Phase II Trial of Lurbinectedin Combined With Avelumab as Switch Maintenance Firstline Therapy

Inclusion Criteria:

• Patient eligibility should be reviewed and documented by an appropriate member ofthe investigator's study team before patients are included in the study. Patientsmust meet all of the following inclusion criteria to be eligible for enrollment intothe study:

1. Diagnosis:

2. Histologically confirmed, unresectable locally advanced or metastaticpredominant transitional cell carcinoma of the urothelium.

3. Documented Stage IV disease (T4b, N0, M0; any T, N1-N3, M0; any T, any N,M1) at the start of first-line chemotherapy.

4. Measurable disease prior to the start of first-line chemotherapy by RECISTv1.1.

5. Prior first-line chemotherapy must have completed 4-10 weeks beforeregistration and consisted of at least 4 cycles and no more than 6 cycles ofplatinum-based chemotherapy. No other chemotherapy regimens are allowed in thisstudy 3. Patients without progressive disease as per RECIST v1.1 guidelines (ie, with an ongoing CR, PR, or SD) following completion of 4 to 6 cycles offirst-line chemotherapy.

6. Eligibility based on this criterion will be determined by investigatorreview of pre-chemotherapy and post-chemotherapy radiological assessments (CT/MRI scans)

7. Tumor samples: Provision of a recent formalin-fixed, paraffin-embedded (FFPE)tumor tissue block or slides from the most recent primary or metastatic tumorbiopsy or resection obtained prior to treatment with first line chemotherapy isdesirable (but not mandatory). If an FFPE tissue block cannot be provided, 15unstained slides of 5 µM sections (10 minimum) will be acceptable.

8. Evidence of a signed and dated informed consent document indicating that thepatient (or a legally acceptable representative, as allowed by localguideline/practice) has been informed of all pertinent aspects of the study. 6.Patients who are willing and able to comply with scheduled visits, treatmentplans, laboratory tests, and other study procedures.

9. Age >18 years. 8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2. 9. Adequate bone marrow function, including:

10. Absolute neutrophil count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L;

11. Platelets ≥100,000/mm3 or ≥100 x 109/L;

12. Hemoglobin ≥8 g/dL (may have been transfused). 10. Adequate renal function,defined as estimated creatinine clearance ≥30 mL/min as calculated using theCockcroft-Gault equation.

13. Adequate liver function, including: a. Total serum bilirubin ≥1.5 x upperlimit of normal (ULN); b. Aspartate aminotransferase (AST) and alanineaminotransferase (ALT) ≥2.5 x ULN.

14. Serum pregnancy test (for females of childbearing potential) negative atscreening.

15. Male patients able to father children and female patients of childbearingpotential and at risk for pregnancy must agree to use 2 highly effectivemethods of contraception throughout the study and for at least 60 daysafter the last dose of assigned treatment

Exclusion Criteria:

• Patients with any of the following characteristics/conditions will not be includedin the study:

1. Patients whose disease progressed by RECIST v1.1 on or after first-linechemotherapy for urothelial cancer.

2. Prior adjuvant or neoadjuvant therapy within 12 months of registration

3. Prior immunotherapy with IL-2, PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, orCTLA-4 antibody (including ipilimumab), or any other antibody or drugspecifically targeting T-cell co-stimulation or immune checkpoint pathways.

4. Major surgery <4 weeks or major radiation therapy <2 weeks prior torandomization. Prior palliative radiotherapy (10 fractions) to metastaticlesion(s) is permitted, provided it has been completed at least 48 hours priorto patient randomization.

5. Patients with known symptomatic central nervous system (CNS) metastasesrequiring steroids. Patients with previously diagnosed CNS metastases areeligible if they have completed their treatment and have recovered from theacute effects of radiation therapy or surgery prior to randomization, havediscontinued corticosteroid treatment for these metastases for at least 4 weeksand are neurologically stable.

6. Persisting toxicity related to prior therapy NCI CTCAE v5.0 Grade >1; however,sensory neuropathy Grade ≤2 is acceptable.

7. Diagnosis of any other malignancy within 2 years prior to randomization, exceptfor adequately treated basal cell or squamous cell skin cancer, or carcinoma insitu of the breast or of the cervix, or low-grade (Gleason ≤6) prostate canceron surveillance without any plans for treatment intervention (eg, surgery,radiation, or castration), or any other cancer that is felt by the PI to beclinically insignificant not requiring systemic therapy in future.

8. Participation in other studies involving investigational drug(s) within 4 weeksprior to randomization. Observational studies are permitted.

9. Active autoimmune disease that might deteriorate when receiving animmunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, orhypo or hyperthyroid disease not requiring immunosuppressive treatment areeligible.

10. Any of the following in the previous 6 months: myocardial infarction,severe/unstable angina, coronary/peripheral artery bypass graft, symptomaticcongestive heart failure, cerebrovascular accident, transient ischemic attack,deep vein thrombosis, or symptomatic pulmonary embolism.

11. Active infection requiring systemic therapy.

12. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3),any history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features ofasthma symptom control per the Global Initiative for Asthma 2015).

13. Known prior or suspected hypersensitivity to study drugs or any component intheir formulations.

14. Current or prior use of immunosuppressive medication within 7 days prior toregistration, EXCEPT the following:

15. Intranasal, inhaled, topical steroids, or local steroid injections (eg,intra-articular injection);

16. Systemic corticosteroids at physiologic doses equivalent;

17. Steroids as premedication for hypersensitivity reactions (eg, CT scanpremedication).

18. Diagnosis of prior immunodeficiency or organ transplant requiringimmunosuppressive therapy, or known human immunodeficiency virus (HIV) oracquired immunodeficiency syndrome (AIDS)-related illness.

19. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicatingacute or chronic infection.

20. Vaccination within 4 weeks of the first dose of study treatment and while ontrial is prohibited except for administration of inactivate vaccines (forexample, inactivated influenza vaccines).

21. Patients who are investigational site staff members directly involved in theconduct of the study and their family members, site staff members otherwisesupervised by the investigator, or patients who are Jazz Pharma employeesdirectly involved in the conduct of the study.

22. Pregnant female patients; breastfeeding female patients; male patients able tofather children, and female patients of childbearing potential who areunwilling or unable to use 2 highly effective methods of contraception asoutlined in the protocol for the duration of the study and for at least 60 daysafter the last dose of investigational product.

23. Other severe acute or chronic medical conditions including colitis,inflammatory bowel disease, and pneumonitis; psychiatric condition includingrecent (within the past year) or active suicidal ideation or behavior; orlaboratory abnormality that may increase the risk associated with studyparticipation or study treatment administration or may interfere with theinterpretation of study results and, in the judgment of the investigator, wouldmake the patient inappropriate for entry into this study.