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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Multi-Center Phase 2 Trial of Single-Agent Amrubicin as Second-Line Therapy in Patients With Advanced/Metastatic Refractory Urothelial Carcinoma

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: Amrubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Age > 18 years Karnofsky performance status of ≥ 80% Histological or cytological proof of transitional cell carcinoma of the urothelial tract. The primary site may include: urethra, bladder, ureters, and renal pelvis. 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. Measurable disease according to RECIST 1.1 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. Females of childbearing potential must have a negative pregnancy test within 7 days prior to being registered for protocol therapy. 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: Has had major surgery within 30 days of starting study treatment. Has active CNS metastases. Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis. 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. Has had treatment with another anticancer agent or investigational agent within 30 days prior to being registered for protocol therapy. 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. Has a clinically significant infection as judged by the treating investigator. Pregnant or nursing females. 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. History of congestive heart failure History of recent myocardial infarction History of interstitial lung disease, pulmonary fibrosis or symptomatic pulmonary disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Amrubicin<br>35 mg/m2/day intravenously | Drug: Amrubicin<br>* Patients will receive 35 mg/m2/day of amrubicin intravenously for 3 consecutive days as the initial dose starting on Day 1 of a 21-day cycle for up to 6 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate as Measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) | Response to treatment based on tumor measurements via CT chest, abdomen, and pelvis for restaging after every 2 cycles. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | The median progression-free survival After the last dose of Amrubicin, patients will have follow-up every 3 months with a repeat CT scan of the chest, abdomen, and pelvis until the time of disease progression is documented. | Every 3 months post Amrubicin administration | 
| Overall Survival | The median overall survival | 1 year | 
| Safety as Measured by the Frequency and Type of Adverse Events as Per the Common Terminology for Adverse Events (CTCAE) Version 4.0. | Types of adverse events listed in Adverse Event Section | Day 1 of each treatment cycle; and 21 days after the last dose of amrubicin | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bladder Cancer, Urothelial Cancer, Chemotherapy, Second-line, Metastatic