Phase I Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases
Overview
- Phase
- Phase 1
- Intervention
- Ipilimumab
- Conditions
- Recurrent Melanoma
- Sponsor
- Sidney Kimmel Cancer Center at Thomas Jefferson University
- Enrollment
- 17
- Locations
- 2
- Primary Endpoint
- Maximum Tolerated Dose (MTD) of Ipilimumab
- Status
- Completed
- Last Updated
- 11 months ago
Overview
Brief Summary
This phase I trial studies the side effects and best dose of ipilimumab when given together with whole brain radiation therapy or stereotactic radiosurgery in treating patients with melanoma with brain metastases. Monoclonal antibodies, such as ipilimumab, can block tumor growth in different ways. Some block the ability of the tumor to grow and spread. Others find Tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy, such uses high-energy x-rays and other types of radiation to kill tumor cells. Giving radiation therapy in different ways may kill more tumor cells. Giving ipilimumab together with whole-brain radiation therapy or stereotactic radiosurgery may kill more tumor cells.
Detailed Description
Melanoma patients with brain metastases have a very poor outcome. Most patients with brain metastases will die from CNS related death. Radiation therapy is an effective treatment for patients with brain metastases for symptom palliation and survival benefit. Patients with multiple metastases are typically treated with whole brain radiation treatment (WBRT). For patients with a few metastases, stereotactic radiosurgery (SRS) alone can be used as an alternative. CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) antibody, Ipilimumab has shown efficacy in metastatic melanoma and unresectable melanoma. Treatment with high doses of radiation therapy would result in tumor cell death, releasing tumor debris and liberating potential tumor antigens. We hypothesize that combining radiation therapy with Ipilimumab will facilitate immune recognition of these novel tumor-specific antigens, yielding a synergistic effect. Further, the hypothesis of this study is that this combination could focus the immune system on tumor antigens and minimize the aberrant immune activation in normal tissues, consequently reducing the incidence of irAE's (immune related adverse effect). Combination of radiation treatment with Ipilimumab will likely result in better local control, decrease the risk of developing new brain metastases, and improved overall survival. However, the safety profile and toxicities of combining Ipilimumab with brain radiation treatment are unknown. The current phase I study will assess the safety profile of combining different doses of Ipilimumab with standard dose radiation treatment either with WBRT or SRS. The MTD (maximum tolerated dose) will be determined, as well as a recommended phase II trial dose of Ipilimumab.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patient age is \>= 18 years
- •Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, or
- •Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
- •Patients must meet the following laboratory criteria:
- •WBC \>= 2000/uL
- •ANC \>= 1000/uL
- •Platelets \>= 75 x 10\^3/uL
- •Hemoglobin \>= 9 g/dL (\>= 80 g/L; may be transfused)
- •AST/ALT \<= 2.5 x ULN for patients without liver metastasis
- •AST/ALT \<= 5 times for liver metastases
Exclusion Criteria
- •Patient with leptomeningeal carcinomatosis.
- •Autoimmune disease: 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).
- •Major surgery or radiation therapy within 2 weeks of starting the study treatment.
- •If patients are receiving chemotherapy or other investigational drugs, they must be discontinued 4 weeks prior to enrollment.
- •NCI CTCAE grade 3 hemorrhage within 4 weeks of starting the study treatment.
- •Any of the following within the 6 months prior to study drug administration:
- •myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism. Patients with known cardiac disease will be required to have an ECHO or MUGA scan at baseline and at the completion of study.
- •Ongoing cardiac dysrhythmias of NCI CTCAE grade \>=
- •Hypertension that cannot be controlled by medications (\>150/100 mm Hg despite optimal medical therapy).
- •Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication.
Arms & Interventions
Arm A (Ipilimumab and Whole Brain Radiation Therapy)
Patients receive ipilimumab IV over 90 minutes once in weeks 1, 4, 7, and 10. Patients also undergo WBRT 5 days a week in weeks 1-2.
Intervention: Ipilimumab
Arm A (Ipilimumab and Whole Brain Radiation Therapy)
Patients receive ipilimumab IV over 90 minutes once in weeks 1, 4, 7, and 10. Patients also undergo WBRT 5 days a week in weeks 1-2.
Intervention: Whole-Brain Radiation Therapy (WBRT)
Arm B (Ipilimumab and Stereotactic Radiosurgery)
Patients receive ipilimumab IV over 90 minutes as in Arm A. Patients also undergo SRS on day 1 in week 1.
Intervention: Ipilimumab
Arm B (Ipilimumab and Stereotactic Radiosurgery)
Patients receive ipilimumab IV over 90 minutes as in Arm A. Patients also undergo SRS on day 1 in week 1.
Intervention: Stereotactic Radiosurgery (SRS)
Outcomes
Primary Outcomes
Maximum Tolerated Dose (MTD) of Ipilimumab
Time Frame: 30 days following the completion of radiation therapy
(MTD) when combined with WBRT or SRS, defined as the last dose studied or the previous dose, based on clinical judgment of the degree of toxicity seen at the last dose
Secondary Outcomes
- Number of Subjects With Response of Extracranial Disease(Up to 5 years)
- Rate of Developing New Brain Metastases in Each Arm(Up to 5 years)
- Overall Survival (OS) Rate(Up to 5 years)
- Number of Patients With Progression Free Survival (PFS) Rate(Up to 5 years)
- Number of Participants With Adverse Events and Serious Adverse Events(4 weeks following the last dose of ipilimumab)