JAVELIN Bladder Medley

1.Are ≥ 18 years of age at the time of signing the informed consent.

2.Has

a.Histologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma. Both transitional cell and mixed transitional/nontransitional 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. 

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. 

Research Nurse: Sirjana Devkota (x3766) Sirjana.Devkota@LTHTR.nhs.uk

Administrator: Nathan Fish (x3766)