Nab-paclitaxel Plus Gemcitabine as First-line Therapy for Cisplatin-ineligible or Cisplatin-incurable Advanced Urothelial Carcinoma

This open-label, non-randomized phase II trial evaluates the efficacy and toxicity of
first-line treatment with a combination of gemcitabine and nab-paclitaxel, followed by
maintenance therapy with nab-paclitaxel alone in patients with metastatic or locally
advanced unresectable urothelial cancer. Two groups of patients are eligible: (1) patients
who are poor candidates for treatment with cisplatin, and (2) patients with visceral
metastases who are incurable and unlikely to derive long-term benefit from treatment with
cisplatin-based regimens. Eligible patients will receive a minimum of 3 cycles and up to 6
cycles of treatment with the gemcitabine/nab-paclitaxel combination. Patients having an
objective response or stable disease will continue maintenance treatment with single-agent
nab-paclitaxel until disease progression, intolerable toxicity, or patient decision to
discontinue treatment. Up to 55 patients are planned for enrollment.

KEY POINTS:

Inclusion Criteria:

1. Histologically confirmed diagnosis of urothelial carcinoma (UC) that is either
metastatic (any N+ M1) or locally advanced and unresectable (T4bN0). A component of
urothelial (transitional cell) carcinoma is required.

2. Two groups of patients are eligible:

1. Poor candidates for cisplatin-based chemotherapy based on the presence of ≥ 1
the following:

- Glomerular filtration rate of 30-60 ml/min (Cockcroft-Gault formula)

- ECOG performance status score of 2

- Hearing loss (trouble communicating with hearing aids or hearing loss at ≤
3 KHz)

- Grade ≥3 heart failure

- Age ≥80 years

- Other concurrent illness which may make the patient a poor candidate for
receiving cisplatin.

Note: Enrollment of patients with 2 or more of these criteria should occur only
after careful consideration by the treating physician regarding the patient's
ability to tolerate combination chemotherapy.

OR

2. Poor prognosis and defined as cisplatin-incurable due to the presence of
metastasis to at least one visceral site (these patients are not required to
have any of the cisplatin-ineligibility criteria).

- ECOG performance status score of 0, 1, or 2.

3. Measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors
(RECIST) version 1.1.

4. Patients with brain metastases are allowed if treatment was completed at least 4
weeks prior to study treatment, neurologic symptoms are minimal and stable during the
preceding 4 weeks, and maintenance dexamethasone is not required.

5. Adequate hematologic, liver and kidney function.

6. Willingness and ability to comply with study requirements and give written informed
consent.

Exclusion Criteria:

1. Previous systemic chemotherapy for UC with the exception of perioperative
(neoadjuvant or adjuvant) treatment or treatment with concurrent chemoradiation for
locally advanced disease. All of these treatments must have been completed more than
1 year previously.

2. Presence of small-cell or sarcomatoid component in tumor histology.

3. Women who are pregnant or breast-feeding.

4. Major surgical procedures ≤28 days of beginning study drug, or minor surgical
procedures ≤7 days. No waiting required following port-a-cath placement.

5. Cardiac diseases currently or within the last 6 months:

6. Inadequately controlled hypertension.

7. Currently receiving treatment with therapeutic doses of warfarin sodium. (A maximum
daily dose of 1 mg will be permitted for port line patency. Low molecular weight
heparin is allowed.)

8. Serious active infection at the time of treatment, or another serious underlying
medical condition that would impair the ability of the patient to receive protocol
treatment.

9. Known diagnosis of human immunodeficiency virus, hepatitis B or hepatitis C
(screening for these diseases is not required.).

10. Presence of other active cancers, or history of treatment for invasive cancer ≤5
years previously. Patients with Stage I cancer who have received definitive local
treatment and are considered unlikely to recur are eligible. All patients with
previously treated in situ carcinoma (i.e., non-invasive) are eligible, as are
patients with history of non-melanoma skin cancer.