A Phase II Study of Open Label Low Dose Ipilimumab in Combination With Pembrolizumab in Metastatic Melanoma Patients With Brain Metastases
Overview
- Phase
- Phase 2
- Intervention
- Ipilimumab
- Conditions
- Not specified
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- Clinical Benefit Rate (CBR) in PD-1 naïve Patients
- Status
- Completed
- Last Updated
- 3 months ago
Overview
Brief Summary
This phase II trial studies the side effects and how well low dose ipilimumab works in combination with pembrolizumab in treating patients with melanoma that has spread to the brain. Immunotherapy with monoclonal antibodies, such as ipilimumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
Detailed Description
PRIMARY OBJECTIVE: I. To assess clinical benefit rate (CBR), defined as complete response (CR) + partial response (PR) + stable disease (SD) \> 6 months, in the brain in subjects with melanoma brain metastasis (MBM) per modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria who are treatment naive to anti-PD-1 agents in the metastatic setting (prior adjuvant anti-PD1 allowed). SECONDARY OBJECTIVES: I. To assess clinical benefit rate (CBR) in the brain in subjects with MBM per modified RECIST 1.1 in patients who previously progressed on PD-1 inhibitors. II. To assess overall survival (OS) and progression free survival (PFS). III. To evaluate the brain-specific safety and tolerability of the combination regimen in subjects with or without stereotactic radiotherapy (SRT) received prior to study entry, or on study. IV. To evaluate cytokine levels and changes in the T-cell population in the cerebrospinal fluid (CSF) and blood in patients treated with combination low dose ipilimumab and pembrolizumab. V. To assess changes in relative apparent diffusion coefficient as measured by magnetic resonance imaging (MRI) as an early predictor of response. VI. To assess changes in circulating cfDNA (cell-free deoxyribonucleic acid) as determinants of response and/or markers of early progression. VII. To evaluate molecular and immunological changes in extracranial lesions. OUTLINE: Patients receive ipilimumab intravenously (IV) over 90 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles for ipilimumab and up to 35 cycles for pembrolizumab in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 6 weeks for the first year, and then every 12 weeks thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Life expectancy \> 12 weeks.
- •Subjects must have signed and dated an IRB/IEC (Institutional Review Board/Independent Ethics Committee) approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care.
- •Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.
- •Histologically confirmed malignant melanoma with measurable metastases in the brain (\>= 0.5 cm).
- •At least one measurable intracranial target lesion, which previously was not treated with local therapy (no prior stereotactic radiosurgery \[SRS\] to this lesion). Largest diameter of \>= 0.5 cm, but =\< 3 cm as determined by contrast-enhanced MRI.
- •Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks are preferred) OR at least 4 unstained slides with an associated pathology report for testing of tumor PD-L1 expression:
- •Tumor tissue should be of good quality based on total and viable tumor content.
- •Patients who do not have tissue specimens may undergo a biopsy during the screening period. Acceptable samples include core-needle biopsies for deep tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.
- •Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not acceptable.
- •However, if repeat biopsy is not feasible, and no archival tissue available patient still may be enrolled
Exclusion Criteria
- •History of known leptomeningeal involvement (lumbar puncture not required).
- •Previous stereotactic or highly conformal radiotherapy within 2 weeks before the start of dosing for this study. Note the stereotactic radiotherapy field must not have included the brain index lesion(s).
- •Subjects previously treated with SRT \> 5 lesions in the brain
- •Brain lesion size \> 3 cm.
- •Prior checkpoint inhibitor therapy. Allowable prior therapy: Approved adjuvant therapies, which may include molecularly-targeted agents, IFN-·, and ipilimumab.
- •Patients who received ipilimumab as adjuvant or neoadjuvant therapy must have a 6 month washout before receiving any dosing on this study.
- •Cohort A: Prior anti-PD in the adjuvant setting is allowed, but washout period is 6 months.
- •For Cohort B: Patients with unresectable metastatic melanoma who received either anti-PD-1 or PDL-1 in the past are eligible. Washout period a minimum 3 weeks.
- •Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
- •Subjects with major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy or assessments should not be enrolled.
Arms & Interventions
Treatment (ipilimumab, pembrolizumab)
Patients receive ipilimumab IV over 90 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles for ipilimumab and up to 35 cycles for pembrolizumab in the absence of disease progression or unacceptable toxicity.
Intervention: Ipilimumab
Treatment (ipilimumab, pembrolizumab)
Patients receive ipilimumab IV over 90 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles for ipilimumab and up to 35 cycles for pembrolizumab in the absence of disease progression or unacceptable toxicity.
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Clinical Benefit Rate (CBR) in PD-1 naïve Patients
Time Frame: Baseline to 2 years
clinical benefit rate (CBR), defined as CR + PR + SD \> 6 months, in the brain in subjects with MBM per modified RECIST 1.1 criteria who are treatment naïve to anti-PD-1 agents in metastatic setting (prior adjuvant anti-PD1 allowed).
Secondary Outcomes
- CBR for Patients Who Progressed on PD-1 Inhibitors(Baseline to 2 years)
- Overall Survival (OS) & Progression-free Survival (PFS)(Baseline to 2 years)
- Brain-specific Safety and Tolerability(Baseline to 2 years)