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Prospective Randomized Study of Cell Transfer Therapy for Metastatic Melanoma Using Tumor Infiltrating Lymphocytes Plus IL-2 Following Non-Myeloablative Lymphocyte Depleting Chemo Regimen Alone or in Conjunction With 12Gy Total Body Irradiation (TBI)


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

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Trial Information

Prospective Randomized Study of Cell Transfer Therapy for Metastatic Melanoma Using Tumor Infiltrating Lymphocytes Plus IL-2 Following Non-Myeloablative Lymphocyte Depleting Chemo Regimen Alone or in Conjunction With 12Gy Total Body Irradiation (TBI)


Background:

- Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes can mediate
the regression of bulky metastatic melanoma when administered along with high-dose
aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy
preparative regimen consisting of cyclophosphamide and fludarabine.

- In a series of consecutive trials using this chemotherapy preparative regimen alone or
with 2 Gy or 12 Gy total body irradiation (TBI) objective response rates using RECIST
criteria were 49%, 52%, and 72%, respectively. Complete regression rates in these three
consecutive trials were 12%, 20%, and 40%, respectively-strongly suggesting that the
addition of TBI could improve the complete regression rate. Of the 20 complete
regressions seen in this trial, 19 are on-going at 37 to 82 months.

- Because of the complexity of developing selected TIL for use in adoptive transfer, we
have recently developed a simplified method for producing TIL that is more applicable
to use in outside institutions. Utilizing young TIL cells (sometimes with CD8
purification) in 105 patients, the objective response rate was 34% with a 6.6 %
incidence of complete regressions. All patients in this trial received the
cyclophosphamide fludarabine regimen alone.

- Because of the strong suggestion that the addition of TBI to the chemotherapy regimen
could increase durable, complete regression rates in patients with metastatic melanoma,
we are now attempting to definitively determine whether the addition of TBI to the
chemotherapy preparative regimen can improve complete response rates, and overall
survival in patients receiving young TIL .

Objectives:

- To determine, in a prospective randomized trial, the complete response rate and
survival of patients with metastatic melanoma receiving ACT using young TIL plus
aldesleukin treatment following either a chemotherapy preparative regimen alone, or the
same chemotherapy preparative regimen plus TBI.

- Response rate and progression free survival will be evaluated as a secondary endpoint,
as will the toxicity of these two treatment regimens.

Eligibility:

-Patients who are 18 years or older must have:

- Evaluable metastatic melanoma;

- Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL;

- No contraindications to high-dose aldesleukin administration or total body irradiation;

- No concurrent major medical illnesses or any form of immunodeficiency

Design:

-Patients with metastatic melanoma will have lesions resected and after TIL growth is
established patients with will be prospectively randomized to receive ACT with young TIL
plus aldesleukin following either a non-myeloablative chemotherapy preparative regimen or
this same regimen plus TBI.

Inclusion Criteria


-INCLUSION CRITERIA:

1. Measurable metastatic melanoma with at least one lesion that is resectable for TIL
generation. The lesion must be of at least 1cm in diameter that can be surgically
removed with minimal morbidity (defined as any operation for which expected
hospitalization less than or equal to 7 days).

2. 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.

3. Greater than or equal to 18 years of age.

4. Willing to practice birth control during treatment and for four months after
receiving all protocol related therapy.

5. Life expectancy of greater than three months

6. Willing to sign a durable power of attorney.

7. Able to understand and sign the Informed Consent Document

8. Clinical performance status of ECOG 0 or 1.

9. Hematology:

- Absolute neutrophil count greater than 1000/mm(3)

- Hemoglobin greater than 8.0 g/dl

- Platelet count greater than 100,000/mm(3)

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, or hepatitis C antibody or antigen.

11. Chemistry:

- Serum ALT/AST less than three times the upper limit of normal.

- Calculated creatinine clearance (eGFR) > 50 ml/min.

- Total bilirubin less than or equal to 2 mg/dl, except in patients with

Gilbert s Syndrome who must have a total bilirubin less than 3 mg/dl.

12. More than four weeks must have elapsed since any prior systemic therapy at the time
of randomization, and patients toxicities must have recovered to a grade 1 or less
(except for alopecia or vitiligo). Patients must have stable or progressing disease
after prior treatment.

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
inclusion criteria.

13. Six weeks must have elapsed since any prior anti-CTLA4 antibody therapy to allow
antibody levels to decline.

14. Patients who have previously received any anti-CTLA4 antibody and have documented GI
toxicity must have a normal colonoscopy with normal colonic biopsies.

EXCLUSION CRITERIA:

1. Prior cell transfer therapy which included a non-myeloablative or myeloablative
chemotherapy regimen.

2. Women of child-bearing potential who are pregnant or breastfeeding because 10 of the
potentially dangerous effects of the preparative chemotherapy on the fetus or infant.

3. Systemic steroid therapy requirement.

4. 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.

5. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease and AIDS).

6. 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.)

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

8. History of coronary revascularization or ischemic symptoms.

9. Any patient known to have an LVEF less than or equal to 45%.

10. In patients > 60 years old, documented LVEF of less than or equal to 45%.

11. Documented FEV1 less than or equal to 60% predicted tested in patients with:

- A prolonged history of cigarette smoking

- Symptoms of respiratory dysfunction

12. Prior radiation therapy that, in the judgment of the radiation oncologist, precludes
the administration of total body irradiation.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Compare the complete response rate and survival in pts with metastatic melanoma receiving ACT using young TIL plus aldesleukin treatment following either a lymphodepleting chemo or a chemo/total body irradiation preparative regimen.

Outcome Time Frame:

5 years

Safety Issue:

No

Principal Investigator

Steven A Rosenberg, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

110123

NCT ID:

NCT01319565

Start Date:

March 2011

Completion Date:

May 2014

Related Keywords:

  • Metastatic Melanoma
  • Skin Cancer
  • Metastatic Melanoma
  • Immunotherapy
  • Cell Therapy
  • Skin Cancer
  • Skin Neoplasms
  • Melanoma

Name

Location

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