Brain Metastases, Melanoma
Conditions
Keywords
melanoma, brain, metastases, Patients with melanoma and brain metastases
Brief summary
Ipilimumab adds a clinical benefit to radiation therapy in patients with melanoma metastatic to the brain. Melanoma is the third most common cancer causing brain metastases, after cancers of the lung and breast, which appears to reflect the relative propensity of melanoma to metastasize to the central nervous system (CNS). Brain metastases are responsible for 20 to 54 percent of deaths in patients with melanoma, and among those with documented brain metastases, these lesions contribute to death in up to 95 percent of cases, with an estimated median overall survival ranging between 1.8 and 10.5 months, depending upon other prognostic factors. Ipilimumab is an anti-Cytotoxic T-Lymphocyte Antigen 4 (anti-CTLA4) monoclonal antibody that has demonstrated a clinically relevant and statistically significant improvement in overall survival, either alone (second line) or in combination with dacarbazine (DTIC) in 1st line. Ipilimumab has shown activity against brain metastases. According to the European Medicines Agency (EMA) approved label for Yervoy®, the use of glucocorticoids at baseline (commonly prescribed when brain metastases are diagnosed) should be avoided before the administration of ipilimumab. Data show that the use of even high doses of glucocorticoids for the management of immune-related adverse events do not decrease the efficacy of Yervoy®. There is no documented experience on the efficacy of Yervoy® when given concomitantly with radiation therapy and glucocorticoids. In experimental models, radiation therapy is synergistic to anti-Cytotoxic T-Lymphocyte Antigen 4 (anti-CTLA4) strategies (abscopal effect). There are no published results from clinical trials on the interaction between radiation therapy and ipilimumab.
Interventions
DRUGIpilimumab
Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles
Sponsors
Bristol-Myers Squibb
Grupo Español Multidisciplinar de Melanoma
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. Willing and able to give written informed consent. 2. Histologic diagnosis of melanoma. 3. First episode of radiological evidence of brain metastases 4. Be over the age of 18 years old 5. Radiation Therapy Oncology Group-recursive partitioning analysis (RTOG-RPA) class 2 6. Karnofsky performance status (PS) more than 70% 7. Barthel Index of Activities of Daily Living more than 10 8. Measurable disease (mWHO criteria). 9. Adequate organ function as determine by the following criteria: * White blood count (WBC) more or equal to 2000/ microliter (uL) * Absolute neutrophil count (ANC) more than 1.5 x 109/L. * Platelet count more than 75 x 109/L. * Hemoglobin more than 9 g/dL. If the patient received a red blood count (RBC) transfusion, the required value of hemoglobin should be met at least 1 week after the most recent transfusion. * Serum creatinine less or equal to 2.0 x upper limit of normal (ULN). * Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) less or equal to 2.5 x ULN for patients without liver metastasis, or less or equal to 5 times for liver metastases. * Total bilirubin less or equal 2.0 x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL) 10. Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 26 weeks after ipilimumab is stopped
Exclusion criteria
1. Patients with melanoma and brain metastases with any of the following disease-specific characteristics: * Documented evidence of prior progression of melanoma to an ipilimumab-containing regimen (i.e. received at least 2 doses of ipilimumab for either advanced disease or in the adjuvant setting and the disease progressed/relapsed (according to mWHO criteria) within 24 weeks since the first dose of ipilimumab) * Prior radiation therapy to the brain * Other prior antineoplastic therapies for brain metastases. * Patients with cerebral metastases as the only location of the disease, for which local therapy (neurosurgery, radiosurgery) could achieve a disease-free status * Patients with a rapid clinical deterioration, or with risk of herniation, or who require unstable ascending dosing of supportive medication in the last week -including anti-convulsivants, steroids and analgesics-, or who require dexamethasone more than 16 mg/d (or other glucocorticoid at an equipotent dose), or with a high lactate dehydrogenase (LDH) more than 2 x ULN. 2. Any other malignancy form which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix, or incidental prostate cancer. 