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|NCT01703507 : Ipilimumab and Whole-Brain Radiation Therapy or Stereotactic Radiosurgery in Treating Patients With Melanoma With Brain Metastases|
|Ages||Min: 18 Years Max: N/A|
1. Patient age is >= 18 years
2. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, or
3. Ability to provide written informed consent obtained prior to participation in the
study and any related procedures being performed
4. 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
- Bilirubin <= 2.0 x ULN, (except patients with Gilbert's Syndrome, who must have
a total bilirubin less than 3.0 mg/dL)
- Serum creatinine <= 2.0 x ULN or 24-hour creatinine clearance >= 50 ml/min
- Total serum calcium (corrected for serum albumin) or ionized calcium >= lower
limit of normal (LLN)
- Serum potassium >= LLN
- Serum sodium >= LLN
- Serum albumin >= LLN or 3g/dl
- Patients with any elevated Alkaline Phosphatase due to bone metastases can be
5. No active or chronic infection with HIV, Hepatitis B, or Hepatitis C.
6. Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone
supplements to treat underlying hypothyroidism.
7. Women of childbearing potential (WOCBP) 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 post-menopausal. Post-menopause is defined as:
- Amenorrhea >= 12 consecutive months without another cause, or
- For women with irregular menstrual periods and taking hormone replacement
therapy (HRT), a documented serum follicle stimulating hormone (FSH) level >= 35
- Women who are using oral contraceptives, other hormonal contraceptives (vaginal
products, skin patches, or implanted or injectable products), or mechanical
products such as an intrauterine device or barrier methods (diaphragm, condoms,
spermicides) to prevent pregnancy, or are practicing abstinence or where their
partner is sterile (eg, vasectomy) should be considered to be of childbearing
- WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25
IU/L or equivalent units of HCG) within 72 hours before the start of ipilimumab.
8. Men of fathering potential must be using an adequate method of contraception to avoid
conception 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.
9. A pathological diagnosis of melanoma is required, from either the primary or a
metastasis. This also includes uveal melanoma.
10. A radiological diagnosis (CT or MRI) of one or more brain metastases is required.
11. Resolution of all acute toxic effects of prior chemotherapy or radiotherapy or
surgical procedures to NCI CTCAE Version 4.0 grade <= 1.
12. Specific eligibility criteria for the two arms
- Arm A WBRT and Ipilimumab:
- Patients have 5 or more brain metastases, or patients have any brain
metastases exceeding the limit for SRS (maximum diameter is > 4 cm).
- OR Patient has only one brain metastasis and completely resected, the
resection cavity is > 4 cm in diameter.
- Arm B SRS and Ipilimumab:
- Patients have 4 or fewer brain metastases. All the brain metastases are <=
4 cm in diameter.
- Patients have only one brain metastasis and completely resected, the
resection cavity is <= 4 cm in diameter.
- OR If a patient is found to have progression of brain metastases that
exceed 4 cm in diameter based on the MRI scan on the time of SRS procedure,
the patient should be re-assigned to WBRT arm or withdrawn from the study.
The study PI should be notified.
- OR If a patient is found to have progression of brain metastases that
exceed 4 lesions based on the MRI scan on the time of the SRS procedure,
the patient can either be treated with SRS to all the lesions (up to 10
lesions), re-assigned to WBRT arm, or withdrawn from the study per the
treating physician. The study PI should be notified.
1. Patient with leptomeningeal carcinomatosis.
2. 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).
3. Major surgery or radiation therapy within 2 weeks of starting the study treatment.
4. If patients are receiving chemotherapy or other investigational drugs, they must be
discontinued 4 weeks prior to enrollment.
5. NCI CTCAE grade 3 hemorrhage within 4 weeks of starting the study treatment.
6. 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.
7. Ongoing cardiac dysrhythmias of NCI CTCAE grade >= 2.
8. Hypertension that cannot be controlled by medications (>150/100 mm Hg despite optimal
9. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in
the normal range with medication.
10. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
(AIDS)-related illness or other active infection.
11. Pregnancy or breastfeeding. Female subjects must be surgically sterile or be
postmenopausal, or must agree to use effective contraception during the period of
therapy. All female subjects with reproductive potential must have a negative
pregnancy test (serum or urine) prior to enrollment. Male subjects must be surgically
sterile or must agree to use effective contraception during the period of therapy.
The definition of effective contraception will be based on the judgment of the
principal investigator or a designated associate.
12. Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration, or may interfere with the interpretation of study results, and
in the judgment of the investigator would make the subject inappropriate for entry
into this study.
13. Concomitant therapy with any of the following: IL-2, interferon, or other non-study
immunotherapy regimens, cytotoxic chemotherapy, immunosuppressive agents,
vermurafenib, or other investigational therapies.
14. All efforts need to be taken to avoid/minimize the use of cortical steroid during
radiation period (1 week prior to start radiation, during radiation, and 1 week after
finishing radiation). Any steroid used considered necessary by the treating physician
should be closely documented, including medication, route of administration, dose,
15. Active infection with hepatitis B, or hepatitis C.
16. Patients who had prior brain radiation treatment.
17. Patients are excluded if they have a history of any other malignancy from which the
patient has been disease-free for less than 2 years, with the exception of adequately
treated basal or squamous cell carcinoma of skin, superficial bladder cancer or
carcinoma in situ of cervix, AJCC (version 7.0) stage 0 or I breast cancer, AJCC
(version 7.0) stage I, or II prostate cancer.
18. Patients are excluded if they have a history of autoimmune disease, as follows:
Patients with a history of inflammatory bowel disease are excluded from this study as
are patients with a history of symptomatic disease (e.g., rheumatoid arthritis,
systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus,
autoimmune vasculitis [e.g., Wegener's Granulomatosis]). Patients with motor
neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and
Myasthenia Gravis) are excluded. Patients with a history of autoimmune thyroiditis
are eligible if their current thyroid disorder is treated and stable with replacement
or other medical therapy.
19. Patients who are allergic to Ipilimumab.
20. Patients who received ipilimumab before.
21. Patients who are allergic to MRI contrast agent or have contraindication for MRI.
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