Brain Cancer, Brain Metastases, Brain Tumor
Conditions
Keywords
Radiation, Immune therapy, Stereotactic Radiosurgery
Brief summary
This study will evaluate the rate of radiation necrosis following treatment with immune checkpoint inhibitor (ICI) treatment and radiation therapy in subjects with metastatic brain cancer. Subjects will be treated with the standard of care immunotherapy followed by radiation therapy via stereotactic radiosurgery at a reduced dose.
Detailed description
This is a prospective, single arm, pilot study to determine the symptomatic radiation necrosis rate at 6 months utilizing dose-reduced stereotactic radiosurgery with immunotherapy for subjects with a diagnosis of 1-10 brain metastases from MRI and tissue diagnosis of primary malignancy. Primary end-point is 6 month symptomatic radiation necrosis, defined as a 6-month rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. Follow-up MRIs will be fused with the planning scan for this assessment.
Interventions
RADIATIONReduced Dose SRS
Subjects will receive SRS treatment at a reduced dose based on the brain tumor size
Sponsors
Indiana University
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
1. Brain MRI-confirmed 1-10 solid tumor brain metastases 2. Biopsy-confirmed primary malignancy 3. ds-GPA estimated median survival of at least 6 months, for histologies not included in the ds-GPA, publications or noted online at brainmetgpa.com, the PI will use either published or validated data or their best clinical judgment to determine the patient's expected survival 4. Stereotactic radiosurgery candidate per treating Radiation Oncologist 5. ≥ 18 years old at the time of informed consent 6. Ability to provide written informed consent and HIPAA (Health Insurance Portability and Accountability Act) authorization. 7. ALC \> 800/ul (Ku et al., 2010) 8. Patients currently on cytotoxic chemotherapy are eligible 9. Patients receiving ICI up to 30 days prior to delivery of SRS are eligible 10. Patients having undergone operative resection for metastatic brain disease within 30 days of immune checkpoint inhibitor (ICI) administration are eligible.
Exclusion criteria
1. Major medical illnesses or psychiatric impairments, which in the investigator's opinion will prevent administration or completion of the protocol therapy and/or interfere with follow-up 2. Patients unable to receive MRI Brain 3. Patients with more than 10 brain metastases on MRI Brain imaging 4. Any lesion \> 4 centimeter maximum diameter 5. Total volume of metastatic disease more than 30 cubic centimeters 6. Previous whole brain radiation therapy 7. For Cohort 1: Previous stereotactic radiosurgery where the 50% isodose line overlaps with current treatment field 8. For Cohort 2: Patients whose treatment will have a dose overlap within the target from prior treatments of 20% or greater 9. Already receiving chronic dexamethasone (chronic = \> 2 weeks) prior to SRS 10. Not a radiosurgical candidate per Radiation Oncology discretion 11. Existing autoimmune disease 12. Patients who have an unknown primary cancer 13. Histology not amenable for SRS (i.e. lymphoma). (Small Cell Lung Cancer IS amenable.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Symptomatic Radiation Necrosis Proportion | 6 months | The observed proportion of evaluable patients with symptomatic radiation necrosis by 6-months. Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Symptomatic Radiation Necrosis by SRS Group | 12 months | Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of symptomatic radiation necrosis was calculated. Patients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired. |
| Symptomatic Radiation Necrosis by Brain Metastases Group | 12 months | Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of symptomatic radiation necrosis was calculated. Patients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired. |
| Symptomatic Radiation Necrosis by Immune Checkpoint Inhibitor (ICI) Group | 12 months | Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of symptomatic radiation necrosis was calculated. Ppatients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired. |
| Local Control | 6 months | Local control was defined as the rate of any new, recurrent, or progressing tumor as defined by Response Assessment in Neuro-oncology (RANO) criteria within the planning target volume. This measure details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last known alive or at the date of death if they expired. |
| Symptomatic Radiation Necrosis Rate | 6 months | Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. This measure details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of symptomatic radiation necrosis was calculated. Patients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired. |
| Local Control by Brain Metastases Group | 12 months | Local control was defined as the rate of any new, recurrent, or progressing tumor as defined by Response Assessment in Neuro-oncology (RANO) criteria within the planning target volume. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last known alive or at the date of death if they expired. |
| Local Control by Immune Checkpoint Inhibitor (ICI) Group | 12 months | Local control was defined as the rate of any new, recurrent, or progressing tumor as defined by Response Assessment in Neuro-oncology (RANO) criteria within the planning target volume. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last known alive or at the date of death if they expired. |
| Radiographic Radiation Necrosis Rate | 6 months | Radiographic radiation necrosis was defined as brain imaging findings on magnetic resonance imaging (MRI), magnetic resonance (MR) perfusion, MR Spectroscopy, and/or positron emission tomography (PET) imaging consistent with radiation necrosis. This measure details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of radiographic radiation necrosis was calculated. Patients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired. |