3. Uncontrolled diabetes mellitus (HbA1c more than 9 %) 4. Autoimmune disease other than vitiligo or past thyroiditis under substitutive hormone therapy: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[eg, Wegener's Granulomatosis\]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis). 5. Other chronic intestinal diseases associated with diarrhea. 6. Active infection or other serious illness or medical condition. 7. Known active or chronic infection with HIV, Hepatitis B, or Hepatitis C. 8. Concomitant therapy with any of the following: interleukin-2 (IL-2), interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids (used for the management of non-cancer related illnesses), either concomitantly or during the last 30 days prior to the beginning of the treatment. 9. Any experimental therapy administered in the past 30 days prior to the beginning of the treatment. 10. Any non-oncology vaccine therapy used for the prevention of infectious diseases (for up to 4 weeks prior to or after any dose of blinded study drug) (see definitions in protocol text) 11. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious) illness. 12. Any other general, medical or psychological conditions which in the opinion of the investigator will make the administration of ipilimumab hazardous, or that would preclude appropriate informed consent or compliance with the protocol, or obscure the interpretation of eventual adverse events (AEs).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 1-year Survival Rate | From date of inclusion until the date of first documented date of death from any cause, assessed every 3 weeks during for the first 6 months, then every 3 months. Up to 1 year | During treatment period, there will be assessments every cycle. After end of treatment every 3 month. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Within 4 weeks before start treatment, week 12, 17+/-1 and every 9 + / -1 weeks until progression up to 12 months after last patient treatment initiation. | Median time from treatment initiation to progression of disease. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
| Intracranial PFS | Within 4 weeks before start treatment, week 12, 17+/-1 and every 9 + / -1 weeks until progression up to 12 months after last patient treatment initiation. | median, 6-month PFS rate |
| Extracranial PFS | Within 4 weeks before start treatment, week 12, 17+/-1 and every 9 + / -1 weeks until progression up to 12 months after last patient treatment initiation. | median, 6-month PFS rate |
| Overall Survival | From date of inclusion until the date of first documented date of death from any cause, assessed every 3 weeks during for the first 6 months, then every 3 months. | median value for OS estimated by kaplan meier method |
| Adverse Event Rates | From date of inclusion until the date of first documented date of death from any cause or end of study, assessed every 3 weeks during for the first 6 months, then every 3 months. | Number of patients with at least one treatment-related toxicity, classified by grade. |
| Rate of Dose Delays/Reductions and Treatment Exposure. | Expected average of 3 weeks during for the first 6 months, then every 3 months. | Treatment feasibility. Number of patients with treatment delays and reductions, categorized as function of the number of events (reductions/delays) |
| Response Rate | Within 4 weeks before start treatment, week 12, 17+/-1 and every 9 + / -1 weeks until progression up to 12 months after last patient treatment initiation. | Measured according to Who response criteria and Immune-related response criteria. Response for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Correlation of Biomarker Expression and PFS. | Within 28 days before start treatment, just before the start treatment, then expected average of 3 weeks for the first 12 weeks | Translational study. PFS outcome reported by subgroups according to BRAF mutation status |
| Intrapatient Variation of Quantitative Apparent Diffusion Coefficients of Serial Diffusion-weighted Magnetic Resonance Imaging | Baseline and 4 weeks after WBRT | — |
Countries
Spain
Participant flow
Recruitment details
58 patients were enrolled and fulfilled the inclusion criteria, analyzed for safety. During the trial 7 patients discontinued treatment before completion, so the total of patients for efficacy analysis was 51.
