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A Phase II Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Melanoma


Phase 2
18 Years
N/A
Not Enrolling
Both
Melanoma, Malignant Melanoma, Melanoma, Experimental, Experimental Melanomas

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Trial Information

A Phase II Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Melanoma


Background:

- Tumor Infiltrating Lymphocytes (TIL) can mediate the regression of bulky metastatic
melanoma when administered to an autologous patient with high dose (HD) IL-2 following
a non-myeloablative (NMA) but lymphodepleting chemotherapy preparative regimen.

- Clinical investigations and preclinical animal models have demonstrated that less time
in culture, longer telomeres, and a less differentiated lymphocyte phenotype are
associated with TIL that are capable of mediating objective clinical responses and
persisting long term in the host.

- Previous methods for generating TIL require screening for anti-tumor specificity using
gamma-interferon (IFN) production by the TIL. However, in vitro screening depends on
autologous tumor reagents that are often unavailable; and gamma-IFN release in vitro
may not be the best correlate to in vivo efficacy. Additionally, this method
necessitates long in vitro culture times (44 days), and therefore reduces the clonal
heterogeneity of TIL cultures, and results in TIL cultures with shorter telomere
lengths and phenotypes that are skewed toward a more differentiated phenotype.

- In Surgery Branch pre-clinical experiments, we evaluated a method for rapidly
generating young TIL from melanoma tumors with optimal phenotypic characteristics.

Objectives:

- In cohort 1, to determine the ability of autologous TIL cells infused after minimal in
vitro culture in conjunction with high dose aldesleukin (IL-2) following a
non-myeloablative lymphodepleting preparative regimen to mediate tumor regression in
patients with metastatic melanoma.

- In cohort 2, to determine the ability of autologous cluster of differentiation 4 (CD4+)
cell depleted TIL cells infused after minimal in vitro culture in conjunction with high
dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting preparative
regimen to mediate tumor regression in patients with metastatic melanoma.

- In cohort 3, to determine the ability of autologous CD4+ cell depleted TIL cells
infused after minimal in vitro culture in conjunction with high dose aldesleukin
following chemoradiation lymphoid depleting regimen to mediate complete tumor
regression in patients with metastatic melanoma.

- In a prospective randomized fashion, to compare the ability of autologous TIL cells
(cohort 4) and autologous CD4plus cell depleted TIL cells (cohort regimen, to mediate
tumor regression, progression free survival, and overall survival in patients with
metastatic melanoma.

- Evaluate the toxicity of these treatment regimens.

- Determine the rate of repopulation of the young TIL cells in treated patients and
establish in vitro correlates of TIL cultures that mediate objective response and in
vivo persistence.

Eligibility:

Patients who 18 years of age or older must have:

- Metastatic melanoma;

- Normal values for basic laboratory values.

Patients may not have:

- Received prior cell transfer therapy that included non-myeloablative or ablative
chemotherapy;

- Concurrent major medical illnesses;

- Any form of immunodeficiency;

- Severe hypersensitivity to any of the agents used in this study;

- Contraindications for high dose IL-2 administration.

Design:

- Patients will undergo resection to obtain tumor for generation of autologous TIL
cultures.

- Cohort 1:

- 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/m^2/day IV) on days -5 through -1.

- On day 0 patients will receive the infusion of autologous TIL and then begin
high-dose aldesleukin (720,000 IU/kg IV every 8 hours for up to 15 doses).

- Clinical and Immunologic response will be evaluated about 4-6 weeks after TIL
infusion.

- Using a small optimal two-stage Phase II design, initially 21 patients will be
enrolled, and if two or more of the first 21 patients has a clinical response
(partial response (PR) or complete response (CR)), accrual will continue to 41
patients, targeting a 20% goal for objective response. Cohort 1 will be closed
with amendment D.

- Cohort 2 will be initiated with amendment D whereby CD4+ cells will be eliminated from
the cultures, using the Miltenyi Clinimacs apparatus, prior to performing the rapid
expansion of the young TIL cells. Patients in cohort 2 will receive CD4+ cell depleted
young unselected TIL. Patients will also receive high dose IL-2 after non-myeloablative
but lymphodepleting chemotherapy preparative regimen as described above for cohort 1.
Clinical and immunologic response will be evaluated about 4-6 weeks after TIL infusion.
Using a small optimal two-stage Phase II design, initially 18 patients will be
enrolled, and if three or more of the first 18 patients have a clinical response (PR or
CR), accrual will continue to 35 patients, targeting a 30% goal for objective response.
With the initiation of Cohort 3 with amendment H, patients will only be accrued to
Cohort 2 if they are not eligible to receive 600 cGy due to prior radiation, or to
inability to mobilize cluster of differentiation 34 (CD34+) cells. Also at this time,
accrual will be expanded to a total of 50 patients in cohort 2. Cohort 2 will be
closed with amendment K.

