Trial of Amrubicin as Second-Line Therapy in Patients With Advanced/Metastatic Refractory Urothelial Carcinoma

Multiple small phase II trials exploring a variety of agents as second-line therapy for
metastatic urothelial carcinoma have been performed. Overall, the most active of these agents
have shown response rates of approximately 10-20% . Currently, there are no FDA approved
agents for the second-line treatment of metastatic urothelial carcinoma.

The current study will explore the safety and activity of the novel anthracycline, amrubicin,
as second-line chemotherapy in patients with advanced urothelial carcinoma.

The primary objective will be to evaluate the activity (as determined by objective response
rate) of amrubicin as second-line chemotherapy in patients with metastatic urothelial
carcinoma. The secondary objectives will be to evaluate progression-free survival, survival
at 1 year, and the safety of amrubicin as second-line therapy in patients with metastatic
urothelial carcinoma.

Subjects will receive amrubicin IV daily x 3 days, every 21-days, with prophylactic
granulocyte colony stimulating factor. This 21-day time period is referred to as a cycle.
Subjects will undergo repeat computed tomography (CT) scans after every 2 cycles. In the
absence of progressive cancer, or prohibitive side effects, subjects will receive up to 6
cycles of treatment with amrubicin.

Inclusion Criteria:

1. Written informed consent

2. Age > 18 years

3. Karnofsky performance status of ≥ 80%

4. Histological or cytological proof of transitional cell carcinoma of the urothelial
tract. The primary site may include: urethra, bladder, ureters, and renal pelvis.

5. Progressive advanced/metastatic disease despite prior chemotherapy:

- Patients may have received one prior chemotherapy regimen.

- Prior chemotherapy may have been administered in the perioperative setting
(neoadjuvant or adjuvant) or 1st line metastatic setting.

6. Measurable disease according to RECIST 1.1

7. Females of childbearing potential and males must be willing to use an effective method
of contraception (hormonal or barrier method of birth control; abstinence) from the
time consent is signed until 8 weeks after treatment discontinuation.

8. Females of childbearing potential must have a negative pregnancy test within 7 days
prior to being registered for protocol therapy.

9. Adequate organ function including the following:

- Adequate bone marrow reserve: absolute neutrophil count (segmented and bands)
(ANC) ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, and hemoglobin ≥ 9 mg/L,

- Hepatic: bilirubin ≤ 1.5 x the upper limit of normal (ULN), ALT and AST ≤ 3.0 x
ULN (or ≤ 5.0 x ULN in the presence of hepatic metastases)

- Renal: serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 60
mL/min,

- Cardiac: Left ventricular ejection fraction (LVEF) ≥ 50% or ≥ the lower limit of
the institutional normal by echocardiogram (ECHO) or multiple gated acquisition
scan (MUGA);

Exclusion Criteria:

1. Has had major surgery within 30 days of starting study treatment.

2. Has active CNS metastases. Subjects with neurological symptoms must undergo a head CT
scan or brain MRI to exclude brain metastasis.

3. Has a history of a prior malignancy with the exception of the following: adequately
treated basal cell or squamous cell skin cancer, in situ cervical cancer, clinically
localized prostate cancer treated with definitive local therapy and without evidence
of recurrent disease and without the need for androgen deprivation therapy, or other
cancer for which the subject has been disease-free for at least 5 years.

4. Has had treatment with another anticancer agent or investigational agent within 30
days prior to being registered for protocol therapy.

5. Has had prior radiation therapy to > 25% of the bone marrow.

- NOTE: No radiation therapy within 30 days prior to being registered for protocol
therapy.

6. Has a clinically significant infection as judged by the treating investigator.

7. Pregnant or nursing females.

8. Patients with known history of seropositive human immunodeficiency virus (HIV) or
patients who are receiving immunosuppressive medications that would, in the opinion of
the investigator, increase the risk of serious neutropenic complications.

9. History of congestive heart failure

10. History of recent myocardial infarction

11. History of interstitial lung disease, pulmonary fibrosis or symptomatic pulmonary
disease