Participants by arm
| Arm | Count |
|---|---|
| Ipilimumab Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles Whole-brain radiotherapy (WBRT) 30 Gy in 10 fractions (or radiobiological equivalent schedule, after Sponsor approval), starting between Cycle 1 Day 2 and Cycle 2 Day 1
Ipilimumab: Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles | 58 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 1 |
| Overall Study | treatment discontinuation | 6 |
Baseline characteristics
| Characteristic | Ipilimumab |
|---|---|
| Age, Continuous | 66 Years |
| Barthel index 15-20 | 56 Participants |
| Barthel index Lower than 15 | 2 Participants |
| BRAF mutational status Mutated | 20 Participants |
| BRAF mutational status Native | 30 Participants |
| BRAF mutational status Not evaluated (NE) | 8 Participants |
| Corticoid use No | 33 Participants |
| Corticoid use Yes | 25 Participants |
| Karnofsky performance status (KPS) 70-80 | 15 Participants |
| Karnofsky performance status (KPS) 90-100 | 42 Participants |
| Karnofsky performance status (KPS) Not evaluable (NE) | 1 Participants |
| Lactate dehydrogenase (LDH) blood levels Levels higher than 1.5X Upper limit normal (ULN) No | 49 Participants |
| Lactate dehydrogenase (LDH) blood levels Levels higher than 1.5X Upper limit normal (ULN) Yes | 9 Participants |
| Lactate dehydrogenase (LDH) blood levels Levels higher than Upper limit normal (ULN) No | 34 Participants |
| Lactate dehydrogenase (LDH) blood levels Levels higher than Upper limit normal (ULN) Yes | 24 Participants |
| Number of brain metastasis Multiple brain lesions | 43 Participants |
| Number of brain metastasis Not especified (NE) | 1 Participants |
| Number of brain metastasis Single brain lesion | 14 Participants |
| Number of previous treatment lines 1 previous line | 20 Participants |
| Number of previous treatment lines 2 or more previous lines | 9 Participants |
| Number of previous treatment lines No previous lines | 29 Participants |
| Region of Enrollment Spain | 58 Participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 40 / 58 |
| other Total, other adverse events | 57 / 58 |
| serious Total, serious adverse events | 33 / 58 |
Outcome results
Primary
1-year Survival Rate
During treatment period, there will be assessments every cycle. After end of treatment every 3 month.
Time frame: From date of inclusion until the date of first documented date of death from any cause, assessed every 3 weeks during for the first 6 months, then every 3 months. Up to 1 year
Population: Efficacy cohort, all patients that fulfill eligibility and completed the treatment with radiotherapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ipilimumab | 1-year Survival Rate | 31.8 Percentage of patients alive at 1 year |
Secondary
Adverse Event Rates
Number of patients with at least one treatment-related toxicity, classified by grade.
Time frame: From date of inclusion until the date of first documented date of death from any cause or end of study, assessed every 3 weeks during for the first 6 months, then every 3 months.
Population: Safety population
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Ipilimumab | Adverse Event Rates | Grade 3 or higher toxicity | No | 47 Participants |
| Ipilimumab | Adverse Event Rates | Any grade toxicity | Yes | 37 Participants |
| Ipilimumab | Adverse Event Rates | Any grade toxicity | No | 21 Participants |
| Ipilimumab | Adverse Event Rates | Grade 3 or higher toxicity | Yes | 11 Participants |
Secondary
Extracranial PFS
median, 6-month PFS rate
Time frame: Within 4 weeks before start treatment, week 12, 17+/-1 and every 9 + / -1 weeks until progression up to 12 months after last patient treatment initiation.
Population: Data were not collected
Secondary
Intracranial PFS
median, 6-month PFS rate
Time frame: Within 4 weeks before start treatment, week 12, 17+/-1 and every 9 + / -1 weeks until progression up to 12 months after last patient treatment initiation.
Population: Data were not collected
Secondary
Overall Survival
median value for OS estimated by kaplan meier method
Time frame: From date of inclusion until the date of first documented date of death from any cause, assessed every 3 weeks during for the first 6 months, then every 3 months.
Population: Efficacy population (patients that comply with eligibility and completed radiotherapy treatment)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ipilimumab | Overall Survival | 4.73 Months |
Secondary
Progression-Free Survival (PFS)
Median time from treatment initiation to progression of disease. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: Within 4 weeks before start treatment, week 12, 17+/-1 and every 9 + / -1 weeks until progression up to 12 months after last patient treatment initiation.
Population: Efficacy population (patients that fulfill eligibility and completed the treatment with radiotherapy)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ipilimumab | Progression-Free Survival (PFS) | 3.11 Months |
Secondary
Rate of Dose Delays/Reductions and Treatment Exposure.
Treatment feasibility. Number of patients with treatment delays and reductions, categorized as function of the number of events (reductions/delays)
Time frame: Expected average of 3 weeks during for the first 6 months, then every 3 months.
