Brain Metastases, Metastatic Melanoma
Conditions
Keywords
Metastatic melanoma, Brain metastases, Radiation therapy, Immune therapy
Brief summary
This is a study to test the efficacy of using standard immune therapy for melanoma prior to stereotactic radiosurgery (ipilimumab induction), as compared to stereotactic radiosurgery followed by immune therapy. The study's hypothesis is that ipilimumab induction is as good as or better than controlling brain metastases as compared to stereotactic radiosurgery followed by immune therapy.
Detailed description
This is a randomized Phase II selection study investigating the use of ipilimumab induction prior to stereotactic radiosurgery (SRS), versus no induction, for melanoma brain metastases. Participants will be randomized to Arm A Induction (two doses of ipilimumab prior to SRS, two doses of ipilimumab after SRS) versus Arm B No induction (SRS first, followed by 4 doses of ipilimumab). Participants will undergo multiple dynamic contrast-enhanced MRIs of the brain and submit blood samples for immune testing.
Interventions
DRUGIpilimumab
Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses.
PROCEDUREStereotactic Radiosurgery
Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.
Sponsors
University of Michigan Rogel Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with a histologically-confirmed diagnosis of melanoma who have imaging findings suggestive of 1 to 4 brain metastases * At least one lesion in the brain that is measurable, which is defined as ≥5 x 5mm (Prior craniotomy and surgical resection is allowed, as long as there is at least one remaining measurable lesion in the brain) * Patients must be candidates for stereotactic radiosurgery (SRS) and planning to undergo SRS * Patients must be candidates for ipilimumab as determined by the treating physician * Patients must be neurologically asymptomatic, or very minimally symptomatic, as judged by the treating physicians * At least 3 weeks has elapsed from any prior therapy, and the patient has recovered from side effects to ≤ grade 1 toxicities per Common Terminology Criteria (CTC) for Adverse Events * Age \> or = 18 years old * Performance status of ECOG of 0 or 1 (ECOG is the Eastern Oncology Cooperative Group Scoring system used to quantify cancer patients' general well-being and activities of daily life; scores range from 0 to 5 where 0 is perfect health and 5 is death) * Adequate organ and marrow function: alanine aminotransferase (ALT ) \< 2.5x's upper limit of normal (ULN) of the institutional normal reference range, aspartate aminotransferase (AST) \< 2.5x's ULN of the institutional normal reference range, Bilirubin \< 1.5x's ULN of the institutional normal reference range, Creatinine \< 2.0 milligrams per deciliter, Platelets \> 50,000 per microliter * Women of child-bearing potential must agree to use adequate contraception, defined as complete abstinence from intercourse with men or two methods * Ability to understand and the willingness to sign a written informed consent
Exclusion criteria
* Previous radiotherapy to the lesion(s) of interest, including prior treatment with whole brain radiation therapy (WBRT). Prior treatment with SRS is allowed if the index lesion(s) is in a different, non-contiguous location than the previously treated lesion. * Patients who have previously received ipilimumab, PD-1 inhibitors or PD-L1 inhibitors are excluded due to the potential of effects on primary outcome * Patients who require WBRT or surgery at the time of enrollment * Neurologic symptoms or imaging findings that necessitate the use of steroids on the day of enrollment or in the prior 7 days * Highly suspicious magnetic resonance imaging (MRI) or cerebrospinal fluid evidence of leptomeningeal metastases, unless all measurable disease is localized and SRS is considered the treatment of choice * Concurrent treatment with any other anti-neoplastic drug or concurrent participation in another therapeutic clinical trial * Patients unable to undergo or tolerate MRI scans (presence of cardiac pacemaker, implanted cardiac defibrillator, aneurysm clips, history of allergic reaction/hypersensitivity to gadolinium) * Women who are pregnant or are nursing * Patients with absolute lymphocyte count of \<500 cells/microliter, who are known to be HIV positive, who have clinically significant active autoimmune disease, or are receiving immunosuppression following solid organ or stem cell transplant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Local Control Rate | 6 months | The number of patients in each arm who are free from progression in the index (radiated) lesions in the brain at 6 months. Immune related response criteria was used to assess response to treatment. Immune-related Progressive Disease (irPD) in this trial is defined as an increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden), with confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival Rate | Up to 5 years | Number of participants alive at 5 years after enrollment. |
| Regional (Intracranial) Control Rate | 6 months | The proportion of patients in each arm who are free from progression in the index (radiated) lesions and free from new brain metastases at 6 months. |
| Intracranial Response Rate | Up to 12 months | Response of treated (irradiated) brain metastases to combination therapy with ipilimumab and stereotactic radiosurgery using immune-related response criteria. |
| Time to Progression | From date of enrollment to up to 2 years | Time to progression in the brain due to treated metastases or new brain metastases. Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) was used to assess response. Progression was defined as an increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden), with confirmation by a repeat, consecutive assessment no less than 4 wk from the date first documented. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Imaging Correlates on Dynamic-contrast Enhanced MRI of the Brain | 6 months | Exploratory endpoints: Interval changes in dynamic MRI parameters such as perfusion, blood volume, vascular permeability (Ktrans), and diffusion tensor imaging; the change in 3D tumor volume. |
| Immune Correlates | 6 months | Exploratory endpoints: Interval changes in immune markers in the blood |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| B: No Induction Participants will undergo stereotactic radiosurgery (SRS) followed 2-3 weeks later by ipilimumab, which is given once every 3 weeks for a total of 4 doses.
Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses.
Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours. | 1 |
| A: Induction Patients will receive 2 doses of ipilimumab, which is given once every 3 weeks, prior to stereotactic radiosurgery (SRS), followed by 2 more doses of ipilimumab, for a total of 4 doses.
Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses.
Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours. | 3 |
| Total | 4 |
Baseline characteristics
| Characteristic | B: No Induction | A: Induction | Total |
|---|---|---|---|
| Age, Continuous | 69 years | 55 years | 58 years |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 4 |
| other Total, other adverse events | 4 / 4 |
| serious Total, serious adverse events | 0 / 4 |
Outcome results
Primary
Local Control Rate
The number of patients in each arm who are free from progression in the index (radiated) lesions in the brain at 6 months. Immune related response criteria was used to assess response to treatment. Immune-related Progressive Disease (irPD) in this trial is defined as an increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden), with confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| B: No Induction | Local Control Rate | 1 Participants |
| A: Induction | Local Control Rate | 3 Participants |
Secondary
Intracranial Response Rate
Response of treated (irradiated) brain metastases to combination therapy with ipilimumab and stereotactic radiosurgery using immune-related response criteria.
Time frame: Up to 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| B: No Induction | Intracranial Response Rate | 1 Participants |
| A: Induction | Intracranial Response Rate | 3 Participants |
Secondary
Overall Survival Rate
Number of participants alive at 5 years after enrollment.
Time frame: Up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| B: No Induction | Overall Survival Rate | 1 participants |
| A: Induction | Overall Survival Rate | 2 participants |
Secondary
Regional (Intracranial) Control Rate
The proportion of patients in each arm who are free from progression in the index (radiated) lesions and free from new brain metastases at 6 months.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| B: No Induction | Regional (Intracranial) Control Rate | 1 Participants |
| A: Induction | Regional (Intracranial) Control Rate | 3 Participants |
Secondary
Time to Progression
Time to progression in the brain due to treated metastases or new brain metastases. Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) was used to assess response. Progression was defined as an increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden), with confirmation by a repeat, consecutive assessment no less than 4 wk from the date first documented.
Time frame: From date of enrollment to up to 2 years
Population: Of the 4 patients, 2 patients remained progression-free throughout the 2-year time frame for data collection for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| B: No Induction | Time to Progression | 5 months, 27 days | 0 participants |
| B: No Induction | Time to Progression | 19 months, 3 days | 1 participants |
| A: Induction | Time to Progression | 5 months, 27 days | 1 participants |
| A: Induction | Time to Progression | 19 months, 3 days | 0 participants |
Other Pre-specified
Imaging Correlates on Dynamic-contrast Enhanced MRI of the Brain
Exploratory endpoints: Interval changes in dynamic MRI parameters such as perfusion, blood volume, vascular permeability (Ktrans), and diffusion tensor imaging; the change in 3D tumor volume.
Time frame: 6 months
Other Pre-specified
Immune Correlates
Exploratory endpoints: Interval changes in immune markers in the blood
Time frame: 6 months