial fibrillation that is well controlled with antiarrhythmic medication).
7.Active infection 48 hours before randomization requiring systemic therapy.
8.Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3), any history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more features of asthma symptom control per the Global Initiative for Asthma 2015).
9.Known prior or suspected hypersensitivity to study drugs or any component in their formulations.
10.Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive therapy.
11.Pregnant female participants; breastfeeding female participants; and female participants of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in the protocol for the duration of the study and for at least 30 days after the last dose of investigational product.
12.Other severe acute or chronic medical conditions including but not limited to inflammatory bowel disease (colitis, Crohn's disease) or gastrointestinal (GI) perforation within 6 months of enrollment, pneumonitis, and pulmonary fibrosis; psychiatric condition including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the participants inappropriate for entry into this study.
13.Prior adjuvant or neoadjuvant systemic therapy within 12 months of randomization.
14.Prior immunotherapy with IL-2, IL-15, IFN-α, or an anti PD-1, anti PD-L1, anti PD-L2, anti CD137, or CTLA-4 antibody (including ipilimumab), anti TROP2, any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways, or any of the investigational drugs used in combination with avelumab.
15.Major surgery ≤ 4 weeks or major radiation therapy ≤ 2 weeks prior to randomization. Prior palliative (pain management or hemostatic) radiotherapy is permitted, provided it has been completed at least 48 hours prior to randomization.
16.Current or prior use of immunosuppressive medication within 7 days prior to randomization, EXCEPT the following:
a.Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection);
b.Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent;
c.Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
Please refer to Protocol for the full list.
|E.5 End points |
|E.5.1||Primary end point(s)|| |
|-Progression-free survival (PFS) as defined from date of randomization to PD according to RECIST v1.1 as assessed by Investigator or death, occurring within two scheduled tumor assessments after last evaluable assessment or randomization. |
-Occurrence of TEAEs, treatment- related AEs, and AESIs as per Qualitative Toxicity Scale (NCI-CTCAE 5.0).
|E.5.1.1||Timepoint(s) of evaluation of this end point|| |
|PFS will be evaluated when 56 PFS events per treatment-control comparison have been observed (interim analysis). Then it will be evaluated again when 65 PFS events per treatment-control comparison have been observed (primary analysis). |
Occurrence of TEAEs, treatment- related AEs, and AESIs will be monitored during safety DMCs as well as for interim and primary analysis as defined for the PFS endpoint.
|E.5.2||Secondary end point(s)|| |
|-Overall survival (OS) as measured by time from randomization to death. |
-Objective response (OR) according to RECIST v1.1 assessed by Investigator.
-DoR according to RECIST v1.1 assessed by Investigator defined as time from first documentation of objective response to PD or death, occurring within two scheduled tumor assessments after last evaluable assessment or randomization.
-Concentration will be listed and descriptively summarized as appropriate. Population PK and exposure-response results will be reported separately in a standalone report, as it may also include data from other studies.
-Immunogenicity of avelumab, SG, NKTR-255 and M6223, as measured by ADA assay.
-Change from baseline score of NCCN FACT FBlSI-18 DRS-P.
|E.5.2.1||Timepoint(s) of evaluation of this end point|| |
|OS, OR and DoR will be evaluated when 56 PFS events per treatment-control comparison have been observed (interim analysis). Then it will be evaluated again when 65 PFS events per treatment-control comparison have been observed (primary analysis). |
PK will be evaluated for safety DMCs as well as for interim and primary analysis as defined above.
Immunogenicity and change from baseline score of NCCN FACT FBlSI-18 DRS-P will be evaluated for primary analysis.
|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|| Yes |
|E.6.11||Pharmacogenomic|| Yes |
|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.126.96.36.199||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||4 |
|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||2 |
|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|| |
|Korea, Republic of |
|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 || |
|The end of the study is defined as the date of two years after treatment start of the last participant or until all the participants discontinued the study, whichever occurs first. |
|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||8 |
|E.8.9.1||In the Member State concerned days||25 |
|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||2 |