Evaluation of Tumor Response to Ipilimumab in the Treatment of Melanoma With Brain Metastases

Study Overview
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Brief Summary
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To assess the response of melanoma with brain metastases to ipilimumab treatment while maintaining acceptable tolerability.

Official Title
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A Multi-Center Phase II Study to Evaluate Tumor Response to Ipilimumab (BMS-734016) Monotherapy in Subjects With Melanoma Brain Metastases

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Ipilimumab
* Drug: Corticosteroid: Betamethasone
* Drug: Corticosteroid: Dexamethasone
* Drug: Corticosteroid: Fludrocortisone
* Drug: Corticosteroid: Hydrocortisone
* Drug: Corticosteroid: Meprednisone
* Drug: Corticosteroid: Methylprednisolone
* Drug: Corticosteroid: Prednisolone
* Drug: Corticosteroid: Prednisone
* Drug: Corticosteroid: Triamcinolone


Participation Criteria
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Eligibility Criteria
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Key inclusion criteria Histologically confirmed malignant melanoma At least 1 measurable index brain metastasis >0.5 cm and no larger than 3 cm in diameter that had not been previously irradiated, and/or 2 measurable lesions >0.3 cm visible on contrast magnetic resonance Index brain lesion must have resolved consequences of prior therapy that could have confounded attribution of tumor response including edema and hemorrhage Participants in ipilimumab monotherapy arm (including the first 21 who were enrolled in Stage 1) were to be free of neurologic symptoms related to metastatic brain lesions and must not have required or received systemic corticosteroid therapy in the 10 days prior to beginning ipilimumab therapy Eastern Cooperative Oncology Group performance status of 0 or 1 Required values for initial laboratory tests: White blood cell count ≥2000/μL Absolute neutrophil count ≥1000/μL Platelets ≥100*10^3/μL Hemoglobin level ≥9 g/dL (may have been transfused) Aspartate aminotransferase/alanine aminotransferase (AST/ALT) level ≤2.5*ULN for participants without liver metastasis AST/ALT level ≤5*ULN for those with liver metastasis Bilirubin level ≤2*ULN (except participants with Gilbert's Syndrome, who must have had a total bilirubin level less than 3.0 mg/dL) Age 16 years and older Males and females Women of childbearing potential (WOBP) must be using an adequate method of contraception to avoid pregnancy throughout the study (and for up to 26 weeks after the last dose of investigational product) in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Key exclusion criteria History of carcinomatous meningitis, with prior stereotactic or highly conformal radiotherapy and/or whole brain irradiation within 14 days before the first dose of ipilimumab, and documented history of autoimmune disease Prior stereotactic or highly conformal radiotherapy and/or whole brain irradiation within 14 days prior to start of ipilimumab dosing for this study. Note the stereotactic radiotherapy field must not have included the brain index lesion or the lesion must have been detected and confirmed to be active and progressing after receiving whole brain irradiation.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ipilimumab, 10 mg/kg, IV in corticosteroid-free patients<br>Participants who had not received corticosteroid therapy for at least 10 days before starting study drug received ipilimumab,10 mg/kg, as a 90-minute intravenous (IV) infusion every 3 weeks (Weeks 1, 4, 7, and 10) during the Induction Phase. Those eligible (patients who did not discontinue due to toxicity, did not show progression at 24 weeks, and who remained clinically stable) for the Maintenance Phase continued to receive ipilimumab, 10 mg/kg IV, every 12 weeks, beginning at Week 24. | Drug: Ipilimumab<br>* 10 mg/kg, administered as an intravenous infusion every 3 weeks during induction and every 12 weeks during maintenance<br>* Other names: MDX-010;|
| Experimental: Ipilimumab, 10 mg/kg, IV in corticosteroid-dependent patients<br>Participants who were dependent on corticosteroid therapy received ipilimumab, 10 mg/kg, as a 90-minute intravenous (IV) infusion every 3 weeks (Weeks 1, 4, 7, and 10) during the Induction Phase. Those eligible (patients who did not discontinue due to toxicity, did not show progression at 24 weeks, and who remained clinically stable) for the Maintenance Phase continued to receive ipilimumab, 10 mg/kg IV, every 12 weeks, beginning at Week 24. | Drug: Ipilimumab<br>* 10 mg/kg, administered as an intravenous infusion every 3 weeks during induction and every 12 weeks during maintenance<br>* Other names: MDX-010;Drug: Corticosteroid: Betamethasone<br>* Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with betamethasone<br>Drug: Corticosteroid: Dexamethasone<br>* Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with dexamethasone<br>Drug: Corticosteroid: Fludrocortisone<br>* Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with fludrocortisone<br>Drug: Corticosteroid: Hydrocortisone<br>* Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with hydrocortisone<br>Drug: Corticosteroid: Meprednisone<br>* Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with meprednisone<br>Drug: Corticosteroid: Methylprednisolone<br>* Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with methylprednisolone<br>Drug: Corticosteroid: Prednisolone<br>* Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with prednisolone<br>Drug: Corticosteroid: Prednisone<br>* Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with prednisone<br>Drug: Corticosteroid: Triamcinolone<br>* Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with triamcinolone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate by Modified World Health Organization (mWHO) Tumor Assessment Criteria | Disease control rate is defined as the number of patients with a best overall response of complete response (CR), partial response (PR), or stable disease (SD) (global, in brain, or outside of brain) based on mWHO criteria divided by the number of patients who received treatment. By mWHO criteria: CR=complete disappearance of all index lesions. PR=decrease, relative to baseline, of 50% or greater in the sum