| Local Control by SRS Group | 12 months | Local control was defined as the rate of any new, recurrent, or progressing tumor as defined by Response Assessment in Neuro-oncology (RANO) criteria within the planning target volume. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last known alive or at the date of death if they expired. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Reduced Dose Stereotactic Radiosurgery Subjects will receive one stereotactic radiosurgery (SRS) treatment at a reduced dose based on the brain tumor size concurrently with their standard of care immunotherapy. Subjects will undergo follow up with clinical exams and brain MRI scans at 1, 3, 6, 9, and 12 months post SRS treatment
Reduced Dose SRS: Subjects will receive SRS treatment at a reduced dose based on the brain tumor size | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Reduced Dose Stereotactic Radiosurgery |
|---|---|
| Age, Continuous | 63.08 years STANDARD_DEVIATION 7.59 |
| Corticosteroid Use at Baseline No | 10 Participants |
| Corticosteroid Use at Baseline Yes | 2 Participants |
| Diagnosis-Specific Graded Prognostic Assessment (ds-GPA) Median Survival at Baseline | 11.75 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Number of Lesions at Baseline | 1.50 lesions |
| Primary Site of Initial Cancer Diagnosis Adrenal Gland | 1 Participants |
| Primary Site of Initial Cancer Diagnosis Brain | 1 Participants |
| Primary Site of Initial Cancer Diagnosis Kidney/Renal Pelvis | 2 Participants |
| Primary Site of Initial Cancer Diagnosis Lung | 6 Participants |
| Primary Site of Initial Cancer Diagnosis Melanoma | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 11 Participants |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 18 |
| other Total, other adverse events | 7 / 18 |
| serious Total, serious adverse events | 1 / 18 |
Outcome results
Primary
Symptomatic Radiation Necrosis Proportion
The observed proportion of evaluable patients with symptomatic radiation necrosis by 6-months. Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis.
Time frame: 6 months
Population: Includes those patients who were evaluable for the 6-month outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reduced Dose Stereotactic Radiosurgery With Immunotherapy | Symptomatic Radiation Necrosis Proportion | 0.083 proportion of participants |
Comparison: The observed proportion of evaluable patients with symptomatic radiation necrosis was calculated and tested against a baseline 6-month symptomatic radiation necrosis rate of 16% at a type I error rate of 5% using a one-sided binomial exact test. The null hypothesis is that the observed proportion is equivalent to 16% or 0.160.p-value: 0.23495% CI: [0.002, 0.385]Exact Binomial Test
Secondary
Local Control
Local control was defined as the rate of any new, recurrent, or progressing tumor as defined by Response Assessment in Neuro-oncology (RANO) criteria within the planning target volume. This measure details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last known alive or at the date of death if they expired.
Time frame: 6 months
Population: Includes patients evaluable for 6-month outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reduced Dose Stereotactic Radiosurgery With Immunotherapy | Local Control | 1.00 survival probability |
Secondary
Local Control
Local control was defined as the rate of any new, recurrent, or progressing tumor as defined by Response Assessment in Neuro-oncology (RANO) criteria within the planning target volume. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last known alive or at the date of death if they expired.
Time frame: 12 months
Population: Includes patients evaluable for 12-month outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reduced Dose Stereotactic Radiosurgery With Immunotherapy | Local Control | 0.913 survival probability |
Secondary
Local Control by Brain Metastases Group
Local control was defined as the rate of any new, recurrent, or progressing tumor as defined by Response Assessment in Neuro-oncology (RANO) criteria within the planning target volume. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last known alive or at the date of death if they expired.
Time frame: 12 months
Population: Includes patients who were evaluable for the 12-month outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reduced Dose Stereotactic Radiosurgery With Immunotherapy | Local Control by Brain Metastases Group | 1.00 survival probability |
| Linear Accelerator | Local Control by Brain Metastases Group | 0.900 survival probability |
Comparison: The method of Klein et al., (Klein et.al., 2007) was used to compare the 12-month survival probabilities across brain metastases groups. The null hypothesis was that the survival probabilities were equal.p-value: 0.292Klein Method
Secondary
Local Control by Immune Checkpoint Inhibitor (ICI) Group
Local control was defined as the rate of any new, recurrent, or progressing tumor as defined by Response Assessment in Neuro-oncology (RANO) criteria within the planning target volume. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last known alive or at the date of death if they expired.
Time frame: 12 months
Population: Includes patients who were evaluable for the 12-month outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reduced Dose Stereotactic Radiosurgery With Immunotherapy | Local Control by Immune Checkpoint Inhibitor (ICI) Group | 0.889 survival probability |
| Linear Accelerator | Local Control by Immune Checkpoint Inhibitor (ICI) Group | 1.00 survival probability |
Comparison: The method of Klein et al., (Klein et.al., 2007) was used to compare the 12-month survival probabilities across ICI groups. The null hypothesis was that the survival probabilities were equal.p-value: 0.289Klein Method
Secondary
Local Control by SRS Group
Local control was defined as the rate of any new, recurrent, or progressing tumor as defined by Response Assessment in Neuro-oncology (RANO) criteria within the planning target volume. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last known alive or at the date of death if they expired.
