PR-104 and Docetaxel or Gemcitabine in Treating Patients With Solid Tumors

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of PR-104 in combination with docetaxel or gemcitabine hydrochloride in patients with solid tumors.

Secondary

• Determine the safety of PR-104 in combination with docetaxel or gemcitabine hydrochloride in these patients.
• Determine the antitumor activity of these regimens using disease-specific parameters, such as exams, scans, and tumor markers, in these patients.
• Determine the pharmacokinetics of PR-104 and its alcohol metabolite in these patients.
• Determine the pharmacokinetics of docetaxel and gemcitabine hydrochloride when administered with PR-104.
• Collect plasma samples for assessment of potential biomarkers of tumor hypoxia from these patients.
• Examine metabolic changes in tumors using fludeoxyglucose F 18 positron emission tomography (PET) and PET imaging with fluoromisonidazole F 18 (a hypoxia-targeted radiopharmaceutical) in these patients.

OUTLINE: This is a nonrandomized, open-label, uncontrolled, multicenter, dose-escalation study of PR-104. Patients are assigned to 1 of 2 treatment groups according to patient's malignancy and prior treatment history.

• Group 1: Patients receive docetaxel IV over 60 minutes and PR-104 IV over 60 minutes on day 1.
• Group 2: Patients receive gemcitabine hydrochloride IV over 30 minutes and PR-104 IV over 60 minutes on days 1 and 8.

In both groups, treatment repeats every 21 days for up to 8 courses in the absence of unacceptable toxicity or disease progression.

Cohorts of 3-6 patients in each group receive escalating doses of PR-104 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Blood is collected at baseline and periodically during course 1 for pharmacokinetic analysis. Plasma samples are analyzed for biomarkers of tumor hypoxia at baseline and on days 2 and 8.

PROJECTED ACCRUAL: A total of 24 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed solid tumor malignancy
• Treatment with either docetaxel or gemcitabine hydrochloride in combination with an investigational agent is reasonable
• Measurable or evaluable disease

PATIENT CHARACTERISTICS:

• ECOG performance status of 0-1
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 9.0 g/dL (red blood cell transfusion allowed)
• Bilirubin normal
• ALT and AST ≤ 2.5 times upper limit of normal (ULN)
• Creatinine ≤ 1.5 times ULN
• PT/INR or aPTT ≤ 1.1 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 30 days after completion of study therapy
• No evidence of any other significant medical disorder, including uncontrolled infection or infection requiring a concurrent parenteral antibiotic, or laboratory finding that, in the opinion of the investigator, would preclude study compliance
• No known HIV positivity
• No hepatitis B surface antigen positivity
• No hepatitis C positivity with abnormal liver function test

PRIOR CONCURRENT THERAPY:

• No prior radiotherapy to > 25% of bone marrow
• No prior high-dose chemotherapy (including conditioning for either myeloablative or nonmyeloablative transplantation)
• No more than 3 prior chemotherapy regimens
• More than 4 weeks since prior major surgery
• More than 4 weeks since prior investigational or traditional anticancer therapy (including radiotherapy) (6 weeks for nitrosoureas and mitomycin C)
• The following medications/treatments are not permitted during the trial:

• Any other licensed or investigational anticancer treatment
• Prophylactic hematopoietic growth factors
• Irradiation therapy (palliative or therapeutic) unless given in the absence of tumor progression
• Concurrent systemic steroids allowed provided the patient is on a stable dose for ≥ 2 weeks prior to study treatment
• Concurrent androgen-deprivation therapy allowed