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Phase II Study in Patients With Metastatic Melanoma Using a Non-Myeloablative Lymphocyte Depleting Regimen of Chemotherapy Followed by Infusion of gp100 Reactive Peripheral Blood Lymphocytes (PBL) and High or Low Dose Aldesleukin


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

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Trial Information

Phase II Study in Patients With Metastatic Melanoma Using a Non-Myeloablative Lymphocyte Depleting Regimen of Chemotherapy Followed by Infusion of gp100 Reactive Peripheral Blood Lymphocytes (PBL) and High or Low Dose Aldesleukin


Background:

- Tumor infiltrating lymphocytes (TIL) transfer studies in patients with metastatic
melanoma following lymphodepletion have resulted in 50% objective response rates with a
10-15% rate of complete responses.

- Pre-clinical and clinical studies of adoptive immunotherapy have suggested that
effective lymphocytes for transfer have high avidity for the target antigen, undergo
limited in vitro antigen and IL-2 stimulation, and have high expression of cluster of
differentiation 27+ (CD27+).

- We have developed a novel in vitro strategy using high throughput polymerase chain
reaction (PCR) screening to rapidly isolate low frequency antigen specific cluster of
differentiation 8+ (CD8+) T cells from the peripheral blood repertoire that have these
characteristics, and that recognize the gp100:154-162 epitope, an abundantly expressed
melanoma antigen, presented by human leukocyte antigens (HLAA2) on the tumor surface.

- The current proposed transfer of gp100:154-162 reactive lymphocytes administered in
conjunction with a lymphodepleting preparative regimen and aldesleukin would represent
a significantly novel approach to adoptive immunotherapy.

Objectives:

- To determine whether gp100:154-162 reactive cluster of differentiation 4+ (CD4+) T cell
depleted lymphocytes infused in conjunction with the administration of high-dose
aldesleukin or low-dose aldesleukin may result in clinical tumor regression in patients
with metastatic melanoma receiving a non-myeloablative lymphoid depleting preparative
regimen.

- To evaluate the safety of the treatment in patients receiving the non-myeloablative
conditioning regimen, cell transfer, and high-dose or low-dose aldesleukin.

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

Eligibility:

-Patients with refractory metastatic melanoma who are greater than or equal to 18 years of
age, are HLA-A2+, who have gp100:154-162 reactive peripheral blood lymphocytes available and
are physically able to tolerate non-myeloablative chemotherapy. Patients must be refractory
to prior high dose aldesleukin treatment if they are medically eligible to receive it.
Patients who can tolerate high-dose aldesleukin will receive it with cell infusion; those
who cannot tolerate high-dose will receive low-dose aldesleukin.

Design:

- Patients will receive a non-myeloablative lymphocyte depleting preparative regimen
consisting of cyclophosphamide (60 mg/kg/day X 2 days intravenous (IV)), fludarabine
(25 mg/m^2/day IV X 5 days).

- Patients will receive intravenous adoptive transfer of gp100:154-162 reactive
peripheral blood lymphocytes (minimum 1 X 10^9) and up to a maximum of 3 X 10^11)
lymphocytes) followed by high-dose intravenous (IV) aldesleukin (720,000 IU/kg/dose
every 8 hours for up to 15 doses) or low-dose subcutaneous (SQ) aldesleukin (125,000 IU
IL-2/kg/dose for 5 days for 6 weeks with 2 days rest per week).

- A complete evaluation of evaluable lesions will be conducted 4-6 weeks after the last
dose of aldesleukin in the high dose arm and 2-4 weeks after the last dose of
aldesleukin in the low dose arm. Patients will be enrolled into two cohorts. The cohort
receiving high dose aldesleukin will be conducted 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. For
the cohort who will receive low dose aldesleukin, the study will be conducted as a
Minimax two-stage phase II trial. Initially 12 evaluable patients will be enrolled to
this cohort, and if 1 or more the first 12 have a response, then accrual would continue
until a total of 21 patients, targeting a 20% goal for objective response.

Inclusion Criteria


-INCLUSION CRITERIA:

1. Measurable metastatic melanoma. The diagnosis of metastatic melanoma and positivity
for gp100 will be confirmed by the Laboratory of Pathology of the the National Cancer
Institute (NCI).

2. Patients must be refractory to high dose aldesleukin treatment if they are medically
eligible to receive it. Patients with noncutaneous melanoma are not required to be
refractory to high dose aldesleukin.

3. gp100:154-162 reactive peripheral blood lymphocytes derived from a

leukapheresis.

4. HLA-A*0201 positive.

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

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

7. Life expectancy of greater than three months.

8. Willing to sign a durable power of attorney.

9. Able to understand and sign the Informed Consent Document.

10. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1 for
the high dose aldesleukin cohort or ECOG 0, 1 or 2 for the low dose aldesleukin
cohort.

11. 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.

12. 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.

13. Chemistry:

- Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than
less or equal to 2.5 times the upper limit of normal.

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

- Total bilirubin less than or equal to 2.0 mg/dl, except in patients with
Gilbert's Syndrome who must have a total bilirubin less than 3 mg/dl.

14. Negative pregnancy test in women of child bearing potential because of the
potentially dangerous effects of the preparative chemotherapy on the fetus.

15. 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 within 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.

16. Six weeks must have elapsed since prior cytotoxic T-lymphocyte antigen 4 (anti-CTLA4)
antibody therapy to allow antibody levels to decline.

17. Patients who have previously received anti-CTLA4 antibody and experienced treatment
must have a normal colonoscopy with normal colonic biopsies.

EXCLUSION CRITERIA:

1. 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.

2. Systemic steroid therapy required.

3. For patients receiving high dose IL-2 only: 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.

4. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease).

5. 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.)

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

7. The following patients will be excluded from the high-dose IL-2 arm (but will be
eligible for the low-dose arm):

1. History of coronary revascularization or ischemic symptoms

2. Any patient known to have an left ventricular ejection fraction (LVEF) less than
or equal to 45%.

3. 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

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

- A prolonged history of cigarette smoking (20 pk/yrs of 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:

Response

Outcome Description:

Response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is a 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. Progression (PD) is at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD.

Outcome Time Frame:

30 months

Safety Issue:

No

Principal Investigator

Joohee Sul, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

080104

NCT ID:

NCT00665470

Start Date:

April 2008

Completion Date:

April 2012

Related Keywords:

  • Skin Cancer
  • Metastatic Melanoma
  • Malignant Melanoma
  • HLA-A2
  • Immunotherapy
  • Clinical Response
  • Skin Cancer
  • Skin Neoplasms
  • Melanoma

Name

Location

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