Time frame: 12 months
Population: Includes patients who were evaluable for the 12-month outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reduced Dose Stereotactic Radiosurgery With Immunotherapy | Local Control by SRS Group | 1.00 survival probability |
| Linear Accelerator | Local Control by SRS Group | 0.750 survival probability |
Comparison: The method of Klein et al., (Klein et.al., 2007) was used to compare the 12-month survival probabilities across SRS groups. The null hypothesis was that the survival probabilities were equal.p-value: 0.248Klein Method
Secondary
Radiographic Radiation Necrosis Rate
Radiographic radiation necrosis was defined as brain imaging findings on magnetic resonance imaging (MRI), magnetic resonance (MR) perfusion, MR Spectroscopy, and/or positron emission tomography (PET) imaging consistent with radiation necrosis. This measure details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of radiographic radiation necrosis was calculated. Patients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired.
Time frame: 6 months
Population: Includes the patients who were evaluable for the 6-month outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reduced Dose Stereotactic Radiosurgery With Immunotherapy | Radiographic Radiation Necrosis Rate | 0.818 survival probability |
Secondary
Radiographic Radiation Necrosis Rate
Radiographic radiation necrosis was defined as brain imaging findings on magnetic resonance imaging (MRI), magnetic resonance (MR) perfusion, MR Spectroscopy, and/or positron emission tomography (PET) imaging consistent with radiation necrosis. This measure details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of radiographic radiation necrosis was calculated. Patients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired.
Time frame: 12 months
Population: Includes the patients who were evaluable for the 12-month outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reduced Dose Stereotactic Radiosurgery With Immunotherapy | Radiographic Radiation Necrosis Rate | 0.818 survival probability |
Secondary
Symptomatic Radiation Necrosis by Brain Metastases Group
Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of symptomatic radiation necrosis was calculated. Patients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired.
Time frame: 12 months
Population: Includes the patients who were evaluable for the 12-month outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reduced Dose Stereotactic Radiosurgery With Immunotherapy | Symptomatic Radiation Necrosis by Brain Metastases Group | 1.000 survival probability |
| Linear Accelerator | Symptomatic Radiation Necrosis by Brain Metastases Group | 0.900 survival probability |
Comparison: The method of Klein et al., (Klein et.al., 2007) was used to compare the 12-month survival probabilities across brain metastases groups. The null hypothesis was that the survival probabilities were equal.p-value: 0.292Klein Method
Secondary
Symptomatic Radiation Necrosis by Immune Checkpoint Inhibitor (ICI) Group
Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of symptomatic radiation necrosis was calculated. Ppatients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired.
Time frame: 12 months
Population: Includes the patients who were evaluable for the 12-month outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reduced Dose Stereotactic Radiosurgery With Immunotherapy | Symptomatic Radiation Necrosis by Immune Checkpoint Inhibitor (ICI) Group | 0.889 survival probability |
| Linear Accelerator | Symptomatic Radiation Necrosis by Immune Checkpoint Inhibitor (ICI) Group | 1.000 survival probability |
Comparison: The method of Klein et al., (Klein et.al., 2007) was used to compare the 12-month survival probabilities across ICI groups. The null hypothesis was that the survival probabilities were equal.p-value: 0.289Klein Method
Secondary
Symptomatic Radiation Necrosis by SRS Group
Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of symptomatic radiation necrosis was calculated. Patients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired.
Time frame: 12 months
Population: Includes the patients who were evaluable for the 12-month outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reduced Dose Stereotactic Radiosurgery With Immunotherapy | Symptomatic Radiation Necrosis by SRS Group | 0.875 survival probability |
| Linear Accelerator | Symptomatic Radiation Necrosis by SRS Group | 1.000 survival probability |
Comparison: The method of Klein et al., (Klein et.al., 2007) was used to compare the 12-month survival probabilities across SRS groups. The null hypothesis was that the survival probabilities were equal.p-value: 0.285Klein Method
Secondary
Symptomatic Radiation Necrosis Rate
Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. This measure details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of symptomatic radiation necrosis was calculated. Patients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired.
Time frame: 6 months
Population: Includes the patients who were evaluable for the 6-month outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reduced Dose Stereotactic Radiosurgery With Immunotherapy | Symptomatic Radiation Necrosis Rate | 0.913 survival probability |
Secondary
Symptomatic Radiation Necrosis Rate
Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of symptomatic radiation necrosis was calculated. Patients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired.
Time frame: 12 months
Population: Includes the patients who were evaluable for the 12-month outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reduced Dose Stereotactic Radiosurgery With Immunotherapy | Symptomatic Radiation Necrosis Rate | 0.913 survival probability |