Second-Line Docetaxel + ASA404 for Advanced Urothelial Carcinoma

A Phase II Trial of Docetaxel Plus ASA404 as Second-Line Therapy in Patients With Advanced Urothelial Carcinoma: Hoosier Oncology Group GU09-144

The purpose of this study is to explore the safety and activity of docetaxel + ASA404 as second-line chemotherapy in patients with advanced urothelial carcinoma.

OUTLINE: This is a multi-center study.

21 Day Cycle Treatment Regimen:

• Docetaxel IV 75 mg/m2 over approximately 60 minutes on Day 1
• ASA404 (given after Docetaxel) IV 1800 mg/m2 over approximately 20 minutes on Day 1

Treatment will continue until disease progression or intolerable treatment related adverse effects.

Karnofsky performance status of ≥ 70% within 7 days prior to registration for protocol therapy.

Life Expectancy: Not specified

Hematopoietic:

• Hemoglobin (Hgb) > 9 g/dL
• Platelets > 100 K/mm3
• Absolute neutrophil count (ANC) > 1.5 K/mm3
• INR or Prothrombin Time (PT) < 1.5 x ULN

Hepatic:

• Bilirubin < 1.5 x ULN
• Aspartate aminotransferase (AST, ALT) < 2.5 x ULN

Renal:

• Calculated creatinine clearance of > 45 cc/min using the Cockcroft-Gault formula

Cardiovascular:

• No congestive heart failure (NY Heart Association class III or IV)
• No myocardial infarction within 12 months of study registration for protocol therapy or with implanted cardiac pacemaker
• No unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris

Inclusion Criteria:

• Histological or cytological proof of transitional cell carcinoma (TCC) of the bladder, urethra, ureter, or renal pelvis (urothelial carcinoma). Histology may be mixed, but still requires a component of TCC.
• Measurable disease according to RECIST (version 1.1) and obtained by imaging within 30 days prior to registration for protocol therapy. Note: Sites of measurable disease can not be within a previously irradiated site.
• Written informed consent and HIPAA authorization for release of personal health information.
• Age > 18 years at the time of consent.
• Must have received only one prior chemotherapy regimen, which must have included one of the following chemotherapeutic agents: cisplatin, carboplatin, or gemcitabine. Note: Prior chemotherapy may have been administered in the perioperative (neoadjuvant/adjuvant) or advanced/metastatic setting. Patients may have received prior treatment with paclitaxel.
• 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 12 weeks after treatment discontinuation.
• Females of childbearing potential must have a negative pregnancy test within 7 days prior to registration for protocol therapy.
• Females must not be breastfeeding.

Exclusion Criteria:

• No prior treatment with docetaxel.
• No symptomatic brain metastases. Patients with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis. NOTE: Patients with treated brain metastasis must be off steroids and have completed radiation at least 14 days prior to registration for protocol therapy.
• No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, Gleason < grade 7 prostate cancers, or other cancers for which the patient has been disease-free for at least 5 years
• No treatment with any investigational agent or chemotherapeutic agent within 30 days prior to registration for protocol therapy.
• No radiotherapy within 14 days prior to registration for protocol therapy. Patients must have recovered from all radiotherapy-related toxicities.
• No major surgery within 30 days prior to registration for protocol therapy (major surgery is defined by the use of general anesthesia).
• No minor surgery 14 days prior to registration for protocol therapy. NOTE: Insertion of a vascular access device is allowed.
• No history of any medical condition resulting in ≥ CTC grade 2 dyspnea.
• Patients without long QT syndrome
• No history of labile hypertension or poor compliance with anti-hypertensive regimen NOTE: No patients with systolic BP >140 mm Hg and/or diastolic BP > 90 mm Hg while on medication for hypertension.
• No presence of atrial tachyarrhythmia (e.g., atrial fibrillation, atrial flutter, multifocal atrial tachycardia, supraventricular tachycardia) if not effectively rate-controlled.
• No history of a sustained ventricular tachycardia
• No history of ventricular fibrillation or Torsades de Pointes
• No right bundle branch block and left anterior or posterior hemiblock (bifascicular block)
• No bradycardia defined as heart rate <50 beats per minute
• No concomitant use of drugs with risk of causing Torsades de Pointes.
• No concomitant use of drugs that are inducers and inhibitors of UGT1A9 and UGT2B7.