Adult Liposarcoma, Recurrent Adult Soft Tissue Sarcoma, Stage III Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma
Conditions
Brief summary
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
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.
Interventions
DRUGnelfinavir mesylate
Given orally
PROCEDUREbiopsy
Correlative studies
OTHERlaboratory biomarker analysis
Correlative studies
OTHERpharmacological study
Correlative studies
GENETICgene expression analysis
Correlative studies
GENETICwestern blotting
Correlative studies
GENETICreverse transcriptase-polymerase chain reaction
Correlative studies
OTHERimmunoenzyme technique
Correlative studies
Sponsors
City of Hope Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity (DLT) (Phase I) | 4 weeks from start of treatment, up to 2 years | 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 |
| Maximum Tolerated Dose (MTD) (Phase I) | 4 weeks from start of treatment, up to 2 years | 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. |
| Overall Response Rate (Phase II) | After 3 cycles of treatment, up to 2 years. | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I Phase I dose escalation portion of the study. Initial dose of oral Nelfinavir was 1250 mg bid with escalation to the MTD at 4250 mg bid using a standard 3+3 dose escalation scheme. | 17 |
| Phase II Oral Nelfinavir at 3000 mg bid | 12 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase I | Phase II | Total |
|---|---|---|---|
| Age, Continuous | 64 years | 63 years | 64 years |
| Region of Enrollment United States | 17 participants | 12 participants | 29 participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 11 Participants | 6 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 3 / 3 | 3 / 3 | 4 / 4 | 12 / 12 |
| serious Total, serious adverse events | 2 / 4 | 0 / 3 | 2 / 3 | 1 / 3 | 0 / 4 | 2 / 12 |
Outcome results
Primary
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
Time frame: 4 weeks from start of treatment, up to 2 years
Population: All patients receiving treatment were evaluated for DLT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Dose Level I | Dose Limiting Toxicity (DLT) (Phase I) | 0 participants with DLTs |
| Phase I: Dose Level II | Dose Limiting Toxicity (DLT) (Phase I) | 0 participants with DLTs |
| Phase I: Dose Level III | Dose Limiting Toxicity (DLT) (Phase I) | 0 participants with DLTs |
| Phase I: Dose Level IV | Dose Limiting Toxicity (DLT) (Phase I) | 0 participants with DLTs |
| Phase I: Dose Level V | Dose Limiting Toxicity (DLT) (Phase I) | 0 participants with DLTs |
Primary
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.
Time frame: 4 weeks from start of treatment, up to 2 years
Population: All patients observed for 28 days while receiving a full course of therapy or who experienced a DLT. Patients withdrawing before completion of the first course, for reasons other than DLT, were replaced.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Dose Level I | Maximum Tolerated Dose (MTD) (Phase I) | 3000 mg |
Primary
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
Time frame: After 3 cycles of treatment, up to 2 years.
Population: Patients who complete 3 cycles of treatment or who terminate treatment for reasons of toxicity, or who progress prior to the completion of 3 cycles of therapy on the Phase II portion of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Dose Level I | Overall Response Rate (Phase II) | 1 participants |