Recurrent Melanoma, Stage IV Skin Melanoma
Conditions
Brief summary
This phase II trial studies how well stereotactic body radiotherapy and ipilimumab work in treating patients with stage IV melanoma. Stereotactic body radiotherapy (SBRT) may be able to send x-rays directly to the tumor and cause less damage to normal tissue. Monoclonal antibodies, such as ipilimumab, target certain cells to interfere with the ability of tumor cells to grow and spread. Giving SBRT with ipilimumab may kill more tumor cells.
Detailed description
PRIMARY OBJECTIVES: I. To determine feasibility and immune-related clinical responses associated with SBRT when given in conjunction with ipilimumab. SECONDARY OBJECTIVES: I. To determine late toxicity and immune pharmacodynamic changes after SBRT followed by ipilimumab. OUTLINE: Patients undergo a total of 3 fractions of stereotactic body radiotherapy between days 1-13. Patients then receive ipilimumab intravenously (IV) every 3 weeks. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up within 60 days, and then every effort will be made to obtain records of patients during this follow up, and permission will be sought for the investigators and/or study team to re-contact the patient directly with regard to health status and toxicity.
Interventions
BIOLOGICALIpilimumab
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
RADIATIONStereotactic Body Radiation Therapy
Undergo SBRT
Sponsors
National Cancer Institute (NCI)
University of Washington
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
* Histologically confirmed diagnosis of melanoma * Previously treated or previously untreated stage IV melanoma by American Joint Committee on Cancer (AJCC) staging criteria * Presence of an index lesion between 1 and 5 cm * Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 * Signed informed consent document * Adequate renal, hepatic, and hematologic indices for ipilimumab therapy * Ability to tolerate stereotactic body radiation therapy (e.g. lie flat and hold position for treatment)
Exclusion criteria
* Prior systemic therapy within 14 days of study enrollment; patients must be adequately recovered from prior systemic therapy side effects as deemed by the treating investigator * Clinical contraindication to stereotactic body radiotherapy (e.g. active systemic sclerosis, active inflammatory bowel disease if bowel is within target field, etc) * Presence of central nervous system metastasis (including active brain metastasis); active brain metastasis would be defined as untreated brain metastases; if the brain metastases have received prior treatment (usually either with surgery or radiation), they are no longer active * Long-term use of systemic corticosteroids; patients with replacement steroids and not immunosuppressive steroids may enroll in the study * Prior radiation therapy (RT) that precludes the delivery of SBRT
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Immune-related Clinical Response, Defined as Proportion of Patients Treated at the Maximum-tolerated Dose (MTD) Who Achieve Either a Complete or Partial Immune-related Response | Up to 60 days after last ipilimumab injection | Scored on a non-index lesion using immune-related response criteria according to immune-related Response Evaluation Criteria in Solid Tumors version 1.1. The number of immune-related responses will be tabled by stratum and SBRT fraction dose level. At the MTD, the immune-related response rate and 95% exact confidence interval will be estimated separately for previously untreated and previously treated metastatic patients. |
| Immune-related Progression-free Survival (irPFS) | Time from first day of radiotherapy to first documented immune-related progressive disease, death due to any cause or last patient contact alive and progression-free, assessed at 6 months | irPFS will be estimated by the Kaplan-Meier method separately for previously untreated and previously treated metastatic patients who were treated at the MTD.. For some patients no scans were available for irRECIST reads, in which case change of management was determined to be the point of progression. |
| Late Toxicities, Graded According to the Radiation Therapy Oncology Group/European Organization for Research, the Treatment of Cancer Late Morbidity Scoring System, and the Common Terminology Criteria for Adverse Events Version 4.0 | Up to 3 years | Defined generally as an adverse event associated with the treatment which occurs beyond 30 days after last injection (i.e., adverse events which are observed months after treatment are most likely associated with SBRT). All dose-limiting toxicities and late toxicities will be graded and tabled by lesion site stratum and SBRT fraction dose level. Toxicity attribution to either SBRT or ipilimumab will be described if possible. |
| Overall Survival | Time from first day of radiotherapy to death due to any cause or last patient contact alive, assessed at 12 months | Will be estimated by the Kaplan-Meier method separately for previously untreated and previously treated metastatic patients who were treated at the MTD. |
Countries
United States
Participant flow
Recruitment details
As of January 2018, 23 participants consented to the study during accrual duration of 36 months. The participants with metastatic melanoma were recruited from the clinic at Department of Radiation Oncology, University of Washington Medical Center.
Pre-assignment details
The total number of participants that consented to the study are 23, however 1 participant was a screen-fail due to brain metastasis.
