Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Ocular Melanoma
Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Ocular Melanoma
Background:

 - The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy
 that involves taking white blood cells from patients' tumors, growing them in the laboratory
 in large numbers, and then giving the cells back to the patient. These cells are called Tumor
 Infiltrating Lymphocytes, or TIL and we have given this type of treatment to over 200
 patients with melanoma. This study will use chemotherapy to prepare the immune system before
 this white blood cell treatment. After receiving the cells, the drug aldesleukin (IL-2) may
 be given to help the cells stay alive longer.

 Objectives:

 - To see if chemotherapy and white blood cell therapy is a safe and effective treatment for
 advanced ocular melanoma.

 Eligibility:

 - Individuals at least greater than or equal to 16 years to less than or equal to 75 years
 who have advanced ocular melanoma.

 Design:

 -  Work up stage: Patients will be seen as an outpatient at the National Institutes of
 Health (NIH) clinical Center and undergo a history and physical examination, scans,
 x-rays, lab tests, and other tests as needed.

 -  Surgery: If the patients meet all of the requirements for the study they will undergo
 surgery to remove a tumor that can be used to grow the TIL product.

 -  Leukapheresis: Patients may undergo leukapheresis to obtain additional white blood
 cells. {Leukapheresis is a common procedure, which removes only the white blood cells
 from the patient.}

 -  Treatment: Once their cells have grown, the patients will be admitted to the hospital
 for the conditioning chemotherapy, the TIL cells and aldesleukin. They will stay in the
 hospital for about 4 weeks for the treatment.

 -  Follow up: Patients will return to the clinic for a physical exam, review of side
 effects, lab tests, and scans about every 1-3 months for the first year, and then every
 6 months to 1 year as long as their tumors are shrinking. Follow up visits take up to 2
 days.
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