Nelfinavir Mesylate in Treating Patients With Recurrent, Metastatic, or Unresectable Liposarcoma

Study Overview
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Brief Summary
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RATIONALE: Antiviral drugs, such as nelfinavir mesylate, may help prevent cancer cells from spreading. PURPOSE: This phase I/II trial is studying the side effects and best dose of nelfinavir mesylate and to see how well it works in treating patients with recurrent, metastatic, or unresectable liposarcoma.

Detailed Description
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OBJECTIVES: I. To assess the toxicity and tolerance of nelfinavir in patients with liposarcoma. II. To define the maximum tolerated dose (MTD) of nelfinavir when given daily as a single agent and to describe the toxicities at each does studied. III. To evaluate the pharmacokinetics of nelfinavir. IV. To assess the response rate and progression free survival in patients with liposarcoma treated with nelfinavir. V. To evaluate the expression and activity of certain proteins in the tumors of patients entered on this study, which may be important to the cytotoxicity of nelfinavir (SREBP-1, p21, NFkB (NFkappaB), caspase 3). OUTLINE: This is a phase I, dose-escalation study followed by a phase II study. Patients receive oral nelfinavir mesylate twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Official Title
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A Phase I/II Study of Nelfinavir in Liposarcoma

Conditions
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Adult Liposarcoma, Recurrent Adult Soft Tissue Sarcoma, Stage III Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: nelfinavir mesylate
* Procedure: biopsy
* Other: laboratory biomarker analysis
* Other: pharmacological study
* Genetic: gene expression analysis
* Genetic: western blotting
* Genetic: reverse transcriptase-polymerase chain reaction
* Other: immunoenzyme technique


Participation Criteria
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Eligibility Criteria
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Inclusion Patients must have histologically confirmed liposarcoma, which is recurrent, metastatic or unresectable There is no limit to prior chemotherapy regimens; in addition, patients may have prior radiation All patients must have measurable disease, defined as lesions that can be accurately measured in at least one dimension (>= 20 mm with conventional techniques or >= 10mm with spiral CT scan); pleural effusions and ascites will not be considered measurable, but may be present in addition to the measurable lesion(s) ECOG (Eastern Cooperative Oncology Group) performance status of 0, 1, or 2; patients should have an expected survival of at least 3 months Absolute neutrophil count >= 1,000/ul Platelets >= 75000/ul Total bilirubin =< 2.0 g/dl AST(SGOT)/ALT(SGPT) =< 2.0X institutional upper limit of normal Brain metastasis is not an exclusion; however, patients are only eligible if they have had successful control of the brain tumor(s) by surgery or radiation therapy All prior therapy must have been completed at least 3 weeks prior to the patient's entry on this trial No concurrent chemotherapy, radiotherapy, immunotherapy or other investigational agents Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation; should a women become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Ability to understand and willingness to sign a written informed consent document Exclusion Patient has had prior treatment with or is currently taking a protease inhibitor Patients enrolled cannot be on the following medications: cisapride, triazolam, midazolam, ergot derivatives, amiodarone, quinidine, dihydropyridine calcium antagonists (amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, and nisoldipine), sildenafil, dilantin, rifampin or oral contraceptives Uncontrolled intercurrent illness Patients must have recovered from any expected toxicities of previous chemotherapy or radiation therapy

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 oral nelfinavir mesylate twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: nelfinavir mesylate<br>* Given orally<br>* Other names: Viracept;Procedure: biopsy<br>* Correlative studies<br>* Other names: biopsies;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Genetic: gene expression analysis<br>* Correlative studies<br>Genetic: western blotting<br>* Correlative studies<br>* Other names: Western Blot;Genetic: reverse transcriptase-polymerase chain reaction<br>* Correlative studies<br>* Other names: RT-PCR;Other: immunoenzyme technique<br>* Correlative studies<br>* Other names: immunoenzyme techniques;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity (DLT) (Phase I) | DLT is defined as any grade III toxicity not reversible to grade II or less within one week, or any grade IV toxicity. Hyperlipidemia, hyperglycemia, nausea, vomiting and diarrhea are not DLTs unless they are uncontrolled grade 3/4. Dose delays lasting more than 2 weeks due to toxicity are considered a DLT. Dose escalation schedule for nelfinavir: 1250 mg bid ; 1500 mg bid; 2125 mg bid; 3000 mg bid; 4250 mg bid ; 6000 mg bid ; 8500 mg bid ; 12000 mg bid | 4 weeks from start of treatment, up to 2 years | 
| Maximum Tolerated Dose (MTD) (Phase I) | The highest dose tested in which fewer than 33% of patients experience an attributable DLT to the study drug, when at least 6 patients are treated at that dose and are evaluable for toxicity. If PK analysis of 3 patients treated at 4250 mg bid and 3 patients at 3000 mg bid confirms that the first dose area under the curve and Cmax of nelfinavir does not increase appreciably at doses greater than 1875 mg BID then 3000 mg BID will be deemed the MTD. | 4 weeks from start of treatment, up to 2 years | 
| Overall Response Rate (Phase II) | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | After 3 cycles of treatment, up to 2 years. |