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Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Ocular Melanoma

Information source: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Metastatic Ocular Melanoma; Metastatic Uveal Melanoma

Intervention: Aldesleukin (Drug); Cyclophosphamide (Drug); Fludarabine (Drug); Young TIL (Biological)

Phase: Phase 2

Status: Recruiting

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Udai S Kammula, M.D., Principal Investigator, Affiliation: National Cancer Institute (NCI)

Overall contact:
Ellen Bodurian, Phone: (301) 594-2644, Email: ncisbirc@mail.nih.gov

Summary

Background:

- The 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 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.

Clinical Details

Official title: Phase II Study in Patients With Metastatic Ocular Melanoma Using a Non-Myeloablative Lymphocyte Depleting Regimen of Chemotherapy Followed by Infusion of Autologous Tumor-Infiltrating Lymphocytes With or Without High Dose Aldesleukin

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Determine whether objective reponses can be mediated in patients with ocular melonoma treated with young TIL with or without high dose aldesleukin

Detailed description: 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 (60 mg/kg/day IV) on days - 7 and -6 and fludarabine (25 mg/m2/day

IV) on days - 5 through -1.

- On day 0 patients will receive between 1x109 to 2x1011 young TIL and then begin high

dose aldesleukin (720,000 IU/kg 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

3 (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 (PR or 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.

Eligibility

Minimum age: 16 Years. Maximum age: 75 Years. Gender(s): Both.

Criteria:

- INCLUSION CRITERIA:

1. Measurable metastatic ocular melanoma. 2. Confirmation of diagnosis of metastatic ocular melanoma by the Laboratory of Pathology of the 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 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 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 RT-PCR and be HCV 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/mm3 without the support of

filgrastim

- 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 ALT/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 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 patient s ability to tolerate aldesleukin

Locations and Contacts

Ellen Bodurian, Phone: (301) 594-2644, Email: ncisbirc@mail.nih.gov

National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States; Recruiting
For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center, Phone: 866-820-4505, Email: ncisbirc@mail.nih.gov
Additional Information

NIH Clinical Center Detailed Web Page

Related publications:

Woodman SE. Metastatic uveal melanoma: biology and emerging treatments. Cancer J. 2012 Mar-Apr;18(2):148-52. doi: 10.1097/PPO.0b013e31824bd256. Review.

Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR, Morton KE, Laurencot CM, Steinberg SM, White DE, Dudley ME. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011 Jul 1;17(13):4550-7. doi: 10.1158/1078-0432.CCR-11-0116. Epub 2011 Apr 15.

Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology. 2011 Sep;118(9):1881-5. doi: 10.1016/j.ophtha.2011.01.040. Epub 2011 Jun 24. Review.

Starting date: March 2013
Last updated: July 29, 2015

Page last updated: August 23, 2015

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