Stereotactic Body Radiation With Nelfinavir for Oligometastases

Study Overview
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Brief Summary
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Patients with metastatic lesions of the lung, liver, or bone will be candidates for treatment. Within three weeks of the initial treatment planning, a 15 Gy dose (per lesion site) of SBRT will be administered. Prior to SBRT, patients will initiate Nelfinavir oral therapy twice daily for 7 days. Once SBRT is completed, the patient will repeat the same Nelfinavir therapy for an additional 7 days for a total of 14 days of treatment.

Detailed Description
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The use of radiation therapy to treat metastatic tumors is well established and promising data are emerging with the use of SBRT for metastatic disease. However, the use of a single large fraction concurrent with a radiosensitizer as is being proposed is not of proven benefit. This investigation aims to confirm the safety and efficacy for SBRT used concurrently with a radiosensitizer in the setting of oligometastatic disease. The dose selected has been chosen with the belief that it is safe and effective based on prior experience with SBRT of lung cancer, pancreatic cancer and brain radiosurgery. All patients will be treated with a single fraction (per lesion site), targeted to the lesion concurrently with the radiosensitizer Nelfinavir. On the basis of this preclinical evidence, we propose a phase II study of Nelfinavir combined with SBRT in patients with oligometastatic disease. Because the standard dose of Nelfinavir for HIV patients is known to be safe and does inhibit the phosphorylation of Akt and decrease tumor hypoxia, we propose to study this in conjunction with a 15 Gy dose of SBRT. Experience with single-fraction pulmonary and pancreas SBRT provides a useful dose for this trial. With published data establishing the relative safety of large single-fraction SBRT to the lungs and pancreas, we have decided to proceed to determine the safety of 15 Gy SBRT concurrently with the radiosensitizer Nelfinavir. Once this is established, we propose to continue to enroll more patients to the study at this dose to determine the efficacy of this type of therapy. The proposed study represents an informed estimate based on current knowledge of SBRT doses and those administered in currently approved image-guided protocols (brain, base of skull, cervico-thoracic spine, pancreas and liver). This study will refine the current understanding of single fraction radiation tolerance for normal tissues, thereby making it possible to treat future patients more safely and aggressively.

Official Title
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Single-Arm Phase II Study of Stereotactic Body Radiation Therapy Concurrent With Nelfinavir for Oligometastases

Conditions
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Oligometastases

Intervention / Treatment
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* Drug: Nelfinavir
* Radiation: Stereotactic Body Radiation (SBRT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patient's tumor(s) to be treated is(are) ≤ 5.0 cm or ≤250 cm3 Patient must have metastasis at one or more of the following sites: bone, liver, lymph node and/or lung. No more than five lesions will be treated. Histological confirmation of malignancy (primary or metastatic tumor). Patient may have any prior therapy allowed aside from having had prior radiotherapy to the treatment site (see exclusion criteria 5.2.3). Patient must be ≥ 18 years of age. Patient must have a life expectancy ≥ 9 months. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Patient must have normal organ and marrow function. Patient must have the ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study Patients receiving any other investigational agents Patient who has had any prior radiotherapy to the treatment site(s) Patients taking drugs that are contraindicated with nelfinavir, including any of the following: Amiodarone, Quinidine, Rifampin, Dihydroergotamine, Ergonovine, Ergotamine, Methylergonovine, Hypericum perforatum (St. John's wort), Lovastatin, Simvastatin, Pimozide, Midazolam, Triazolam Women of child bearing potential who refuse to take a pregnancy test prior to treatment Participation in another concurrent treatment protocol while being treated on this protocol and through to 3 months after treatment on this protocol has ended Pregnant women Inability to understand the informed consent document Inability to sign the informed consent document Poor liver function suggestive of cirrhosis or steatohepatitis

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: Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT)<br>Patients with metastatic lesions of the lung, liver, or bone will be candidates for treatment. Within three weeks of the initial treatment planning, a 15 Gy dose (per lesion site) of SBRT will be administered. Prior to SBRT, patients will initiate Nelfinavir oral therapy twice daily for 7 days. Once SBRT is completed, the patient will repeat the same Nelfinavir therapy for an additional 7 days for a total of 14 days of treatment. | Drug: Nelfinavir<br>* Commercially available nelfinavir (1250 mg) will be administered orally twice daily for 14 days.<br>* Other names: Viracept;Radiation: Stereotactic Body Radiation (SBRT)<br>* 15 Gy dose (per lesion site) of SBRT will be administered<br>* Other names: SBRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Freedom From Local Progression (FFLP) | To determine the 6-month Freedom From Local Progression rate (measured as a percentage of participants) in participants treated with radiosensitizer nelfinavir used concurrently with 15 Gy of stereotactic body radiation therapy (SBRT) delivered in 1 fraction in patients with oligometastatic disease. FFLP is defined as the percent of participants who were free from progression at the 6 month time point. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Number of Adverse Events Experienced by Participants | To assess the toxicity of the radiosensitizer Nelfinavir used concurrently with 15 Gy of stereotactic body radiation therapy (SBRT) delivered in 1 fraction (per lesion site) in patients with oligometastatic disease. Toxicity is assessed by the total number of adverse events based on Common Terminology Criteria for Adverse Events (CTCAE). | 1 year | 
| Percent of Lesions With Local Control at 6 Months Post-treatment | To determine percent of lesions with local control at 6-months after SBRT delivered to a dose of 15 Gy in 1 fraction (per lesion site) combined with nelfinavir in patients with oligometastatic disease. | 6 months | 
| Participants' Clinical Progress While in Follow-up in Terms of Survival | To assess the long-term clinical outcomes of this patient population after completion of SBRT in combination with Nelfinavir by determining the percentage of participants with Overall Survival (OS), Freedom From Distant Metastasis (FFDM) and the Progression-Free Survival (PFS). | 18 months | 
| Quality of Life After Completion of Treatment | To assess quality of life following completion of SBRT in combination with nelfinavir | 3 years | 
| Phospho/ Akt Levels With Respect to Lesion Response | Assess phospho-Akt protein in study participants to determine whether there is a correlation between the level protein and improved lesion response rate. | 3 months |