Concurrent Ipilimumab and Stereotactic Ablative Radiation Therapy (SART) for Oligometastatic But Unresectable Melanoma

Primary Objectives:

1. To evaluate the effectiveness of concurrent ipilimumab therapy and SART of melanoma
based on 1-year and 2-year overall survival.

2. To evaluate the safety and tolerability of concurrent ipilimumab therapy and SART of
melanoma based on CTCAE grading of toxicities, and to identify any novel or unexpected
Grade 3 or 4 toxicities thought specifically related to ipilimumab and concurrent SART
during first 3 cycles of ipilimumab therapy (prior to week 9) in a Phase II study.

Secondary Objectives:

1. To evaluate the 1-year and 2-year disease control rates (CR+PR+SD)

2. Assess treatment response based on Immune Related Response Criteria (irRC) and mWHO
criteria.

3. Characterize overall survival by Kaplan-Meier analysis.

Exploratory Objectives:

1. Evaluate individual lesion control (<25% progression) following body SART at 6, 12, 24
months.

2. Describe number of patients requiring retreatment of any local lesion with surgery or
other treatments.

3. Describe the incidence of new brain metastases following ipilimumab therapy.

4. Describe the incidence of treatment related toxicity and/or symptomatic bleeding,
perforation, or necrosis at SART treated tumor sites.

5. Explore the use of circulating melanoma cells and serum metastasis gene expression
levels as prognostic and predictive (intermediate) markers to identify responding
patients.

6. Assess the effect of therapy on quality of life, using ECOG score as a surrogate.

Study Rationale:

Ipilimumab may markedly enhance the immunologic responses to tumor antigen released from
necrotic tumor cells by radiotherapy by promoting cytotoxic T cell activation, while
preventing induction of antigen tolerance. In addition, further beneficial immunologic
effects may be achieved by the reduction in the amount of viable tumor cell mass. The net
effect may be to promote a significantly enhanced antitumor T cell response. This will
result in improved 1-year and 2-year survival, especially if a minimal or microscopic
disease state can be achieved within a patient following SART.

Biologic Correlation Studies:

There are currently no standard prognostic or predictive markers to evaluate or predict
outcome of ipilimumab therapy. This study provides the opportunity for exploratory analysis
of several candidate hypotheses that may predict outcome.

Inclusion Criteria:

- Stage III or IV melanoma (AJCC 6th edition) with 5 or less metastatic sites that are
not amenable to curative surgical resection, but can be adequately delineated for
SART

- All sites of metastatic disease acceptable except brain-only and eye metastases,
provided SART can be safely delivered to the site.

- Up to 2 prior systemic treatments for metastatic disease.

- Mucosal or ocular melanoma is allowed.

- Radiotherapy consultation and insurance preapproval for SART prior to enrollment.

- CT or MRI within 28 days of enrollment showing no evidence of brain metastases. Brain
metastases allowed if stable by scans for ≥ 28 days following treatment.

- CT, PET/CT or MRI scan of chest, abdomen, pelvis (and soft tissue as indicated); bone
scan (as indicated); and photographs of skin lesions (if applicable) within 28 days
of enrollment.

- Hematology, liver function and renal function lab tests within required parameters.

- Recovered from all prior surgery and/or adjuvant treatment.

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

- ECOG Performance Status 0 or 1.

- Men and women ≥ 18 years old.

- Men/Women of childbearing potential must use adequate contraception.

Exclusion Criteria:

- Untreated or uncontrolled brain metastases.

- Prior treatment with CTLA-4 agent, PD-1 or PD-1 ligand mAb or inhibitor for
metastatic disease or as adjuvant therapy (or participation in blinded study).

- History of melanoma-associated retinopathy.

- History of other active malignancy within last 2 years, except adequately treated
basal cell carcinoma or squamous cell skin cancer or carcinoma in situ of cervix,
unless disease-free for 2 years.

- Autoimmune disease (vitiligo is not a basis for exclusion).

- History of clinically active diverticulitis (diverticulosis is not exclusion
criterion per se).

- Serious uncontrolled medical disorder or active infection that would impede
treatment.

- Underlying medical or psychiatric condition that would cause administration of
ipilimumab to be hazardous, or would obscure interpretation of AEs.

- Any non-oncology vaccine therapy up to 1 month before or after any dose of
ipilimumab.

- Concomitant therapy with IL-2, interferon, other non-study immunotherapy, or
cytotoxic chemotherapy; immune-suppressive agents within 30 days of registration;
other investigational therapies; chronic use of systemic corticosteroids (however, a
low stable dose steroid for mild brain edema or adrenal insufficiency is allowed;
topical and inhaled standard dose corticosteroids are allowed).

- Dementia or significantly altered mental status that would prohibit understanding or
rendering of informed consent and compliance with protocol requirements.

- Pregnant or breastfeeding women.

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