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Phase II Study of Metastatic Melanoma Using a Chemoradiation Lymphodepleting Conditioning Regimen Followed by Infusion of Anti-Mart-1 and Anti-gp100 TCR-Gene Engineered Lymphocytes and Peptide Vaccines


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

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Trial Information

Phase II Study of Metastatic Melanoma Using a Chemoradiation Lymphodepleting Conditioning Regimen Followed by Infusion of Anti-Mart-1 and Anti-gp100 TCR-Gene Engineered Lymphocytes and Peptide Vaccines


Background:

- We have engineered human peripheral blood lymphocyte (PBLs) to express a T-cell
receptor (TCR) that recognizes human leukocyte antigens (HLAA*0201) restricted epitopes
derived from the gp100 or the MART-1 melanoma antigen.

- We constructed single retroviral vectors that contain both Alpha and Beta T cell
receptor (TCR) chains and can mediate genetic transfer of this TCR with high efficiency
(greater than 30 percent) without the need to perform any selection.

- In co-cultures with HLA-A*0201 positive melanomas these TCR transduced T cells secreted
significant amount of interferon-gamma (IFN-y) but no significant secretion was
observed in control co-cultures.

- gp100:154-162 TCR or MART-1:27-35 TCR transduced T-cells could efficiently kill
HLAA*0201 positive tumors. There was little or no recognition of normal fibroblasts.

- Adoptive transfer of either of these TCR transferred gene modified peripheral blood
lymphocyte (PBL) following a nonmyeloablative lymphodepleting regimen could mediate
tumor regression in from 13-30 percent of patients with metastatic melanoma though no
complete responses were seen.

Objectives:

Primary objectives:

- In cohort 1 and 2, to determine if the administration of both the anti-gp100:154-162
TCR-engineered and anti- MART-1:27-35 TCR-engineered peripheral blood lymphocytes
(PBL), aldesleukin and either the gp100:154-162 peptide or the MART-1:26-35(27L)
peptide to patients following a chemoradiation lymphodepleting preparative regimen will
result in complete tumor regression in patients with metastatic melanoma.

- In cohort 3 and 4, to determine if the administration of both the anti-gp100:154-162
TCR-engineered and anti-MART-1:27-35 TCR-engineered CD8+ peripheral blood lymphocytes
(PBL), aldesleukin and either the gp100:154-162 peptide or the MART-1:26-35(27L)
peptide to patients following a chemoradiation lymphodepleting preparative regimen will
result in complete tumor regression in patients with metastatic melanoma.

- Determine whether the administration of the specific vaccine (the gp100:154-162 peptide
or the MART-1:26-35(27L) peptide) can increase the persistence of the specific
transferred cells (anti-gp100:154-162 TCR PBL, anti-gp100:154-162 TCR CD8+ PBL, the
anti-MART- 1:27-35 TCR PBL, or the anti-MART-1:27-35 TCR CD8+ PBL), respectively.

Secondary objectives:

- Determine the toxicity profile of these treatment regimen.

Eligibility:

Patients who are HLA-A*0201 positive and 18 years of age or older must have:

- metastatic melanoma with measurable disease

- been previously treated with IL-2 for melanoma;

- normal values for basic laboratory values.

Patients may not have:

- concurrent major medical illnesses;

- any form of primary or secondary immunodeficiency;

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

- contraindications for high dose aldesleukin administration.

Design:

- In cohort 1 and 2:

- Peripheral blood mononuclear cells (PBMC) will be obtained by leukapheresis
(approximately 5 times 10(9) cells) and cultured in the presence of anti-CD3
(OKT3) and aldesleukin and separate aliquots will be transduced with the
anti-gp100:154-162 TCR and the anti-MART-1:27-35 TCR retroviral vector.

- Transduction is initiated by exposure of approximately 10(8) to 5 times 10(8)
cells to supernatant containing the retroviral vectors. These gp100 and MART-1 TCR
transduced cells will be separately expanded and tested for their anti-tumor
activity.

- Once engineered lymphocytes are demonstrated to be biologically active according
to the strict criteria outlined in the Certificate of Analysis, patients will
receive a chemoradiation lymphocyte depleting preparative regimen consisting of
cyclophosphamide and fludarabine and 600 cGy total body irradiation followed by
intravenous infusion of ex vivo tumor reactive, gp100 and MART-1 TCR
gene-transduced cells plus IV aldesleukin (720,000 IU/kg q8h for a maximum of 15
doses).

- Patients will be randomized to receive either the gp100:154-162 peptide or the
MART-1:26-35(27L) peptide emulsified in incomplete Freund's adjuvant.

- Patients will undergo complete evaluation of tumor with physical examination,
computed tomography (CT) of the chest, abdomen and pelvis and clinical laboratory
evaluation four to six weeks after treatment and then monthly for approximately 3
to 4 months or until off study criteria are met.

- The study will be conducted using a phase II optimal design where initially 21
evaluable patients will be enrolled into each of two cohorts. If none of the 21
patients per cohort experiences a complete clinical response, then no further
patients will be enrolled but if 1 or more of the first 21 evaluable patients
enrolled in that cohort have a complete clinical response, then accrual to that
cohort will continue until a total of 41 evaluable patients have been enrolled in
that cohort.

- Cohort 1 and 2 will be closed with the approval of amendment D.

