Stereotactic Radiation Therapy and Ipilimumab in Treating Patients With Metastatic Melanoma

PRIMARY OBJECTIVES:

I. To determine the progression-free survival of patients with oligometastatic melanoma
treated with the combination of stereotactic ablative radiation therapy (SABR) (stereotactic
radiosurgery) and ipilimumab in patients with oligometastatic melanoma using modified World
Health Organization (mWHO) criteria.

SECONDARY OBJECTIVES:

I. To evaluate the 6-month progression-free survival of the combination of SABR and 3 mg/kg
ipilimumab in patients with oligometastatic melanoma using immune related response criteria
(irRC) criteria.

II. To evaluate the tolerability and safety of the combination. III. To evaluate the response
rate based on mWHO & irRC criteria. IV. To evaluate the local control rate. V. To evaluate
the overall survival rate.

TERTIARY OBJECTIVES:

I. Evaluate changes in blood and serum markers: absolute lymphocyte count, T-cell activation
markers, T-cell suppression markers, T-helper cells and related cytokines, T-regulatory
(T-reg) markers, co-stimulatory molecules, and serum cytokines when SABR is added to the
ipilimumab regimen.

II. Evaluate genomic deoxyribonucleic acid (DNA) mutations in key melanoma genes and their
correlation with response, progression-free survival, and overall survival.

OUTLINE:

Patients receive ipilimumab intravenously (IV) over 90 minutes on day 1 in weeks 1, 4, 7, and
10. Treatment repeats every 3 weeks for up to 4 total doses in the absence of disease
progression or unacceptable toxicity. At approximately 5-6 weeks, patients undergo
stereotactic radiosurgery over 2-3 days per week. Patients with stable disease or confirmed
partial or complete response after completion of ipilimumab therapy at week 12 may receive
re-induction ipilimumab at the discretion of the treating physician.

After completion of study treatment, patients are followed up at 30 and 90 days, every 3
months for 2 years, every 6 months for 3 years, and then annually for 5 years.

Inclusion Criteria:

- Willing and able to give written informed consent

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Histologic diagnosis of melanoma with metastatic disease to a visceral organ (lung,
liver, brain, adrenal, nodal station outside the regional lymph drainage of the
primary, vertebral bodies)

- 1-3 sites of metastatic disease able to be targeted by SABR

- White blood cells (WBC) >= 2000/uL

- Absolute neutrophil count (ANC) >= 1000/uL

- Platelets >= 75 x 10^3/uL

- Hemoglobin >= 9 g/dL (>= 80 g/L; may be transfused)

- Creatinine =< 2.0 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN for
patients without liver metastasis, =< 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)

- No active or chronic infection with human immunodeficiency virus (HIV), hepatitis B,
or hepatitis C

- 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 mIU/mL

- 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
potential

- 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

- 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

Exclusion Criteria:

- Any other malignancy from which the patient has been disease-free for less than 3
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

- 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)

- Any underlying medical or psychiatric condition, which in the opinion of the
investigator will make the administration of ipilimumab hazardous or obscure the
interpretation of adverse events (AEs), such as a condition associated with frequent
diarrhea

- Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to
1 month before or after any dose of ipilimumab)

- A history of prior treatment with ipilimumab or prior cluster of differentiation
(CD)137 agonist or cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor or agonist

- A history of prior treatment with anti-programmed death (PD)-1 or anti-PD-L1
antibodies

- Concomitant therapy with any of the following: interleukin (IL)-2, interferon, other
non-study immunotherapy regimens, cytotoxic chemotherapy, other investigation
therapies

- Concomitant therapy with immune-suppressants or chronic use of systemic
corticosteroids

- Must be off prior systemic therapies for 2 weeks prior to enrollment; patients that
have been previously treated with systemic therapy adjuvantly or for metastatic
disease remain eligible as long as they continue to meet all other eligibility
criteria (oligometastatic, no visceral metastasis > 5 cm, eligible for SABR)

- Prior radiation therapy that at the treating physician's discretion makes SABR unsafe

- No evidence of pleural effusion or ascites

- Congestive heart failure > class II New York Heart Association (NYHA) or unstable
angina

- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

- Major surgery, open biopsy or significant traumatic injury within 2 weeks of first
dose of study drug

- A visceral metastasis greater than 5 cm

- A visceral metastasis that due to its location cannot be safely treated with SABR

- Women of childbearing potential (WOCBP), defined above who:

- Are unwilling or unable to use an acceptable method of contraception to avoid
pregnancy for their entire study period and for at least 8 weeks after cessation
of study drug, or

- Have a positive pregnancy test at baseline, or

- Are pregnant or breastfeeding

- Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
treatment of either a psychiatric or physical (eg, infectious) illness

- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO)

- Persons of reproductive potential must agree to use an adequate method of
contraception throughout treatment and for at least 8 weeks after ipilimumab is
stopped

- Sexually active WOCBP must use an effective method of birth control during the course
of the study, in a manner such that risk of failure is minimized; before study
enrollment, WOCBP must be advised of the importance of avoiding pregnancy during study
participation and the potential risk factors for an unintentional pregnancy; all WOCBP
MUST have a negative pregnancy test before first receiving ipilimumab; if the
pregnancy test is positive, the patient must not receive ipilimumab and must not be
enrolled in the study