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

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

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.

Study Overview

• Status: Terminated
• Conditions: Bladder Cancer
• Intervention / Treatment: Drug: Amrubicin

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 Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Simon Cancer Center
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Amrubicin; 35 mg/m2/day intravenously	Drug: Amrubicin; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Matthew Galsky
• Collaborators: Celgene

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (ACTUAL): July 1, 2014
• Study Completion (ACTUAL): July 1, 2015

Study Registration Dates

• First Submitted: April 6, 2011
• First Submitted That Met QC Criteria: April 7, 2011
• First Posted (ESTIMATE): April 8, 2011

Study Record Updates

• Last Update Posted (ACTUAL): April 23, 2018
• Last Update Submitted That Met QC Criteria: March 22, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Metastatic; Chemotherapy; Bladder Cancer; Urothelial Cancer; Second-line
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Antineoplastic Agents; Amrubicin
• Other Study ID Numbers: GCO 10-1341