- Cohort 3 and 4 will be initiated with approval of amendment D.

- Peripheral blood mononuclear cells (PBMC) will be obtained by leukapheresis
(approximately 5 times 10(9) cells) and CD8+ cells will be selected from the
cultures, using the Miltenyi CliniMACS apparatus, prior to being stimulated and
transduced. Separate aliquots of CD8+ cells will be transduced with the
anti-gp100:154-162 TCR and the anti-MART-1:27-35 TCR retroviral vectors.

- Transduction is initiated by exposure of approximately 10(8) to 5 times 10(8) CD8+
cells to supernatant containing the retroviral vectors. These gp100 and MART-1 TCR
transduced cells will be separately expanded and tested for their anti-tumor
activity.

- Once engineered lymphocytes are demonstrated to be biologically active according
to the strict criteria outlined in the Certificate of Analysis, patients will
receive a chemoradiation lymphocyte depleting preparative regimen consisting of
cyclophosphamide and fludarabine and 600 cGy total body irradiation followed by
intravenous infusion of ex vivo tumor reactive, gp100 and MART-1 TCR
gene-transduced CD8+ cells plus IV aldesleukin (720,000 IU/kg q8h for a maximum of
15 doses).

- Patients will be randomized to receive either the gp100:154-162 peptide (cohort 3)
or the MART-1:26-35(27L) peptide (cohort 4) emulsified in incomplete Freund's
adjuvant.

- Patients will undergo complete evaluation of tumor with physical examination, CT
of the chest, abdomen and pelvis and clinical laboratory evaluation four to six
weeks after treatment and then monthly for approximately 3 to 4 months or until
off study criteria are met.

- The study will be conducted using a phase II optimal design where initially 21
evaluable patients will be enrolled into each of cohort 3 and 4. If none of the 21
patients per cohort experiences a complete clinical response, then no further
patients will be enrolled but if 1 or more of the first 21 evaluable patients
enrolled in that cohort have a complete clinical response, then accrual to that
cohort will continue until a total of 41 evaluable patients have been enrolled in
that cohort.

Inclusion Criteria


- INCLUSION CRITERIA:

1. Metastatic melanoma with measurable disease.

2. Previously received aldesleukin (IL-2) and have been either non-responders
(progressive disease) or have recurred.

3. Positive for gp100 and melanoma antigen recognized by T-cells (MART-1) (at least
1 plus and greater than 5 percent) as assessed by immunohistochemistry (IHC) in
the Clinical Laboratory Improvement Amendments (CLIA) approved test in the
Laboratory of Pathology, Center for cancer Research (CCR), National Cancer
Institute (NCI), National Institutes of Health (NIH).

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

5. Willing to sign a durable power of attorney.

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

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

8. Life expectancy of greater than three months.

9. Patients of both genders must be willing to practice birth control from the time
of enrollment on this study and for up to four months after receiving the
preparative regimen.

10. Must be human leukocyte antigens (HLA-A*0201) positive

11. Serology:

1. 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.)

2. Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen
negative.

l. Hematology:

1. Absolute neutrophil count greater than 1000/m^3

2. White blood cell (WBC) (greater than 3000/mm^3.

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

4. Hemoglobin greater than 8.0 g/dl.

m. Chemistry

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

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

3. Total bilirubin less than or equal to 1.5 mg/dl, except in patients with
Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.

n. Women of child-bearing potential must have a negative pregnancy test because of
the potentially dangerous effects of the preparative chemotherapy on the fetus.

o. 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).

p. Six weeks must have elapsed since prior anti-CTLA4 (cytotoxic T-lymphocyte antigen
4) antibody therapy to allow antibody levels to decline, and patients who have
previously received anti-CTLA4 antibody 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. Active systemic infections; coagulation disorders or other major medical illnesses of
the cardiovascular, respiratory or immune system; myocardial infarction; cardiac
arrhythmias; obstructive or restrictive pulmonary disease.

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

4. Systemic steroid therapy.

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

6. History of coronary revascularization

7. Documented left ventricular ejection fraction (LVEF) of less than 45 percent in
patients with:

a) Clinically significant atrial and/or ventricular arrhythmias including but not limited
to: atrial fibrillation, ventricular tachycardia, 2 degree or 3 degree heart block

b) Age greater than or equal to 60 years old

h. Documented forced expiratory volume 1 (FEV1) less than or equal to 60 percent predicted
for patients with:

1. A prolonged history of cigarette smoking (greater than 20 pack/year within the past 2
years)

2. Symptoms of respiratory distress

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Complete Response Rates for Patients With Metastatic Melanoma

Outcome Description:

Complete response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response is a disappearance of all target lesions. Partial response 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 is 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 is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum LD.

Outcome Time Frame:

Every 4-6 weeks after initial treatment regimen. If the patient has stable disease or tumor shrinkage, complete evaluations will be repeated every 1-3 months.

Safety Issue:

No

Principal Investigator

Steven Rosenberg, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health

Authority:

United States: Federal Government

Study ID:

090051

NCT ID:

NCT00923195

Start Date:

December 2008

Completion Date:

August 2011

Related Keywords:

  • Melanoma
  • Skin Cancer
  • Metastatic Melanoma
  • Tumor Regression
  • Safety
  • Immunotherapy
  • Skin Neoplasms
  • Melanoma

Name

Location

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