Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Ocular Melanoma

Background:

- Metastatic ocular melanoma (OM) carries a poor prognosis with estimated survival of 4-6
months. There are no known effective systemic therapies. Metastatic OM is classified as
an orphan disease and there are currently few clinical trial options for these patients.
Thus, novel systemic approaches are desperately needed.

- Administration of autologous tumor infiltrating lymphocytes (TIL) generated from
resected metastatic cutaneous melanoma can induce objective long-term tumor responses.

- Minimally invasive, safe, and effective surgical approaches have been developed in the
Surgery Branch to procure liver tumor tissue for TIL generation.

Objectives:

- To determine whether autologous Young TIL infused with or without the administration of
high-dose aldesleukin may result in clinical tumor regression in patients with
metastatic ocular melanoma receiving a non-myeloablative lymphoid depleting preparative
regimen.

- To study immunologic correlates associated with Young TIL therapy for ocular melanoma.

- To determine the toxicity of this treatment regimen.

Eligibility:

- Patients with metastatic ocular melanoma who are greater than or equal to 16 years of
age, and are physically able to tolerate non-myeloablative chemotherapy. Patients who
can tolerate high-dose aldesleukin will receive it following cell infusion; those who
cannot tolerate high-dose aldesleukin due to medical comorbidities or refuse high dose
aldesleukin will receive cell infusion without aldesleukin.

- There is no requirement for prior systemic therapies, given the lack of known effective
systemic treatments for metastatic OM.

Design:

- Patients will undergo biopsy or resection to obtain tumor for generation of autologous
TIL cultures and autologous cancer cell lines.

- All patients will receive a non-myeloablative lymphocyte depleting preparative regimen
of cyclophosphamide and fludarabine.

- On day 0 patients will receive between 1x10^9 to 2x10^11 young TIL and then begin high
dose aldesleukin (720,000 IU/kg intravenous (IV) every 8 hours for up to 15 doses) or no
aldesleukin if they are not medically eligible to receive it.

- A complete evaluation of evaluable lesions will be conducted 4-6 weeks after the last
dose of aldesleukin in the aldesleukin arm and 4-6 weeks after the cell administration
in the no aldesleukin arm.

- Patients will be enrolled into two cohorts. The cohort receiving high-dose aldesleukin
(cohort A) will be conducted using a small optimal two-stage Phase II design, initially
19 patients will be enrolled, and if 4 or more of the first 19 patients have a clinical
response (partial response (PR) or complete response (CR), accrual will continue to 33
patients, targeting a 35% goal for objective response. For the cohort that will not
receive aldesleukin (cohort B), the study will be conducted as a Minimax two-stage phase
II trial. Initially 12 evaluable patients will be enrolled to this cohort, and if 1 or
more the first 12 have a response, then accrual would continue until a total of 21
patients, targeting a 20% goal for objective response.

- INCLUSION CRITERIA:

1. Measurable metastatic ocular melanoma.

2. Confirmation of diagnosis of metastatic ocular melanoma by the Laboratory of
Pathology of the National Cancer Institute (NCI).

3. Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and
asymptomatic are eligible. Lesions that have been treated with stereotactic
radiosurgery must be clinically stable for 1 month after treatment for the
patient to be eligible. Patients with surgically resected brain metastases are
eligible.

4. Greater than or equal to 16 years of age and less than or equal to age 75.

5. Able to understand and sign the Informed Consent Document

6. Willing to sign a durable power of attorney

7. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1

8. Life expectancy of greater than three months

9. Patients of both genders must be willing to practice birth control from the time
of enrollment on this study and for up to four months after receiving the
treatment.

10. Serology:

- Seronegative for human immunodeficiency virus (HIV) antibody. (The
experimental treatment being evaluated in this protocol depends on an intact
immune system. Patients who are HIV seropositive can have decreased
immune-competence and thus be less responsive to the experimental treatment
and more susceptible to its toxicities.)

- Seronegative for hepatitis B antigen, and seronegative for hepatitis C
antibody. If hepatitis C antibody test is positive, then patient must be
tested for the presence of antigen by reverse transcription-polymerase chain
reaction (RT-PCR) and be hepatitis C virus (HCV) ribonucleic acid (RNA)
negative.

11. Women of child-bearing potential must have a negative pregnancy test because of
the potentially dangerous effects of the treatment on the fetus.

12. Hematology

- Absolute neutrophil count greater than 1000/mm^3 without the support of
filgrastim

- White blood cell (WBC) greater than or equal to 3000/mm^3

- Platelet count greater than or equal 100,000/mm^3

- Hemoglobin > 8.0 g/dl

13. Chemistry:

- Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less
than or equal to 3.5 times the upper limit of normal

- Serum creatinine less than or equal to 1.6 mg/dl

- Total bilirubin less than or equal to 2.0 mg/dl, except in patients with
Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.

14. More than four weeks must have elapsed since any prior systemic therapy at the
time the patient receives the preparative regimen, and patients toxicities must
have recovered to a grade 1 or less (except for toxicities such as alopecia or
vitiligo).

Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as
long as all toxicities have recovered to grade 1 or less or as specified in the eligibility
criteria.

EXCLUSION CRITERIA:

1. Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the treatment on the fetus or infant.

2. Active systemic infections, coagulation disorders or other active major medical
illnesses of the cardiovascular, respiratory or immune system, as evidenced by a
positive stress thallium or comparable test, myocardial infarction, cardiac
arrhythmias, obstructive or restrictive pulmonary disease.

3. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease).

4. Concurrent opportunistic infections (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Patients who have decreased immune
competence may be less responsive to the experimental treatment and more susceptible
to its toxicities).

5. Concurrent systemic steroid therapy.

6. History of severe immediate hypersensitivity reaction to any of the agents used in
this study.

7. The following patients will be excluded from the high-dose aldesleukin arm (but may be
eligible for cells alone arm):

1. History of coronary revascularization or ischemic symptoms

2. Documented left ventricular ejection fraction (LVEF) of less than or equal to
45%. Testing is required in patients with:

- Clinically significant atrial and/or ventricular arrhythmias including but
not limited to: atrial fibrillation, ventricular tachycardia, second or
third degree heart block

- Age greater than or equal to 60 years old

3. Clinically significant patient history which in the judgment of the Principal
Investigator would compromise the patients ability to tolerate aldesleukin