Primary Outcomes:

Primary Outcome 1 - Measure: Phase 1b lead-in: Number of patients with dose-limiting toxicities in first 2 cycles

Primary Outcome 1 - Time Frame: First 6 weeks of treatment

Primary Outcome 2 - Measure: Confirmed objective response (OR)

Primary Outcome 2 - Time Frame: Baseline up to approximately 24 months

Condition:

• Non-small Cell Lung Cancer
• Urothelial Cancer

Eligibility

Criteria:
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.
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Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No