Ex Vivo-Activated Lymph Node Lymphocytes in Treating Patients With Stage IIIC-IV Melanoma

PRIMARY OBJECTIVES:

I. Assess the safety and toxicity profile of repeated infusions of ex-vivo activated
tumor-draining lymphocytes (X-ACT) in participants with advanced melanoma.

SECONDARY OBJECTIVES:

I. Assess the feasibility of multiple infusions of X-ACT. II. Assess the effect of dose and
schedule on immunologic parameters using two novel biomarkers.

III. Observe the clinical outcomes of participants receiving X-ACT therapy.

OUTLINE: This is a dose-escalation study.

STEP 1: Participants undergo lymph node biopsy for collection of at least one
melanoma-draining lymph node (MDLN). MDLN cells will then be cryopreserved into aliquots
until they are needed to generate an activated T cell culture.

STEP 2: Cryopreserved lymph node cells are thawed and then undergo activation with
anti-cluster of differentiation (CD)3/anti-CD28 microbeads. The cultures then undergo
expansion over 14-18 days in the presence of recombinant human interleukin-2 and
anti-vascular endothelial growth factor antibody. The activated X-ACT cells are then
transferred i.v. into the same participant from which they were derived with no additional
therapy.

Inclusion Criteria:

- STEP 1

- Participants must have a histologic diagnosis of melanoma either from a primary
or metastatic site; Participants with brain metastases must have completed
radiation therapy >30 days prior to enrollment

- Participants must have American Joint Committee on Cancer (AJCC) stage IIIC
unresected or IV disease

- Patients with non-measureable or measurable disease are eligible. Measurable
lesions are defined as those that can be accurately measured in at least one
dimension (longest diameter for non-nodal lesions and short axis for nodal
lesions to be recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥
10 mm with calipers by clinical exam. Malignant lymph nodes, to be considered
pathologically enlarged and measurable, must be ≥ 15 mm in short axis when
assessed by CT scan (CT scan slice thickness recommended to be no greater than 5
mm). At baseline and in follow-up, only the short axis will be measured and
followed.

- Tumor lesions that are situated in a previously irradiated area can be
considered measurable as long as ≥ 30 days has passed since radiation to
that area

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

- Life expectancy (untreated) of > 4 months, in the opinion of and as documented by
the investigator

- White blood count > 3,000/mcL

- Absolute neutrophil count > 1,200/mcL

- Platelet count > 100,000/mcL

- Serum creatinine < 2.0 mg/dL

- International normalized ratio (INR) ≤ 2.0

- In the opinion of the investigator, participant must be medically fit to undergo
surgical procedure

- Participants treated with prior chemotherapy, cytotoxic chemotherapy, radiation,
biotherapy, or any investigational agent > 30 days prior to lymph node removal
are eligible

- Women of child-bearing potential must agree to use adequate contraception (double
barrier method of birth control or abstinence) during participation in the study;
should a woman become pregnant or suspect that she is pregnant while she or her
partner is participating in this study, she should inform the treating physician
immediately

- Participants must be disease free of prior invasive malignancies for > 5 years,
with the exception of curatively treated basal cell or squamous cell carcinoma of
the skin or cancer in-situ of the cervix

- Participants must be able to understand and willing to sign a written informed
consent document

- STEP 2

- Successful removal of melanoma-draining lymph node (MDLN)

- ECOG Performance status ≤ 1

- White blood count > 3,000/mcL

- Absolute neutrophil count > 1,500/mcL

- Platelet count > 100,000/mcL

- Serum creatinine < 2.0 mg/dL

- Serum direct bilirubin < 2 x institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])

- Alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) <
2.5 X institutional upper limit of normal

- Participants with liver metastases who do not meet the eligibility parameters may
only be enrolled at the discretion of the principal investigator (PI)

Exclusion Criteria:

Step 1

- Participants who are taking immunosuppressive medications that cannot be discontinued
(corticosteroids); participants who have discontinued immunosuppressive medications
but be at least 1 week post their last dose. Patients who are taking physiologic
replacement doses of corticosteroids equivalent to oral prednisone 10 mg per day will
not be excluded.

- Participants who are receiving any other investigational agents

- Participants with a history of autoimmune disease requiring continuous treatment

- Participants receiving any medications or substances to treat active infection

- Pregnant or breastfeeding

- Participants with human immunodeficiency virus (HIV) or hepatitis, or known active
cytomegalovirus (CMV), Epstein-Barr virus (EBV) or any other viral illness requiring
treatment are ineligible because of the potential for pharmacokinetic interactions
with ACT lymph node lymphocytes

- Any condition or behavior that in the judgment of the investigator, would compromise
the participant's ability to participate in the study and/or comply with study
procedures

- Patients with bleeding disorders are ineligible due to lymph node removal possibly
causing excessive bleeding. Bleeding disorder will be defined by an INR level of > 2.0

Step 2 None