A Combination of Avelumab and Taxane (AVETAX) for Urothelial Cancer

The study is a single institution, phase 1b, single arm non-randomized, open label
prospective clinical trial to evaluate the combination of Avelumab and Docetaxel in adult
subjects with locally advanced or metastatic urothelial carcinoma with disease progression
during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or
adjuvant platinum-containing chemotherapy.

The study has two phases:

1. A Phase 1b dose de-escalation of Docetaxel in combination with Avelumab, to establish
the recommended phase 2 dose (RP2D) for the combination. The dose de-escalation phase
will utilize a 3+3 design over 3 planned dose levels leading to the identification of a
RP2D for the combination of Docetaxel and Avelumab. Note: Dose de-escalation is allowed
only for Docetaxel and no changes will done to standard dose of Avelumab (i.e, 10
mg/kg).

2. In the dose expansion phase of the study, the fixed dose of Docetaxel in combination
with Avelumab will be evaluated. The study is powered to a primary endpoint of overall
response rate (ORR) with the combination of Docetaxel and Avelumab. Enrollment for part
2 will commence only after a RP2D is identified from phase 1.

Inclusion Criteria:

1. Age ≥18 years

2. Histologically or cytologically confirmed locally advanced or metastatic transitional
cell carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder,
urethra). Additional mixed histologies such as squamous, plasmacytoid, adenocarcinoma
are permitted provided the urothelial cancer is the predominant histological
component.

3. Eligible patients must have had either:

- Progressed after treatment with at least 1 platinum-containing regimen, (e.g.,
ciplatin or carboplatin plus another agent such as gemcitabine, methotrexate,
vinblastine, doxorubicin, etc.) for inoperable locally advanced or metastatic
urothelial carcinoma or disease recurrence, or

- Were ineligible for cisplatin-based chemotherapy, with ineligibility to cisplatin
defined by impaired renal function (creatinine clearance < 60 ml/min), a hearing
loss of 25 decibels at 2 contiguous frequencies, or grade ≥ 2 peripheral
neuropathy or

- Locally advanced or metastatic bladder cancer whose disease has progressed within
12 months of neoadjuvant or adjuvant chemotherapy.

4. Biopsy material is required (archival tissue is acceptable if patient could not
provide fresh or recent biopsy)

5. ECOG performance status of 0 to 1

6. Estimated life expectancy ≥3 months

7. At least one measurable lesion by RECIST version 1.1

8. Adequate hematologic function defined by white blood cell count ≥3 × 109/L with
absolute neutrophil count ≥1.5 × 109/L, lymphocyte count ≥ 0.5 × 109/L, platelet count
≥100 × 109/L, and hemoglobin ≥9 g/dL (may have been transfused)

9. Adequate hepatic function defined by a total bilirubin level ≤ the upper limit of
normal range (ULN), an aspartate aminotransferase (AST) level ≤1.5 × ULN, and an
alanine aminotransferase (ALT) level ≤1.5 × ULN

10. Adequate renal function defined by an calculated creatinine clearance > 30 mL/min
according to the Cockcroft-Gault formula

11. Both male and female subjects must be willing to use highly effective contraception
(that is, methods with a failure rate of less than 1% per year) throughout the study
and for at least 30 days after last avelumab treatment administration if the risk of
conception exists (see section 6.1.7). [NOTE: The effects of the study treatment on
the developing human fetus are unknown; thus, women of childbearing potential and men
must agree to use highly effective contraception, as stipulated in national or local
guidelines. Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, the treating physician should be informed
immediately.

12. Signed written informed consent

Exclusion Criteria:

1. Concurrent treatment with an anticancer treatment

2. Prior therapy with any drug targeting T cell coregulatory proteins

3. Major surgery for any reason within 4 weeks or if the patient had not fully recovered
within 4 weeks

4. Concurrent systemic therapy with corticosteroids or other immunosuppressive agents, or
use of any investigational drug within 28 days before starting trial drug; short-term
administration of systemic steroids (that is, for allergic reactions or the management
of immune-mediated adverse events while on study is allowed

5. Patients with active central nervous metastases will be excluded. Appropriately
treated CNS metastases with either surgery or radiation therapy are permitted to
participate in the study

6. Previous malignant disease (other than urothelial carcinoma) within the last 5 years,
with the exclusion of basal or squamous cell carcinoma of the skin, cervical carcinoma
in situ and prostate adenocarcinoma with Gleason score <7, pT2b.

7. Prior organ transplantation, including allogenic stem-cell transplantation

8. Known history of testing positive for HIV/AIDS, HBV, or HCV (including acute and
chronic infection)

9. Active or history of any autoimmune disease or immune-deficiencies (patients with type
1 diabetes, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring
immunosuppressive treatment are eligible)

10. Known monoclonal antibody hypersensitivity, history of anaphylaxis, or uncontrolled
asthma

11. Persisting toxicity related to prior therapy that was > grade 1 according to NCI-CTCAE
v4.0; grade ≤2 sensory neuropathy is allowed

12. Pregnancy or lactation

13. 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 All other significant diseases, which in the investigator's opinion may
influence the patient's tolerance of trial treatment. Other severe acute or chronic
medical conditions including immune colitis, inflammatory bowel disease, immune
pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the
past year) or active suicidal ideation or behavior; or laboratory abnormalities 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 patient inappropriate for entry into this
study

14. Legal incapacity or limited legal capacity, including any psychiatric condition that
would prohibit the understanding or rendering of informed consent

15. Vaccination within 4 weeks of the first dose of Avelumab and while on study was
prohibited except for administration of inactivated vaccines (e.g., inactivated
influenza vaccines)