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


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Metastatic Melanoma, Skin Cancer

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Trial Information

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


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 because of cardiovascular or respiratory problems
or who refuse 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.

Inclusion Criteria


- INCLUSION CRITERIA:

- Measurable metastatic melanoma with available autologous TIL.

- Patients with 3 or less brain metastases are eligible. Note: If lesions are
symptomatic or greater than or equal to 1 cm each, these lesions must have been
treated and stable for 3 months for the patient to be eligible

- Greater than or equal to 18 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 preparative
regimen.

- 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 preparative chemotherapy 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 anti-CTLA4 antibody therapy to allow
antibody levels to decline.

- 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 prolonged smoking history, or who
refuse the IL-2 portion of the ACT.

EXCLUSION CRITERIA:

- Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the preparative chemotherapy 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%).

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Determine whether objective responses can be mediated in patients with metastitic melanoma who have received a lymphodepleting chemotherapy regimen and adoptive transfer of young tumor infiltrating lymphocytes and no IL-2 administration.

Principal Investigator

Steven A Rosenberg, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

110260

NCT ID:

NCT01468818

Start Date:

September 2011

Completion Date:

August 2013

Related Keywords:

  • Metastatic Melanoma
  • Skin Cancer
  • Metastatic Melanoma
  • Skin Cancer
  • Skin Neoplasms
  • Melanoma

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892