Phase I Study of Percutaneous Valrubicin for Upper Tract Urothelial Carcinoma

Eligible patients will receive percutaneous valrubicin beginning no sooner than 10 days
following nephrostomy placement and within 6 weeks of tumor treatment/resection. Therapy
will be administered at one of three dose levels in a 3 + 3 design (200 mg/75 ml diluent,
400 mg/75 ml diluent or 800 mg/75 ml diluent). It is anticipated that at least 3 patients
will be accrued at both of the 200 and 400 mg dose levels. Assuming acceptable toxicity, the
accrual target for the 800 mg dose level will be 9 patients. If the maximum tolerated dose
is determined to be 200 mg or 400 mg, expansion to 9 patients will occur at the maximum
tolerated dose (MTD) dose level. Drug will be administered on a weekly basis for 8 total
treatments.

Inclusion Criteria:

- Zubrod: Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Tissue confirmation of UTUC

- Available tumor grade information

- Treated UTUC (complete resection and or fulguration of tumor as is safely possible,
based on the judgment of the investigators and based on visual inspection of the
involved kidney and ureter) and at least one of the following:

- Low grade urothelial carcinoma

- Percutaneous upper tract Bacillus Calmette-Guérin (BCG) failure and: High grade
urothelial carcinoma or Carcinoma in situ (CIS) with imperative indications for
nephron preservation (solitary kidney, renal insufficiency, bilateral upper
tract tumors, etc.) as determined by study Principal Investigators (PIs)

- Contraindications to percutaneous BCG (e.g. previous adverse systemic or local
reaction to BCG exposure as judged by PIs, or immunosuppression, or other
contraindications to BCG therapy) and: High grade urothelial carcinoma or CIS
with imperative indications for nephron preservation (solitary kidney, renal
insufficiency, bilateral upper tract tumors, etc.) as determined by study PIs

- Normal prothrombin time (PT), partial thromboplastin time (PTT), international
normalized ratio (INR)

- Platelets 100 x 10^9/l or greater

- Absolute neutrophil count (ANC) 1.5 x 10^9/l or greater

- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 3 x upper
limits of normal (ULN) or less

- Able to receive valrubicin within 6 weeks of the initial surgery or within 6 weeks of
a second look surgical procedure

Exclusion Criteria:

- Radiographic or pathologic evidence for locally advanced (muscle invasion,
lymphovascular invasion, lymphadenopathy, renal parenchymal invasion) or distant
metastatic disease

- Contraindications for percutaneous nephrostomy (i.e. bleeding diathesis and/or
patients who must be maintained on therapeutic doses of warfarin or antiplatelet
agents while valrubicin is being administered). Note: 81 mg aspirin acceptable.

- Evidence for renal/ureteral obstruction as determined by radiographic studies
(antegrade nephrostogram, Intravenous pyelography (IVP), Computed tomography (CT)
urogram, retrograde pyelogram, lasix renogram, or a combination thereof)

- Contraindication to percutaneous administration of valrubicin, a metabolite of
valrubicin, or known hypersensitivity to anthra-cyclines or polyoxyl castor oil.

- Symptomatic urinary tract infection based on a combination of urinalysis and urine
culture and patient symptoms (i.e. Fever). Investigators expect patients to have an
abnormal urinalysis based on indwelling urinary devices and prior surgical treatment.

- Urolithiasis in the involved ipsilateral kidney (not including punctuate
calcifications or suspected renal parenchymal or papillary tip calcifications seen on
radiographic studies or visualized endoscopically)

- Patient on renal replacement therapy (hemodialysis or peritoneal dialysis)

- Extravasation of contrast as visualized on antegrade nephrostogram studies. (Note: At
the initial nephrostogram possibly performed in the operating room or with initial
percutaneous nephrostomy placement, extravasation can be visualized. However, a
procedure prior to drug administration confirms there is not further extravasation
present).

- Concurrent malignancy (except basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or concurrent non-muscle invasive bladder cancer that has been
completely resected)

- Congenital or acquired immunodeficiency

- Positive pregnancy test or plans for future pregnancy

- Expected poor compliance as judged by the investigators