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.
Interventional
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Clinical Response
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.
every 1-3 months until disease progression. Total length of time -8/7/2007 to 9/27/2012
No
Deborah E Citrin, M.D.
Principal Investigator
National Cancer Institute (NCI)
United States: Federal Government
070176
NCT00513604
June 2007
November 2012
Name | Location |
---|---|
National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda, Maryland 20892 |