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Phase II Study Using a Myeloablative Lymphocyte Depleting Regimen of Chemotherapy and Intensive Total Body Irradiation Followed by Infusion of Tumor Reactive Lymphocytes and Reconstitution With CD34+ Stem Cells in Metastatic Melanoma


Phase 2
18 Years
N/A
Not Enrolling
Both
Metastatic Melanoma

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Trial Information

Phase II Study Using a Myeloablative Lymphocyte Depleting Regimen of Chemotherapy and Intensive Total Body Irradiation Followed by Infusion of Tumor Reactive Lymphocytes and Reconstitution With CD34+ Stem Cells in Metastatic Melanoma


Background:

The use of immunosuppression prior to adoptive transfer of lymphocytes from tumor bearing
mice was based on a variety of murine models demonstrating improved therapeutic
effectiveness of the adoptive transfer of lymphocytes following immunosuppression of the
host.

Because the degree of immunosuppression has been highly correlated with the ability to
eliminate large tumors in murine models, we have been conducting a clinical trial,
04-C-0288, in which 200cGy of total body irradiation is used in conjunction with the same
cyclophosphamide and fludarabine regimen used in our prior adoptive cell therapy trials
which have demonstrated significant clinical responses.

We have measured T-regulatory cells in patients participating in 04-C-0288 and have
demonstrated that despite the addition of 200cGy total body irradiation (TBI), T-regulatory
cells promptly reconstituted in the host. Complete clinical responses have not been
significantly improved over other adoptive cell therapy regimens.

Thus, in this trial we would like to more adequately test our hypothesis that more intensive
lymphodepletion will increase complete responses and persistence of the transferred cells.

Objective:

To determine whether tumor reactive lymphocytes infused in conjunction with the
administration of high-dose IL-2 in patients who have received prior therapy with IL-2 and
those who have not may result in complete clinical tumor regression in patients with
metastatic melanoma receiving a myeloablative lymphoid depleting preparative regimen.

To evaluate the safety of the treatment in patients receiving the myeloablative conditioning
regimen, cell transfer and IL-2.

To determine the survival in patients, of infused cells following the administration of the
myeloablative regimen, using analysis of the sequence of the variable region of the T cell
receptor or flow cytometry (FACS).

Eligibility:

Patients who are greater than or equal to 18 years of age who have tumor reactive cells
available, with metastatic melanoma, and are physically able to tolerate high-dose IL-2.

Design:

Patients will be assigned to one of two cohorts, those having received prior therapy with
IL-2 and those who have not.

Patients will receive a myeloablative lymphocyte depleting preparative regimen consisting of
cyclophosphamide (60 mg/kg/day x 2 days IV), fludarabine (25mg/m^2/day IV X 5 days) and 1200
cGy total body irradiation (TBI).

Patients will receive intravenous adoptive transfer of tumor reactive lymphocytes (minimum
3 X 10 (9) and up to a maximum of 3 X 10(11) lymphocytes) followed by high-dose intravenous
(IV) IL-2 (720,000 IU/kg/dose every 8 hours for up to 15 doses).

On day 1 of patients will receive intravenous administration of cryopreserved autologous
CD34+ cells.

A complete evaluation of evaluable lesions will be conducted 4-6 weeks after cell infusion.
Patients will be enrolled into two strata, using a phase II optimal design to rule out a
modest CR rate of 24%, with 33-54 patients enrolled in each strata.

Inclusion Criteria


- INCLUSION CRITERIA:

Patients must have tumor reactive cells obtained and evaluated while participating in the
Surgery Branch protocol, "Cell Harvest and Preparation for Surgery Branch Adoptive Cell
Therapy Protocols" or on another Institutional Review Board (IRB) approved Surgery Branch
adoptive cell therapy study, i.e. 99-C-0158 or 03-C-0162.

The first ten patients enrolled must have previously received interleukin-2 (IL-2) and
have been either non-responders (progressive disease) or have recurred.

Patients must be greater than or equal to 18 years of age and must have measurable
metastatic melanoma.

Patients of both genders must be willing to practice birth control during treatment and
for four months after receiving the preparative regimen.

Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0, 1.

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

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

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.

Must be willing to sign a durable power of attorney.

Patients must be able to understand and sign the Informed Consent document.

Patients with resected or stable brain metastases will be eligible.

Left ventricular ejection fraction (LVEF) greater than or equal to 45%.

Carbon monoxide diffusing capacity (DLCO) greater than or equal to 60% predicted.

CELL INFUSION EXCLUSION CRITERIA:

Less than 30 days has elapsed since any prior systemic therapy at the time the patient
receives the preparative regimen, or less than six weeks since prior nitrosurea therapy.
All patients' toxicities must have recovered to a grade 1 or less or as specified in the
eligibility criteria. 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.

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.

Life expectancy of less than three months.

Systemic steroid therapy required.

Hemoglobin less than 8 g/dl unable to be corrected with transfusion.

Any 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.

Any form of primary or secondary immunodeficiency. Must have recovered immune competence
after chemotherapy or radiation therapy as evidenced by normal ANC greater than 1000/mm^3
and absence of 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.)

Seropositive 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.)

Patients with hepatitis B or hepatitis C will be excluded.

Seronegative for Epstein-Barr virus (EBV).

Patients who are not willing to complete a durable power of attorney (DPA) will be
excluded.

Patients who have received prior preparative regimens with cyclophosphamide and
fludarabine on prior Surgery Branch adoptive cell therapies will be excluded.

The following patients will be excluded because of inability to receive high dose IL-2:

Patients will be excluded if they have a history of electrocardiogram (EKG) abnormalities,
symptoms of cardiac ischemia or arrhythmias and have a LVEF less than 45% on a cardiac
stress test (stress thallium, stress multi-gated acquisition scan (MUGA), dobutamine,
echocardiogram or other stress test).

Similarly, patients who are 50 years old or greater with an LVEF less than 45% will be
excluded.

Patients who have a prolonged history of cigarette smoking or symptoms of respiratory
dysfunction will be excluded if they have an abnormal pulmonary function test as evidenced
by a forced expiratory volume 1 (FEV1) less than 60% predicted.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Complete Response

Outcome Description:

Determine if the combination of high dose aldesleukin, reinfused cells after lymphocyte depleting chemotherapy and 1200 cGy total body irradiation (TBI) is able to be associated with a modest fraction of patients with metastatic melanoma who can experience a complete response to therapy. Complete response (CR) is a disappearance of all target lesions.

Outcome Time Frame:

33 months

Safety Issue:

No

Principal Investigator

Steven A Rosenberg, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health

Authority:

United States: Federal Government

Study ID:

060136

NCT ID:

NCT00314106

Start Date:

April 2006

Completion Date:

March 2009

Related Keywords:

  • Metastatic Melanoma
  • Clinical Response
  • Stage IV Melanoma
  • Adoptive Cell Therapy
  • Tumor Infiltrating Lymphocytes
  • Immunologic Response
  • Metastatic Melanoma
  • Melanoma

Name

Location

National Cancer Institute (NCI) Bethesda, Maryland  20892