Pilot Study to Evaluate the Effects of a Vaccine (HSPPC-96) Combined With Ipilimumab in Patients With Advanced Melanoma

This is a randomized, open label, single-center, phase I-II trial to determine the safety,
feasibility and immunogenicity of combination treatment of HSPPC-96 and ipilimumab in
patients with therapeutically unresectable Stage III or Stage IV malignant melanoma.

The main purpose of this study is to assess whether the administration of the combination of
ipilimumab and HSPPC-96 is safe. The rationale for combining the two treatments resides in
their respective roles on the immune system as described below and based on the clinical
experience collected so far. HSPPC-96 is able to initiate a tumor specific immune response
that ipilimumab could theoretically amplify by blocking a checkpoint that naturally
down-regulates T cells.

Inclusion Criteria:Pre-surgery Inclusion criteria:

- Signed informed consent

- ≥ 18 years of age

- Stage III or Stage IV melanoma according to TNM staging criteria/AJCC version 7
determined by PET/MRI/CT scan

- ECOG score 0 or 1

- Life expectancy ≥6 months

- Candidate for surgical resection with viable melanoma tissue to ascertain ≥ 7 grams
of viable cancer tissue (in aggregate), which is equivalent to a ≥ 2 cm lesion on
CT/MRI or clinical examination

- Adequate cardiac function (≤ NYHA class II)

- Adequate bone marrow function, including: absolute granulocyte count (ANC) ≥
1,500x106/L, absolute lymphocyte count (ALC) ≥ 500/mm3, platelets count ≥100,000 x
106/mm3. Adequate liver function including: serum glutamic oxaloacetic
transaminases/aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤
2.5 x the upper limit of institutional normal (IULNs), bilirubin ≤ 1.5 mg/dL or 25
µmol/L (SI units). Adequate renal function: BUN and Serum creatinine of ≤ 1.5 mg/dL
or 130 µmol/L (SI units)

- Female subjects of childbearing potential and fertile males must agree to use
adequate contraception during the course of the study. Adequate contraception
includes condoms with contraceptive foam; oral, implantable or injectable
contraceptives; contraceptive patch; intrauterine device; diaphragm with spermicidal
gel; or a sexual partner who is surgically sterilized or postmenopausal.

- Post-surgery Inclusion Criteria (must be completed within 4 weeks of surgery)

- Histologically and clinically confirmed Stage III and/or Stage IV malignant melanoma
according to TNM Staging Criteria/AJCC version 7 confirmed by PET/CT scan

- Measurable disease for target lesion clinical and radiological monitoring

- ECOG score 0 or 1

- Adequate cardiac function (≤ NYHA class II)

- Adequate bone marrow function, liver, and renal function

- ≥ 6 doses of vaccine for clinical use

Exclusion Criteria: Pre-Surgery Exclusion Criteria:

- Primary mucosal or primary ocular melanomas

- Other malignancies treated within the last five years, except in situ cervix
carcinoma or non-melanoma skin cancer

- Primary or secondary immunodeficiency (including immunosuppressive disease, or
systemic use of corticosteroids or other immunosuppressive medications)

- Patients with history of HIV1 and 2, HTLV-1, HBV or active HCV.

- Patients with history of connective tissue disorders

- Prior ipilimumab or melanoma vaccine therapy

- Prior therapy with IL-2

- Prior chemotherapy, small molecule targeted therapy, interferon within 3 months prior
to enrollment

- Prior investigational products administration within 4 weeks prior to enrollment

- Prior splenectomy

- Symptomatic CNS metastases or spinal cord compression

- Uncontrolled infection or other serious medical illnesses

- Any medical conditions that, in the opinion of the investigator, would preclude use
of ipilimumab, including ipilimumab hypersensitivity

- Women who are pregnant or breast-feeding

- Concurrent participation in investigational trials

- Post-surgery Exclusion Criteria (must be completed within 4 weeks of surgery):

- Emergence of contraindicated clinical condition