Phase II Randomized Trial of Ipilimumab Versus Ipilimumab and Radiotherapy in Metastatic Melanoma

In addition, we propose to perform immune-monitoring of the patients accrued to the trial to
generate important information for hypothesis-driven research about the mechanisms behind the
clinical findings, to be tested in the laboratory.

An attractive area of research regards immune manipulations to recover some of the patient's
immune response to his/her tumor, a strategy that has the advantages of being both natural
and potentially long-lasting.[1] We propose to combine immunotherapy with radiotherapy
directed to a metastatic site, to create a "hub" for in vivo immunization to the tumor, to
enable "tumor rejection" at the other metastatic sites. This "in vivo immunization" is
explored as a viable alternative to an individualized vaccine approach. Preclinical data
generated by us and others support a "proof of principle" clinical trial that may open the
field to an alternative use of radiotherapy in a novel partnership with cancer
immunotherapy.[2]

In addition, we propose to perform immune-monitoring of the patients accrued to the trial to
generate important information for hypothesis-driven research about the mechanisms behind the
clinical findings, to be tested in the laboratory.

The specific aims of the study are:

1. To explore the induction of immunity-mediated tumor response outside the radiation field
(abscopal effect) after radiation/Ipilimumab in metastatic melanoma, by estimating and
comparing response rates in patients treated with Ipilimumab alone (Arm A) versus
ipilimumab and radiation (Arm B).

2. To compare the induction of a T-cell response in patients with metastatic melanoma
treated with either ipilimumab alone or in combination with radiation.

All patients with metastatic melanoma with at least 2 measurable sites of disease are
eligible. Extent of metastatic disease is recorded by CT scanning or MRI before therapy.
Patients will then be randomized to Ipilimumab 3 mg/kg IV over 90 minutes alone versus
Ipilimumab 3 mg/kg IV over 90 minutes plus radiotherapy to one of their measurable lesions, 6
Gy delivered daily x 5 days (Monday through Friday) (conformally or by IMRT/IGRT, to
maximally spare normal tissue), for a total of 30 Gy. For patients assigned to the
Ipilimumab/RT arm, Ipilimumab treatment starts after radiotherapy, with a dose given on day 4
from the first radiotherapy fraction. All patients will then have ipilimumab infusions
repeated on Days 25, 46 and 67. Patients will be re-imaged (CT imaging or MRI) on Week 12 and
evaluated for response (defined as an objective response of another metastatic site outside
the radiation field).

The main immunological end-point will be the induction or boosting of treatment induced T
cells (CD4+ and CD8+) and B cells for defined antigen approaches. In addition, the magnitude
and duration of T- and B-cell responses will be examined. Treatment-induced responses will be
calculated as the difference between the pre-treatment measurement and the measurement at the
different time points at which blood will be collected (time of evaluation) in the same
patient. The percentage of patients with the induction of treatment-induced T- and B-cell
responses will be reported.

Inclusion Criteria:

- Ability to understand and the willingness to sign a written informed consent document;

- Histologic diagnosis of locally unresectable, metastatic melanoma.

- Any BRAF status is permitted

- Any prior therapy is permitted except prior therapy with ipilimumab.

- Patients must have at least 2 distinct measurable metastatic sites, with one of at
least 1 cm or larger in its largest diameter and may have additional non-measurable
but established metastatic lesions (i.e. bone metastases).

- Patients must have adequate organ and marrow function as defined by initial laboratory
tests:

- WBC 2000/uL

- ANC 1000/uL

- Platelets 50 x 103/uL

- Hemoglobin 8 g/dL

- Creatinine 3.0 x ULN

- AST/ALT 2.5 x ULN for patients without liver metastasis

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

- Performance status ECOG 0-1 or Karnofsky > 50%;

- Men and women, ages > 18 year old of age;

- Life expectancy > 3 months

- Stable brain metastases for at least 4 weeks and not steroid dependent;

- Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 8 weeks after the
study.

Exclusion Criteria:

- Patients having no lesions outside the field of radiation thus nullifying the ability
to measure an abscopal effect;

- Autoimmune disease: 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;

- Any underlying medical or psychiatric condition, which in the opinion of the
Investigator, will make the administration of study drug hazardous or obscure the
interpretation of AEs, such as a condition associated with frequent diarrhea;

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

- 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;

- Women who are unwilling or unable to use an acceptable method to avoid pregnancy for
the 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;

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

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