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Phase II Study in Metastatic Melanoma or Kidney Cancer Using Autologous Natural Killer Cells Plus Aldesleukin (IL-2) Following a Lymphodepleting Chemotherapy

Phase 2
18 Years
Not Enrolling
Metastatic Melanoma, Metastatic Kidney Cancer

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Trial Information

Phase II Study in Metastatic Melanoma or Kidney Cancer Using Autologous Natural Killer Cells Plus Aldesleukin (IL-2) Following a Lymphodepleting Chemotherapy


- Natural killer (NK) cells are large granular lymphocytes that are critical effector
cells in the early innate immune response to pathogens and cancer.

- Previous and current clinical investigations have clearly demonstrated that T
lymphocytes can mediate the regression of metastatic melanoma. However, not all
patients with cancer are eligible for this type of immunotherapy either because
resectable tumor is not available, the TIL do not expand sufficiently, or the tumor
infiltrating lymphocytes (TIL) that do proliferate do not exhibit sufficient tumor
specific reactivity.

- We have recently developed techniques for the in vitro isolation and expansion of
anti-tumor NK cells to levels suitable for the treatment of cancer patients and are
proposing in this protocol to evaluate therapy using these NK cells.

- In Surgery Branch pre-clinical experiments, we evaluated lysis of fresh melanoma cell
digests, melanoma cell lines, renal cell carcinoma (RCC) lines, and normal peripheral
blood mononuclear cells (PBMCs) by NK cells from several patients and demonstrated that
NK cells could lyse some fresh melanoma digests, as well as melanoma cell lines and
renal cell cancer (RCC) lines, while sparing normal allogeneic and autologous PBMCs.


- Determine the ability of the administration of autologous natural killer (NK) cells
plus aldesleukin (IL-2) following a non-myeloablative lymphodepleting preparative
regimen to mediate tumor regression in patients with metastatic melanoma or kidney

- Determine the rate of repopulation of the natural killer cells in treated patients.

- Determine the toxicity of this treatment regimen.


- Patients, 18 years of age or older with metastatic melanoma or metastatic kidney cancer
who have previously received high dose IL-2, with an Eastern Cooperative Oncology Group
(ECOG) of 0 or 1.

- Patients may not have any active systemic infections, coagulations disorders, major
medical illnesses of the cardiovascular, respiratory or immune systems or any form of
autoimmune disease or immunodeficiency.

Patients must be eligible to receive high-dose IL-2.


- Patients will undergo apheresis on 03-C-0277 (Cell Harvest and Preparation for Surgery
Branch Adoptive Cell Therapy Protocols) to obtain cells for generation of autologous
natural killer cells.

- All patients will receive a non-myeloablative lymphocyte depleting preparative regimen
of cyclophosphamide (60 mg/kg/day IV) on days -8 and -7 and fludarabine (25 mg/m^2/day
IV) on days -6 through -2.

- On day 0 patients will receive the infusion of autologous natural killer lymphocytes
and then begin the first cycle of high-dose IL-2 (720,000 IU/kg IV every 8 hours for up
to 15 doses). A second cycle of IL-2 will be administered approximately 14 days later.

- Clinical and Immunologic response will be evaluated about 4 to 6 weeks

after the second cycle of IL-2.

-Using a small optimal Phase II design, two cohorts of patients, initially 16 in each
cohort, will be enrolled, and if at least one of the first 16 patients has a clinical
response (partial response (PR) or complete response (CR)), accrual will continue to 29
patients, targeting a 15% goal for objective response.

Inclusion Criteria


1. Patients must have previously received high dose IL-2 (aldesleukin) and have
been either non-responders (progressive disease) or have recurred.

2. Patients who are greater than or equal to 18 years of age, must have measurable
metastatic melanoma or metastatic kidney cancer and no tumor reactive T cells
available for cell transfer therapy.

3. Pathology for metastatic melanoma or metastatic kidney cancer to be confirmed by
the National Cancer Institute (NCI) Laboratory of Pathology.

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

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

6. Absolute neutrophil count greater than 1000/mm^3.

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

8. Hemoglobin greater than 8.0 g/dl.

9. Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than
three times the upper limit of normal.

10. Serum creatinine less than or equal to 1.6 mg/dl.

11. Total bilirubin less than or equal to 2.0 mg/dl, except in patients with
Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.

12. Must be willing to sign a durable power of attorney.


1. Less than four weeks 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.

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. Life expectancy of less than three months.

4. Systemic steroid therapy required.

5. Any active systemic infections, coagulation disorders or other 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.

6. Any form of autoimmune disease (such as autoimmune colitis or Crohn's Disease).

7. 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

8. Seropositive for hepatitis B or C antigen.

9. Seronegative for Epstein-Barr virus (EBV).

10. Patients who are not eligible to receive high-dose Aldesleukin as evaluated by the

1. Patients who are 50 years old or greater who do not have a normal stress cardiac
test (stress thallium, stress multi-gated acquisition scan (MUGA), dobutamine
echocardiogram, or other stress test) will be excluded.

2. Patients who have history of electrocardiogram (EKG) abnormalities, symptoms of
cardiac ischemia or arrhythmias who do not have a normal stress cardiac test
(stress thallium, stress MUGA, dobutamine echocardiogram, or other stress test)
will be excluded.

3. Patients with a prolonged history of cigarette smoking or symptoms of
respiratory dysfunction who do not have a normal pulmonary function test as
evidenced by a forced expiratory volume 1 (FEV1) less than 60% predicted will be

4. Patients who experienced toxicities during prior IL-2 administration that would
preclude redosing with IL-2, i.e. myocardial infarction, mental status changes
requiring intubation, bowel perforation or renal failure requiring dialysis.

Type of Study:


Study Design:

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

Outcome Measure:

Objective Response

Outcome Description:

Objective response (complete response (CR) or partial response (PR)) is measured by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response (CR) is the disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.

Outcome Time Frame:

very 4-6 weeks for up to 1 year, and then every 6 months for up to 5 years.

Safety Issue:



United States: Federal Government

Study ID:




Start Date:

May 2006

Completion Date:

April 2009

Related Keywords:

  • Metastatic Melanoma
  • Metastatic Kidney Cancer
  • Adoptive Cell Therapy
  • Cutaneous Melanoma
  • Clinical Response
  • Rate of Repopulation
  • Toxicity Profile
  • Metastatic Melanoma
  • Metastatic Kidney Cancer
  • Carcinoma, Renal Cell
  • Kidney Neoplasms
  • Melanoma



National Cancer Institute (NCI) Bethesda, Maryland  20892