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

Phase 2

Terminated

• Conditions: Bladder Cancer
• Interventions: Drug: Amrubicin

• Registration Number: NCT01331824
• Lead Sponsor: Matthew Galsky

Brief Summary

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

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.

Study Timeline

• Study Start: 2011-02
• Study First Submitted: 2011-04-06
• Study First Submitted QC: 2011-04-07
• Study First Posted: 2011-04-08
• Primary Completion: 2014-07
• Study Completion: 2015-07
• Results First Submitted: 2015-10-15
• Results First Submitted QC: 2015-11-21
• Results First Posted: 2015-12-24
• Status Verified: 2018-03
• Last Update Submitted: 2018-03-22
• Last Update Posted: 2018-04-23

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 22

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Amrubicin	Amrubicin	35 mg/m2/day intravenously

Primary Outcome Measures

Name	Time	Method
Objective Response Rate as Measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1)	6 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival	Every 3 months post Amrubicin administration	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.
Overall Survival	1 year	The median overall survival
Safety as Measured by the Frequency and Type of Adverse Events as Per the Common Terminology for Adverse Events (CTCAE) Version 4.0.	Day 1 of each treatment cycle; and 21 days after the last dose of amrubicin	Types of adverse events listed in Adverse Event Section

Trial Locations

Locations (3)

Indiana University Simon Cancer Center; 🇺🇸 Indianapolis, Indiana, United States

Banner MD Anderson Cancer Center; 🇺🇸 Gilbert, Arizona, United States

Icahn School of Medicine at Mount Sinai; 🇺🇸 New York, New York, United States