Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Melanoma

Metastatic Melanoma Clinical Trial

Official title:

A Pilot Study of the Administration of Young Tumor Infiltrating Lymphocytes Following a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen in Metastatic Melanoma

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01468818
• Other study ID #: 110260
• Secondary ID: 11-C-0260
• Status: Terminated
• Phase: Phase 2
• First received: October 6, 2011
• Last updated: April 15, 2016
• Start date: September 2011
• Est. completion date: June 2018

Study information

• Verified date: April 2016
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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 with aldesleukin (IL-2) a drug that keeps the white blood cells active. 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. Our prior studies indicate that aldesleukin may not be required for cell transfer.

Objectives:

• To see if chemotherapy and white blood cell therapy without aldesleukin is a safe and effective treatment for metastatic melanoma.

Eligibility:

• Individuals at least 18 years of age and less than or equal to 70 years of age with metastatic 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 will take up to 2 days.

Description:

BACKGROUND:

• Tumor Infiltrating Lymphocytes (TIL) can mediate the regression of bulky metastatic melanoma when administered to the autologous patient along with high-dose aldesleukin

(IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen.

• IL-2 administration has been shown to increase the number of T regulatory cells and in our trials we have found a direct relationship between the number of IL-2 doses and the reconstitution of patients at one week with CD4+ Foxp3+ T regulatory cells.

• In our analysis of factors that relate to the ability of this treatment to mediate objective responses, we have found a highly significant inverse correlation between reconstitution of CD4+ Foxp3+ T regulatory cells and the likelihood of achieving an objective response.

• In our prior clinical trials of cell transfer using TIL after lymphodepletion with or without

2Gy total body irradiation, patients who experienced an objective response received fewer doses of IL-2 compared to non-responders (p=0.007 and 0.03 respectively).

• High levels of the homeostatic T cell growth factor, IL-15, are present in patient serum after the lymphodepleting regimen at the time of cell transfer.

• These factors raise the possibility that IL-2 administration is not required after cell transfer.

OBJECTIVES:

• The primary objective of this trial is to determine whether objective responses can be mediated in patients with metastatic melanoma who have received a lymphodepleting chemotherapy regimen and adoptive transfer of young tumor infiltrating lymphocytes and no IL-2 administration.

• The secondary objective involves the determination of the level of transferred cells in the blood that persist at about 1 week and 1 month after transfer.

ELIGIBILITY:

• Patients greater than or equal to 18 years old with pathologically confirmed diagnosis of metastatic melanoma.

• Patients with measurable disease, absolute neutrophil count greater than 1000/mm(3) and platelet count greater than 100,000/mm(3).

• Patients not eligible to receive IL-2.

DESIGN:

• Patients with metastatic melanoma will undergo resection to obtain tumor for generation of autologous TIL cultures.

• Patients will receive a non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of young

autologous TIL.

• Patients will be evaluated for objective clinical response and for persistence of the transferred cells.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 18
• Est. completion date: June 2018
• Est. primary completion date: June 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

• INCLUSION CRITERIA:

• Measurable metastatic melanoma with available autologous TIL.

• 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.

• Greater than or equal to 18 years of age and less than or equal to 70 years of age.

• Able to understand and sign the Informed Consent Document

• Clinical performance status of ECOG 0 or 1.

• Life expectancy of greater than three months

• 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.

• 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.

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

• Hematology

• Absolute neutrophil count greater than 1000/mm(3) without the support of filgrastim

• WBC greater than or equal to 3000/mm(3)

• Platelet count greater than or equal to 100,000/mm(3)

• Hemoglobin > 8.0 g/dl

• Chemistry:

• Serum ALT/AST less than or equal to to 2.5 times the upper limit of normal

• Serum Creatinine less than or equal to to 1.6 mg/dl

• Total bilirubin less than or equal to to 1.5 mg/dl, except in patients with Gilbert s Syndrome who must have a total bilirubin less than 3.0 mg/dl.

• 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.

• Six weeks must have elapsed since any prior antibody therapy including anti-CTLA4 antibody therapy that could affect any anti-cancer immune response, at the time the patient receives the preparative regimen to allow antibody levels to decline. NOTE: patients who have previously received ipililumab and have documented GI toxicity must have a colonoscopy with normal colonic biopsies.)

• Patients must be ineligible to receive IL-2 based on evidence that may include ischemic heart disease, or arrhythmias, or poor ventricular ejection fraction (< 50%), or respiratory compromise (FEV1 < 60%), or clinically significant patient history which in the judgment of the investigator would compromise the patient s ability to tolerate aldesleukin.

EXCLUSION CRITERIA:

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

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

• 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).

• Concurrent systemic steroid therapy.

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

• Patients with a ventricular ejection fraction (less than or equal to 30%), or respiratory compromise (FEV1 less than or equal to 40%).

Study Design

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

Related Conditions & MeSH terms

• Melanoma
• Metastatic Melanoma
• Skin Cancer
• Skin Neoplasms

Intervention

Drug:
• Cyclophosphamide
Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15 mg/kg/day X 2 days over 1 hr.
• Fludarabine
Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.

Biological:
• Young TIL
Patients will receive non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of young TIL. On day 0, cells (1x10e9 to 2x10e11) will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (between one and four days after the last dose of fludarabine).

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul;17(7):2105-16. Review. — View Citation

Gogas HJ, Kirkwood JM, Sondak VK. Chemotherapy for metastatic melanoma: time for a change? Cancer. 2007 Feb 1;109(3):455-64. Review. — View Citation

Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Determine whether objective responses can be mediated in patients with metastitic melanoma		Approximately 2 Years	Yes