PR-104 in Treating Patients With Advanced Solid Tumors

OBJECTIVES:

Primary

• Evaluate the safety and tolerability of PR-104 in patients with advanced solid tumors.
• Determine the maximum tolerated dose of PR-104 in these patients.

Secondary

• Characterize the pharmacokinetics of PR-104 and its alcohol metabolite in these patients.
• Assess evidence of antitumor activity of this drug in these patients.

Tertiary

• Examine metabolic changes in tumors of these patients using fludeoxyglucose F 18 positron emission tomography scanning.

OUTLINE: This is a multicenter, open-label, prospective, uncontrolled, dose-escalation study.

Patients receive PR-104 IV over 60 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients 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 then periodically during study treatment for pharmacokinetic and tumor marker studies. Patients undergo fludeoxyglucose F 18 positron emission tomography scanning before beginning study treatment and after completion of course 2 to assess metabolic activity of the tumor.

After completion of study treatment, patients are followed at 30 days.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed solid tumor, meeting 1 of the following criteria:

• Not amenable to standard therapy
• Refractory to conventional therapy
• Measurable or evaluable disease

PATIENT CHARACTERISTICS:

• Karnofsky performance status 70-100%
• Life expectancy > 3 months
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin > 9 g/L (transfusion independent)
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT and AST ≤ 2.5 times ULN
• Creatinine clearance ≥ 60 mL/min
• 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 treatment
• No significant cardiac comorbidity including any of the following:

• New York Heart Association class III-IV congenital heart failure
• LVEF < 40%
• Unstable angina
• Myocardial infarction within the past 6 months
• Ventricular arrhythmias requiring drug therapy
• Pacemaker or implanted defibrillator
• No ongoing coagulopathy
• No uncontrolled infection or infection requiring parenteral antibiotics
• No other significant clinical disorder or laboratory finding that would preclude study treatment
• No known HIV positivity
• No known positivity for hepatitis B surface antigen or hepatitis C with abnormal liver tests
• No known allergy to nonplatinum-containing alkylating agents

PRIOR CONCURRENT THERAPY:

• Recovered from prior therapy
• More than 2 weeks since prior hormonal therapy (except for androgen-deprivation therapy)
• More than 4 weeks since prior major surgery
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
• More than 4 weeks since prior radiotherapy
• More than 1 month since prior investigational drugs, therapies, or devices
• No prior radiotherapy to > 25% of bone marrow
• No prior high-dose chemotherapy, either myeloablative or nonmyeloablative (mini-allogeneic transplant)
• No more than 3 prior myelosuppressive chemotherapy regimens
• Concurrent steroids allowed provided dose is stable for ≥ 2 weeks and clinical condition is stable for 1 month

• Nasal, opthalmologic, and topical glucocorticoid preparations allowed
• Physiologic hormone replacement therapies allowed (i.e., oral replacement glucocorticoid therapy for adrenal insufficiency)
• No concurrent prophylactic hematopoietic growth factors
• No concurrent radiotherapy, including local palliative radiotherapy or systemic radioisotopes

• Radioisotopes for protocol specified positron emission tomography allowed
• No other concurrent investigational agents
• No other concurrent chemotherapy, radiotherapy (including palliative local radiotherapy), hormonal therapy (except for androgen-deprivation therapy), and/or biological therapy (including immunotherapy)