Oligometastases
Conditions
Brief summary
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
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.
Interventions
DRUGNelfinavir
Commercially available nelfinavir (1250 mg) will be administered orally twice daily for 14 days.
RADIATIONStereotactic Body Radiation (SBRT)
15 Gy dose (per lesion site) of SBRT will be administered
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
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
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Freedom From Local Progression (FFLP) | 6 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Adverse Events Experienced by Participants | 1 year | 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). |
| Percent of Lesions With Local Control at 6 Months Post-treatment | 6 months | 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. |
| Participants' Clinical Progress While in Follow-up in Terms of Survival | 18 months | 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). |
| Quality of Life After Completion of Treatment | 3 years | To assess quality of life following completion of SBRT in combination with nelfinavir |
| Phospho/ Akt Levels With Respect to Lesion Response | 3 months | Assess phospho-Akt protein in study participants to determine whether there is a correlation between the level protein and improved lesion response rate. |
Countries
United States
Participant flow
Recruitment details
A total of 38 patients were accrued between January 2014 and December 2015 with one who withdrew consent and 37 were included in the analysis.
Participants by arm
| Arm | Count |
|---|---|
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) 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.
Nelfinavir: Commercially available nelfinavir (1250 mg) will be administered orally twice daily for 14 days.
Stereotactic Body Radiation (SBRT): 15 Gy dose (per lesion site) of SBRT will be administered | 37 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) |
|---|---|
| Age, Customized | 65 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 32 Participants |
| Region of Enrollment United States | 37 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 37 |
| other Total, other adverse events | 37 / 37 |
| serious Total, serious adverse events | 3 / 37 |
Outcome results
Primary
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.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Percentage of Participants With Freedom From Local Progression (FFLP) | 78.4 percentage of participants |
Secondary
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).
Time frame: 18 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Participants' Clinical Progress While in Follow-up in Terms of Survival | Overall Survival | 90.7 percentage of participants |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Participants' Clinical Progress While in Follow-up in Terms of Survival | Freedom From Distant Metastasis | 62.4 percentage of participants |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Participants' Clinical Progress While in Follow-up in Terms of Survival | Progression-Free Survival | 57.6 percentage of participants |
Secondary
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.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Percent of Lesions With Local Control at 6 Months Post-treatment | 76.5 percentage of lesions |
Secondary
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.
Time frame: 3 months
Population: Data was not collected for this outcome measure.
Secondary
Quality of Life After Completion of Treatment
To assess quality of life following completion of SBRT in combination with nelfinavir
Time frame: 3 years
Population: Data was not collected for this outcome measure.
Secondary
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).
Time frame: 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Anorexia | 20 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Anxiety | 17 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Cough | 25 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Agitation | 3 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Alanine Amino Trans increased | 3 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Alkaline Phosphatase increased | 4 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Alopecia | 8 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | ALT Increase | 3 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Anemia | 23 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Apnea | 3 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Aspartate Amino Trans increased | 2 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Ataxia | 1 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Bilirubin Increased | 3 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Bloating | 6 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Bronchial Infection | 1 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Bruising | 7 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Chills | 6 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Colonic obstruction | 1 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Concentration Impairment | 7 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Conjunctivitis | 2 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Constipation | 18 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Creatinine increased | 1 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Cytokine Release Syndrome | 1 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Dehydration | 4 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Depression | 15 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Dermatitis | 1 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Diarrhea | 31 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Dizziness | 11 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Dry Mouth | 14 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Dyspepsia | 13 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Dyspnea | 25 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Edema | 21 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Esophageal pain | 3 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Esophagitis | 5 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Fatigue | 32 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Fecal Incontinence | 4 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Fever | 1 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Gastritis | 3 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Headache | 12 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Hearing Loss | 1 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Hematuria | 3 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Hemaglobin Increased | 3 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Hemorrhoids | 12 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Hiccups | 2 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Hot Flashes | 4 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Hyperglycemia | 32 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Hyperkalemia | 4 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Hypernatremia | 1 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Hypertension | 1 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Hypoglycemia | 2 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Hypokalemia | 2 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Hyponatremia | 1 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Hypoxia | 1 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Insomnia | 1 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Lymphocyte absolute decreased | 22 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Malaise | 2 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Nausea | 23 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Neuralgia | 12 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | White blood cells decreased | 22 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Weight Loss | 10 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Weight Gain | 15 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Vomitting | 10 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Urticaria | 2 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Urinary Incontinence | 25 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Urinary Frequency | 2 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Tremor | 3 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Toothache | 2 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Stomatitis | 2 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Stomach Pain | 11 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Oral mucositis | 3 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Perineal Pain | 1 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Periodontal Disease | 1 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Platelet count decreased | 13 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Proctitis | 2 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Pruritis | 9 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Radiation Recall Rctn | 3 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Rash | 2 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Skin Infection | 1 adverse events |
| Nelfinavir w/Stereotactic Body Radiation Therapy (SBRT) | Total Number of Adverse Events Experienced by Participants | Short term memory impairment | 1 adverse events |