Safety And Efficacy Study Of Avelumab Plus Chemotherapy With Or Without Other Anti-Cancer Immunotherapy Agents In Patients With Advanced Malignancies

Inclusion Criteria:

1. Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumor that is not amenable for treatment with curative intent as follows:

   * For all groups:
   * Measurable disease by RECIST v1.1 with at least 1 measurable lesion, and availability of tumor specimen 18 months or less old.
   * No prior systemic treatment for unresectable locally advanced or metastatic disease for the tumor type under study. If prior systemic chemotherapy treatment was given in the adjuvant or neo-adjuvant setting or as part of radiotherapy chemotherapy treatment, disease-free interval after stop of systemic treatment must be more than 6 months for non-squamous NSCLC and more than 12 months for UC;
   * Cohort A1 and Cohort A3: Non-squamous NSCLC, with no activating EGFR mutations, ALK or ROS1 translocations/rearrangements. If monotherapy pembrolizumab is available as a standard of care treatment option, patients must have a tumor proportion score (TPS) \<50% for PD L1 (via the 22C3 pharmDx or the Ventana (SP263) PD L1 IHC assay).
   * Cohort A2 and Cohort A4: Transitional cell carcinoma of the urothelium including the bladder, urethra, renal pelvis, and ureter.
2. ECOG performance status 0 or 1
3. Estimated life expectancy of at least 90 days
4. Adequate bone marrow, renal, and liver function
5. Negative serum pregnancy test at screening
6. Signed and dated informed consent

Exclusion Criteria:

1. Prior immunotherapy with any antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways.
2. Patients with known symptomatic central nervous system metastases requiring steroids.
3. Diagnosis of other malignancy within 2 years prior to enrollment except adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the bladder, breast, or cervix, or low grade (Gleason ≤6) prostate cancer
4. Use of immunosuppressive medication at the time of enrollment
5. Active or prior autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent.
6. Prior organ transplantation including allogenic stem cell transplantation
7. Active infection requiring systemic therapy
8. Known history of HIV or AIDS
9. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening
10. Administration of live vaccine within 4 weeks prior to study entry
11. Known prior severe hypersensitivity to the investigational products or any component in their formulations,
12. Known prior severe hypersensitivity to platinum-related compounds for all cohorts, to pemetrexed for patients enrolled in Cohort A1 and Cohort A3, and to gemcitabine for patients enrolled in Cohort A2 and Cohort A4
13. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade \> 1)
14. Known history of colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis.
15. Ongoing cardiac dysrhythmias of NCI CTCAE v4.03 Grade 2 or prolongation of the QTcF interval to \>480 msec.
16. Clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke (\<6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure, or serious cardiac arrhythmia requiring medication.
17. Major surgery ≤28 days or major radiation therapy ≤14 days prior to enrollment.
18. Participation in other studies involving investigational drug(s) within 28 days prior to study entry.
19. Concurrent treatment with a prohibited medication.
20. Other acute or chronic medical or psychiatric condition
21. Pregnant female patients; breastfeeding female patients; fertile male patients and female patients of childbearing potential who are unwilling or unable to use at least 1 highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 90 days after the last dose of chemotherapy (for male and female patients) or at least 30 days after the last dose of avelumab (for female patients), whichever is longer.