AFP464 in Treating Patients With Advanced Solid Tumors

OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) of AFP464 in patients with advanced solid
tumors.

II. Evaluate the toxicity profile of AFP464. III. Characterize the plasma pharmacokinetics
and urinary excretion of AFP464 and aminoflavone in these patients.

IV. Identify any activity of AFP464 in patients with metastatic cancer. V. Explore whether
AFP464 induces CYP1A1 expression in tumor as measured by pre- and post-treatment tumor
biopsies at the MTD as well as in peripheral lymphocytes during the dose-escalation phase
and at the MTD.

VI. Explore the relationship between the pharmacogenetic analysis and toxicity or response.

OUTLINE: This is a dose-escalation study followed by an open-label study.

Patients receive AFP464 intravenously (IV) over 3 hours on days 1, 8, and 15. Treatment
repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 1-6 patients receive escalating doses of AFP464 until the maximum tolerated dose
(MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients
experience dose-limiting toxicity. An additional 10 patients with accessible metastatic
breast, renal, or ovarian cancer receive AFP464 as above at the MTD. Blood, buccal cells,
and urine are collected before beginning treatment and during course 1 and examined for
biomarkers and biopharmacogenetics. Patients who are treated at the MTD also undergo
biopsies before and after course 1. Samples are analyzed via real time polymerase chain
reaction (RT-PCR) and immunofluorescence.

After completion of study treatment, patients are followed periodically for 3 months.

Inclusion Criteria:

- Histologically confirmed solid tumor

- Metastatic disease refractory to available therapy OR for which no standard
therapy exists

- Diagnosis of breast, ovarian, or renal cell cancer (for patients treated at the
maximum tolerated dose)

- Tumor amenable for paired tumor biopsies

- No CNS metastases

- Hormone receptor status not specified

- Male or female

- ECOG performance status 0-2

- Life expectancy ≥ 12 weeks

- Menopausal status not specified

- Absolute neutrophil count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin > 9.0 g/dL

- Bilirubin normal

- AST and ALT ≤ 2.5 times upper limit of normal (ULN)

- Creatinine ≤ 1.25 times ULN OR creatinine clearance ≥ 60 mL/min

- INR ≤ 1.4

- Adequate pulmonary function, DLCO normal or asymptomatic grade 1 DLCO

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No uncontrolled illness including, but not limited to, any of the following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situation that would preclude study compliance

- No seizure disorder

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to AFP464

- No symptomatic pulmonary disease

- No active smokers or those who have smoked within the past 30 days

- Willing and able to refrain completely from smoking during study treatment

- Willing to provide biologic specimens (blood and urine)

- Recovered from prior chemotherapy

- More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
and recovered

- More than 4 weeks since prior immunotherapy or biologic therapy

- More than 4 weeks since prior radiotherapy

- At least 5 days since prior aspirin

- At least 4 hours since IV heparin prior to biopsy procedures (8 hours for
subcutaneous or low-molecular weight heparin)

- No prior thoracic radiotherapy

- No prior radiotherapy to > 25% of the bone marrow

- No concurrent prophylactic colony-stimulating factors

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No concurrent participation in another study involving a pharmacologic agent (e.g.,
drugs, biologics, immunotherapy, or gene therapy) for symptom control or therapeutic
intent

- No other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary
therapy considered investigational