Participants by arm
| Arm | Count |
|---|---|
| Bone or Lung Index Lesion Participants with bone or lung index lesion with prescription dose per fraction to the Planning Target Volume (PTV) of 8 Gy per fraction. The total dose for dose level 1 (our starting dose level) will be 24 Gy over 3 fractions. If we encounter a dose limiting toxicity, we will then reduce our total dose to dose level -1. The total dose for dose level -1 will be 12 Gy over 2 fractions. | 9 |
| Liver or Subcutaneous Index Lesion Participants with liver or subcutaneous index lesion with prescription dose per fraction to the Planning Target Volume (PTV) of 6 Gy per fraction. The total dose for dose level 1 (our starting dose level) will be 18 Gy over 3 fractions. If we encounter a dose limiting toxicity, we will then reduce our total dose to dose level -1. The total dose for dose level -1 will be 12 Gy over 2 fractions. | 14 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up Clinic Visit | Disease progression | 1 | 1 |
| Follow-up Clinic Visit | Lost to Follow-up | 0 | 1 |
| Follow-up Clinic Visit | Withdrawal by Subject | 0 | 1 |
| Pre-treatment/Baseline | Screen fail- participant had brain mets | 1 | 0 |
| Treatment | Death | 0 | 1 |
| Treatment | Disease progression | 0 | 1 |
| Treatment | Participant did not tolerate Ipilimumab | 0 | 1 |
Baseline characteristics
| Characteristic | Bone or Lung Index Lesion | Liver or Subcutaneous Index Lesion | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 7 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 7 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 14 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 12 Participants | 20 Participants |
| Region of Enrollment United States | 9 participants | 14 participants | 23 participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 5 Participants | 8 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 8 | 11 / 14 |
| other Total, other adverse events | 8 / 8 | 14 / 14 |
| serious Total, serious adverse events | 1 / 8 | 1 / 14 |
Outcome results
Primary
Immune-related Clinical Response, Defined as Proportion of Patients Treated at the Maximum-tolerated Dose (MTD) Who Achieve Either a Complete or Partial Immune-related Response
Scored on a non-index lesion using immune-related response criteria according to immune-related Response Evaluation Criteria in Solid Tumors version 1.1. The number of immune-related responses will be tabled by stratum and SBRT fraction dose level. At the MTD, the immune-related response rate and 95% exact confidence interval will be estimated separately for previously untreated and previously treated metastatic patients.
Time frame: Up to 60 days after last ipilimumab injection
Population: Arms were stratified during tx for safety reasons, but the stated objective to calculate response rate per strata was re-assessed. Due to low accrual per-strata calculations lack the statistical power to draw robust conclusions. Results were not stratified during the statistical analysis of the study data and are reported as such here.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stable Disease | Immune-related Clinical Response, Defined as Proportion of Patients Treated at the Maximum-tolerated Dose (MTD) Who Achieve Either a Complete or Partial Immune-related Response | 6 Participants |
Primary
Immune-related Progression-free Survival (irPFS)
irPFS will be estimated by the Kaplan-Meier method separately for previously untreated and previously treated metastatic patients who were treated at the MTD.. For some patients no scans were available for irRECIST reads, in which case change of management was determined to be the point of progression.
Time frame: Time from first day of radiotherapy to first documented immune-related progressive disease, death due to any cause or last patient contact alive and progression-free, assessed at 6 months
Population: Arms were stratified during tx for safety reasons, but the stated objective to calculate response rate per strata was re-assessed. Due to low accrual per-strata calculations lack the statistical power to draw robust conclusions. Results were not stratified during the statistical analysis of the study data and are reported as such here.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Stable Disease | Immune-related Progression-free Survival (irPFS) | 131 Days | Standard Deviation 30.4 |
| Immune Resistant | Immune-related Progression-free Survival (irPFS) | 121 Days | Standard Deviation 50.3 |
p-value: 0.67Log Rank
Primary
Late Toxicities, Graded According to the Radiation Therapy Oncology Group/European Organization for Research, the Treatment of Cancer Late Morbidity Scoring System, and the Common Terminology Criteria for Adverse Events Version 4.0
Defined generally as an adverse event associated with the treatment which occurs beyond 30 days after last injection (i.e., adverse events which are observed months after treatment are most likely associated with SBRT). All dose-limiting toxicities and late toxicities will be graded and tabled by lesion site stratum and SBRT fraction dose level. Toxicity attribution to either SBRT or ipilimumab will be described if possible.
Time frame: Up to 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stable Disease | Late Toxicities, Graded According to the Radiation Therapy Oncology Group/European Organization for Research, the Treatment of Cancer Late Morbidity Scoring System, and the Common Terminology Criteria for Adverse Events Version 4.0 | 2 Participants |
| Immune Resistant | Late Toxicities, Graded According to the Radiation Therapy Oncology Group/European Organization for Research, the Treatment of Cancer Late Morbidity Scoring System, and the Common Terminology Criteria for Adverse Events Version 4.0 | 1 Participants |
Primary
Overall Survival
Will be estimated by the Kaplan-Meier method separately for previously untreated and previously treated metastatic patients who were treated at the MTD.
Time frame: Time from first day of radiotherapy to death due to any cause or last patient contact alive, assessed at 12 months
Population: Arms were stratified during tx for safety reasons, but the stated objective to calculate response rate per strata was re-assessed. Due to low accrual per-strata calculations lack the statistical power to draw robust conclusions. Results were not stratified during the statistical analysis of the study data and are reported.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Stable Disease | Overall Survival | 154 Days | Standard Deviation 327.6 |
| Immune Resistant | Overall Survival | 307.5 Days | Standard Deviation 282.8 |
p-value: 0.71Log Rank