due to a development decision by the funder

The primary objective of this study is to determine in subjects with metastatic measurable bladder cancer (or urothelial cancers originating elsewhere in the genitourinary tract) who have progressed on 1 prior chemotherapeutic regimen the objective response rate to treatment with amrubicin. 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.

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

The trial was terminated prematurely due to the results of a phase 3 study seeking registration for amrubicin in small cell lung cancer in the United States, leading the industry funder to discontinue further clinical development of amrubicin.