Population: safety population
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Ipilimumab | Rate of Dose Delays/Reductions and Treatment Exposure. | Ipilimumab reductions | 3 events | 1 Participants |
| Ipilimumab | Rate of Dose Delays/Reductions and Treatment Exposure. | Ipilimumab reductions | 4 events | 1 Participants |
| Ipilimumab | Rate of Dose Delays/Reductions and Treatment Exposure. | Ipilimumab reductions | 2 events | 1 Participants |
| Ipilimumab | Rate of Dose Delays/Reductions and Treatment Exposure. | Ipilimumab delay | None | 43 Participants |
| Ipilimumab | Rate of Dose Delays/Reductions and Treatment Exposure. | Ipilimumab delay | 1 event | 12 Participants |
| Ipilimumab | Rate of Dose Delays/Reductions and Treatment Exposure. | Ipilimumab delay | 2 events | 2 Participants |
| Ipilimumab | Rate of Dose Delays/Reductions and Treatment Exposure. | Ipilimumab delay | 3 events | 1 Participants |
| Ipilimumab | Rate of Dose Delays/Reductions and Treatment Exposure. | Ipilimumab delay | 4 events | 0 Participants |
| Ipilimumab | Rate of Dose Delays/Reductions and Treatment Exposure. | Ipilimumab reductions | None | 50 Participants |
| Ipilimumab | Rate of Dose Delays/Reductions and Treatment Exposure. | Ipilimumab reductions | 1 event | 5 Participants |
Secondary
Response Rate
Measured according to Who response criteria and Immune-related response criteria. Response for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Within 4 weeks before start treatment, week 12, 17+/-1 and every 9 + / -1 weeks until progression up to 12 months after last patient treatment initiation.
Population: Efficacy population
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Ipilimumab | Response Rate | modified WHO criteria | Complete Response (CR) | 2 Participants |
| Ipilimumab | Response Rate | modified WHO criteria | Partial response (PR) | 3 Participants |
| Ipilimumab | Response Rate | modified WHO criteria | Stable disease (SD) | 12 Participants |
| Ipilimumab | Response Rate | modified WHO criteria | Progression disease (PD) | 19 Participants |
| Ipilimumab | Response Rate | modified WHO criteria | Not evaluable (NE) | 15 Participants |
| Ipilimumab | Response Rate | Immun related response criteria (irRC) | Complete Response (CR) | 2 Participants |
| Ipilimumab | Response Rate | Immun related response criteria (irRC) | Partial response (PR) | 3 Participants |
| Ipilimumab | Response Rate | Immun related response criteria (irRC) | Stable disease (SD) | 12 Participants |
| Ipilimumab | Response Rate | Immun related response criteria (irRC) | Progression disease (PD) | 17 Participants |
| Ipilimumab | Response Rate | Immun related response criteria (irRC) | Not evaluable (NE) | 17 Participants |
Other Pre-specified
Correlation of Biomarker Expression and PFS.
Translational study. PFS outcome reported by subgroups according to BRAF mutation status
Time frame: Within 28 days before start treatment, just before the start treatment, then expected average of 3 weeks for the first 12 weeks
Population: efficacy population
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Ipilimumab | Correlation of Biomarker Expression and PFS. | BRAF native | No progression | 19 Participants |
| Ipilimumab | Correlation of Biomarker Expression and PFS. | BRAF native | Not applicable | 25 Participants |
| Ipilimumab | Correlation of Biomarker Expression and PFS. | BRAF mutated | Progression disease | 5 Participants |
| Ipilimumab | Correlation of Biomarker Expression and PFS. | BRAF mutated | No progression | 12 Participants |
| Ipilimumab | Correlation of Biomarker Expression and PFS. | BRAF mutated | Not applicable | 34 Participants |
| Ipilimumab | Correlation of Biomarker Expression and PFS. | BRAF native | Progression disease | 7 Participants |
Other Pre-specified
Intrapatient Variation of Quantitative Apparent Diffusion Coefficients of Serial Diffusion-weighted Magnetic Resonance Imaging
Time frame: Baseline and 4 weeks after WBRT