- Cohort 3 will be initiated with amendment H, whereby patients will receive a
chemoradiation lymphocyte depleting preparative regimen consisting of cyclophosphamide,
fludarabine, and 600 cGy total body irradiation followed by intravenous infusion of
autologous CD4+ cell depleted young TIL plus IV high dose IL-2. Clinical and
immunologic response will be evaluated about 4-6 weeks after TIL infusion. Using a
small optimal two-stage Phase II design, initially 26 patients will be enrolled, and if
one or more of the first 26 patients have a complete response (CR), accrual will
continue to 51 patients, targeting a 10% goal for complete response. Cohort 3 will be
closed with amendment K.

Prospective randomization between cohorts 4 and 5:

- Cohort 4:

- 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/m^2/day IV) on days -5 through -1.

- On day 0 patients will receive the infusion of autologous TIL and then begin
high-dose aldesleukin (720,000 IU/kg IV every 8 hours for up to 15 doses).

- Clinical and immunologic response will be evaluated about 4-6 weeks after TIL
infusion.

- Cohort 5

- 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/m^2/day IV) on days -5 through -1.

- On day 0 patients will receive the infusion of autologous CD4+ depleted TIL and
then begin high-dose aldesleukin (720,000 IU/kg IV every 8 hours for up to 15
doses).

- Clinical and immunologic response will be evaluated about 4-6 weeks after TIL
infusion.

Inclusion Criteria


-INCLUSION CRITERIA:

1. Measurable metastatic melanoma with at least one lesion that is resectable for tumor
infiltrating lymphocytes (TIL) generation.

2. Patients with one to three brain metastases are eligible (lesions greater than or
equal to 1 cm each, or symptomatic lesions must have been treated and stable for 3
months).

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

4. Willing to practice birth control during treatment and for four months after
receiving the preparative regimen.

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 Eastern Cooperative Oncology Group (ECOG) 0 or 1.

9. Hematology:

- Absolute neutrophil count greater than 1000/mm^3 without support of filgrastim.

- Normal white blood cell (WBC) (greater than 3000/ mm^3).

- Hemoglobin greater than 8.0 g/dl.

- Platelet count greater than 100,000/ mm^3.

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 or hepatitis C.

11. Chemistry: . Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST)
less than three 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 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
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).
Patients may have undergone minor surgical procedures with the past 3 weeks, as long
as all toxicities have recovered to grade 1 or less or as specified in the
eligibility criteria in Section 2.1.1.

13. Six weeks must have elapsed since prior MDX-010 (Ipilimumab) therapy to allow
antibody levels to decline.

14. Patients who have previously received any anti-CTLA4 (cytotoxic T-lymphocyte antigen
4) antibody and experienced treatment related colitis must have a normal colonoscopy
with normal colonic biopsies.

EXCLUSION CRITERIA:

1. Prior cell transfer therapy that included non-myeloablative or ablative chemotherapy
(for cohorts 4 and 5).

2. 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.

3. Systemic steroid therapy required.

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 Acquired Immune Deficiency Syndrome (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 left ventricular ejection fraction (LVEF) less than or
equal to 45%.

10. Documented LVEF of less than or equal to 45% tested 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.

11. Documented forced expiratory volume 1 (FEV1) less than or equal to 60% predicted
tested in patients with:

- A prolonged history of cigarette smoking

- Symptoms of respiratory dysfunction

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:

Clinical Response

Outcome Description:

Clinical response is defined as complete response (CR)- a disappearance of all target lesions, partial response (PR) - at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progression (PD)- at least a 20% increase in the sum of the LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable disease (SD) - neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD.

Outcome Time Frame:

every 1-3 months until disease progression. Total length of time -8/7/2007 to 9/27/2012

Safety Issue:

No

Principal Investigator

Deborah E Citrin, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

070176

NCT ID:

NCT00513604

Start Date:

June 2007

Completion Date:

November 2012

Related Keywords:

  • Melanoma
  • Malignant Melanoma
  • Melanoma, Experimental
  • Experimental Melanomas
  • Clinical Response
  • Immunotherapy
  • Cancer
  • Cytokines
  • Adoptive Cell Therapy
  • Melanoma
  • Skin Cancer
  • Malignant Melanoma
  • Melanoma
  • Melanoma, Experimental

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892