AFP464 in Treating Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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This phase I trial is studying the side effects and best dose of AFP464 in treating patients with advanced solid tumors. Drugs used in chemotherapy, such as AFP464, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the dose-limiting toxicity and maximum tolerated dose of AFP464 in patients with advanced solid tumors. II. Assess the safety and tolerability of this drug in these patients. SECONDARY OBJECTIVES: I. Observe clinical response in patients treated with this drug. II. Characterize the pharmacokinetics of this drug in these patients. III. Determine the clinical significance of genetic polymorphisms on the genes coding metabolizing enzymes (e.g., CYP1A1, 1A2, 2C9, 2C19, and SULTA1) and on the disposition and efficacy/toxicity of AFP464 and AF. OUTLINE: This a dose-escalation, multicenter study. Patients receive AFP464 IV over 3 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of unacceptable toxicity or disease progression. Cohorts of 2-6 patients receive escalating doses of AFP464 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which ≤ 1 of 6 patients experience dose-limiting toxicity. An additional 10 patients whose tumor is amenable to biopsy are treated at the MTD. Patients undergo blood collection periodically for pharmacokinetic and pharmacodynamic studies. Patients treated at the MTD also undergo tumor tissue biopsies periodically for additional pharmacodynamic and correlative biomarker studies. After completion of study treatment, patients are followed for 4 weeks.

Official Title
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A Phase 1 Study of AFP464 (Aminoflavone Prodrug) in Patients With Advanced Solid Tumors

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: AFP464
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Bilirubin normal Platelet count >= 100,000/mm³ AST and ALT =< 2.5 times upper limit of normal Creatinine normal OR creatinine clearance >= 60 mL/min Adequate pulmonary function DLCO =< grade 1 No symptomatic pulmonary disease Not pregnant or nursing Fertile patients must use effective contraception Negative pregnancy test No history of allergic reactions attributed to compounds of similar chemical or biological composition to AFP464 No uncontrolled intercurrent 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 limit study compliance No smoking within the past 30 days; must be willing and able to completely refrain from smoking during study participation More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas, mitomycin C, or bleomycin) and recovered At least 4 weeks since prior radiotherapy; no prior thoracic radiotherapy; no prior radiotherapy to >= 50% of total marrow volume More than 4 weeks since prior experimental therapy (non-FDA-approved agents), immunotherapy, or targeted agents and recovered More than 8 weeks since prior UCN-01 More than 2 weeks since prior hormonal therapy except for patients on androgen suppression for prostate cancer Concurrent androgen suppression allowed in patients with prostate cancer No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent investigational agents Histologically confirmed malignant solid tumor that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective Tumor amenable to biopsy (maximum tolerated dose expansion cohort) No known brain metastases ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100% Life expectancy > 12 weeks Absolute neutrophil count >= 1,500/mm³ No other concurrent anticancer agents or therapies Renal cell cancer, breast cancer, and non-small cell lung cancer encouraged

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive AFP464 IV over 3 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of unacceptable toxicity or disease progression. Cohorts of 2-6 patients receive escalating doses of AFP464 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which ≤ 1 of 6 patients experience dose-limiting toxicity. An additional 10 patients whose tumor is amenable to biopsy are treated at the MTD. Patients undergo blood collection periodically for pharmacokinetic and pharmacodynamic studies. Patients treated at the MTD also undergo tumor tissue biopsies periodically for additional pharmacodynamic and correlative biomarker studies. After completion of study treatment, patients are followed for 4 weeks. | Drug: AFP464<br>* Given IV<br>Other: laboratory biomarker analysis<br>* Correlative study<br>Other: pharmacological study<br>* Correlative study<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose determined by dose-limiting toxicity |  | 28 days | 
| Types and grades of toxicity | Full frequency distributions of grade of toxicity, by toxicity type, will be generated, by dose level. Among all treated patients, both point and exact confidence interval estimates of the rate of every specific type of Grade 3-4 toxicity will be calculated, by dose level. Grade 2 DLCO rates (point and confidence level) will also be computed, by dose level. | Up to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic, pharmacodynamic, and pharmacogenomic parameters |  | Up to 4 weeks | 
| Response rate | Point and exact confidence interval estimates of response rate will be provided for all eligible patients combined, and if warranted, by specific dose levels. | Up to 4 weeks |