A Pilot Study of Ipilumimab and Radiation in Poor Prognosis Melanoma

Inclusion criteria:

1. Willing and able to give written informed consent.

2. Histologic diagnosis of melanoma

3. Cohort 1: Resected patients at high risk of recurrence. Patients must meet at least
one of the following criteria

a. Melanoma of mucosal origin b. Desmoplastic melanoma c. Primary melanoma of the head
or neck with any lymph node involvement d. Patients with non-head and neck primaries
must have had preoperative/pathologic macroscopic lymph node involvement, defined by
clinically evident on exam or imaging evaluation, plus at least one of the following
by clinical, imaging, or pathologic evaluation: i. ≥ 2 cervical or axillary nodes ii.
≥ 3 groin lymph nodes iii. Extracapsular extension (ECE) of tumor iv. Lymph nodes ≥
3cm

4. Cohort 2: Neoadjuvant/definitive approach for locally advanced patients. Patients must
meet at least one of the following criteria

1. Melanoma of mucosal origin

2. Desmoplastic melanoma

3. Patients with radiographic evidence of tumor invasion into surrounding local
structures rendering them inoperable

4. Macroscopic nodal involvement. In addition, patients must also meet one of the
following criteria

i. Recurrent disease, with any number and size of nodes ii. ≥ 1 parotid node(s) iii. ≥
2 cervical or axillary nodes iv. ≥ 3 groin lymph nodes v. Lymph nodes ≥ 3cm vi. ECE of
tumor

5. Resected patients should begin treatment within 12 weeks of surgery, once adequately
healed as determined by the treating physicians.

6. Local-regional treatment sites must be able to be encompassed within a reasonable
radiation therapy treatment volume

7. Patients with recurrent disease are allowed in cohort 1, provided at least one of the
criteria listed in 3 above is met

8. For patients with a new diagnosis of melanoma treated in cohort 2 who have a cutaneous
primary, the primary site may be addressed surgically (wide local excision; skin
grafting) prior to the initiation of ipilimumab and radiation at the discretion of the
treating surgeon.

9. Required values for initial laboratory tests:

- WBC ≥ 2000/uL

- ANC ≥ 1000/uL

- Platelets ≥ 75 x 103/uL

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

- Creatinine ≤ 2.0 x ULN

- AST/ALT ≤ 2.5 x ULN

- Bilirubin ≤ 2.0 x ULN, (except patients with Gilbert's Syndrome, who must have a
total bilirubin less than 3.0 mg/dL)

10. No active or chronic infection with HIV, Hepatitis B, or Hepatitis C.

11. ECOG performance status ≤ 1

12. Men and women, ≥ 18 years of age

13. 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.

14. Patients must agree to blood sampling to participate in study.

Exclusion criteria:

1. Ocular melanoma

2. Presence of brain metastases

3. Prior radiation therapy for melanoma

4. Any other malignancy form 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, carcinoma in situ of the cervix, or DCIS. Patients
with prior malignancies that are not considered to be an active problem may be
enrolled at the discretion of the investigator, regardless of time frame.

5. 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).

6. 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 AEs, such as a condition associated with frequent diarrhea.

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

8. A history of prior treatment with ipilimumab or prior CD137 agonist or CTLA 4
inhibitor or agonist.

9. Concomitant therapy with any of the following: IL 2, interferon, or other non-study
immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other
investigation therapies; or chronic use of systemic corticosteroids in the previous 4
weeks (defined as prednisone 10mg daily or equivalent.)

10. Women of childbearing potential (WOCBP), defined above in Section 4.1, who:

1. are unwilling or unable to use an acceptable method of contraception to avoid
pregnancy for their entire study period and for at least 26 weeks after cessation
of study drug, or

2. have a positive pregnancy test at baseline, or

3. are pregnant or breastfeeding.

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

12. Persons of reproductive potential must agree to use an adequate method of
contraception throughout treatment and for at least 26 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.