of the 2 largest perpendicular diameters of all index lesions. SD=does not meet criteria for CR or PR, in the absence of progressive disease (PD). Patients with PR or CR not confirmed after at least 4 weeks are scored as SD unless they have new primary lesions. PD=at least 25% increase in the sum of the diameters of all index lesions (taking as reference the smallest sum recorded at or following baseline) and/or the appearance of any new lesions. CNS=central nervous system. | From Day 1, first dose to end of Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate by Immune-related Response Criteria (irRC) | Disease control rate is defined as the number of patients with a best overall response of immune-related (ir) complete response (irCR), partial response (irPR), or stable disease (irSD) divided by the total number of patients who received treatment. By irRC definition: irCR=complete disappearance of all index lesions. irPR=decrease, relative to baseline, of 50% or greater in the sum of the products of the 2 largest perpendicular diameters of all index lesions. irSD=does not meet criteria for irCR or irPR, in the absence of ir progressive disease (irPD). irPD=at least 25% increase in the sum of the products of all index lesions (taking as reference the smallest sum recorded at or following baseline). CNS=central nervous system; non-CNS compartment=extracranial, or outside of the brain. | From Day 1, first dose to end of Week 12 | 
| Best Overall Response Rate (BORR) by Modified World Health Organization (mWHO) Criteria and by Immune-relate Response Criteria (irRC) | BORR is defined as the number of patients whose global best overall response (BOR) was complete (CR) or partial response (PR), divided by the total number of participants who received treatment. CR=complete disappearance of all index lesions. PR=decrease, relative to baseline, of 50% or greater in the sum of the products of the 2 largest perpendicular diameters of all index lesions. The global BOR is the best overall response (OR) designation over the study as a whole for an individual in the study based on overall tumor burden. Both central nervous system (CNS) (brain lesions) and non-CNS compartments (lesions outside the brain) are considered for the global BOR. For the analysis of global BOR of CR or PR (by both modified WHO criteria and immune-related response criteria [irRC]), the OR assessment must be confirmed by a second (confirmatory) evaluation meeting the criteria for response and must be performed no less than 4 weeks after the criteria for response are first met. | From Day 1, first dose until the last tumor assessment, Week 12 | 
| Duration of Response (DOR) by Modified World Health Organization (mWHO) Criteria and by Immune-related Response Criteria (irRC) | DOR is defined in patients whose global best overall response is complete (CR) or partial response (PR) as the time between the date of response of confirmed CR or PR, whichever occurs first, and the date of progressive disease or death, whichever occurs first. For patients who remain alive and have not progressed following response, duration of response will be censored on the date of last evaluable tumor assessment. | From Day 1, first dose to last tumor assessment up to 18.2 months | 
| Progression-free Survival (PFS) by Modified World Health Organization (mWHO) Criteria and by Immune-related Response Criteria (irRC) | PFS is defined as the time between the date of the first dose of study therapy and the date of progression or death, whichever occurs first. A patient who dies without reported prior progression will be considered to have progressed on the date of death. For those who remain alive and have not progressed, PFS will be censored on the date of last evaluable tumor assessment. Participants who have not died and have no recorded postbaseline tumor assessment will be censored on the date of first dose of study therapy. Those who die without any recorded postbaseline tumor assessment will be considered to have progressed on the date of death. | From Day 1, first dose to the date of progression or death, whichever occurred first up to 22 months | 
| Number of Participants Surviving at 6, 12, 18, 24, and 36 Months (Overall Survival [OS] Rate) | OS is defined as the time from the first dose of study drug until the date of death. Overall survival rate is the percentage of participants known to be alive at a timepoint. For those patients who did not die, OS was censored at the recorded last date of patient contact, and those with a missing recorded last date of contact will be censored at the last date the patient was known to be alive. The survival rate at a specified time-point is the probability that a patient is alive at that time following randomization. The rate is calculated for each treatment group using the Kaplan-Meier product-limit method. A corresponding 2-sided 95% bootstrap confidence interval will be calculated. | From first dose to Months 6, 12, 18, 24, and 36 months | 
| Number of Participants Who Died or Had a Treatment-related Adverse Event (AE), Immune-related AE, Immune-related Serious Adverse Event (SAE), Nervous System Disorder, Treatment-related Nervous System Disorder, SAE, and AE Leading to Discontinuation | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death. | Continuously from Day 1, first dose, to 70 days following last dose of ipilimumab | 
| Onset of Response by Modified World Health Organization (mWHO) Criteria and Immune-related Response Criteria (irRC) | Onset of response is defined as the time between the first dose of study therapy and the date when measurement criteria are first met for global best overall response of partial (PR) or complete (CR), whichever occurs first. CR=complete disappearance of all index lesions. PR=decrease, relative to baseline, of 50% or greater in the sum of the 2 largest perpendicular diameters of all index lesions. | From Day 1, first dose to a maximum of 4.2 months | 
| Overall Survival (OS) | OS is defined as the time from date of first dose of study drug until the date of death. For those patients who did not die, OS was censored at the recorded last date of patient contact, and those missing a recorded last date of contact will be censored at the last date the patient was known to be alive. | From first dose to 24 months |