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Protocol Details

Phase I/II Study of the Treatment of Metastatic Cancer that Expresses MAGE-A3 Using Lymphodepleting Conditioning Followed by Infusion of HLA-DP0401/0402 Restricted Anti-MAGE-A3 TCR-Gene Engineered Lymphocytes and Aldesleukin

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

14-C-0052

Sponsoring Institute

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 18
Max Age: 70

Referral Letter Required

No

Population Exclusion(s)

Children

Special Instructions

Currently Not Provided

Keywords

Gene Therapy;
Tumor Regression;
Immunotherapy;
Adoptive Cell Therapy

Recruitment Keyword(s)

None

Condition(s)

Cervical Cancer;
Renal Cancer;
Urothelial Cancer;
Melanoma;
Breast Cancer

Investigational Drug(s)

Anti-MAGE-A3-DP4 TCR PBL

Investigational Device(s)

None

Intervention(s)

Biological/Vaccine: Anti-MAGE-A3-DP4 TCR
Drug: Cyclophosphamide
Drug: Fludarabine
Drug: Aldesleukin

Supporting Site

National Cancer Institute

Background:

The NCI Surgery Branch has developed an experimental therapy for treating patients with metastatic cancer that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. In this protocol, we are modifying the patient s white blood cells with a retrovirus that has the gene for anti-MAGE-A3-DP0401/0402 incorporated in the retrovirus.

Objective:

The purpose of this study is to determine a safe number of these cells to infuse and to see if these particular tumor-fighting cells (anti-MAGE-A3-DP0401/0402 cells) cause tumors to shrink and to be certain the treatment is safe.

Eligibility:

- Adults age 18-70 with metastatic cancer expressing the MAGE-A3 molecule.

Design:

-Work up stage: Patients will be seen as an outpatient at the NIH clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed

-Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti-MAGE-A3-DP0401/0402 cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.}

-Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the anti-MAGE-A3-DP0401/0402 cells and aldesleukin. They will stay in the hospital for approximately 4 weeks for the treatment.

-Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking.

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Eligibility

INCLUSION CRITERIA:

a. Metastatic or locally advanced refractory/recurrent cancer that expresses MAGE-A3 as assessed by one of the following methods: RT-PCR on tumor tissue defined as 30,000 copies of MAGE-A3 per 10^6 GAPDH copies, or by immunohistochemistry of resected tissue defined as 10% or greater of tumor cells being 2-3+ for MAGE-A3, or serum antibody reactive with MAGE-A3. Metastatic cancer diagnosis will be confirmed by the Laboratory of Pathology at the NCI.

b. Patients must have previously received prior first line standard therapy (or effective salvage chemotherapy regimens) for their disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurred.

c. Patients must be HLA-DP4 positive.

d. Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.

e. Greater than or equal to 18 years of age and less than or equal to age 70.

f. Ability of subject to understand and the willingness to sign the Informed Consent Document.

g. Willing to sign a durable power of attorney

h. Clinical performance status of ECOG 0 or 1

i. 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 treatment.

j. Serology:

- Seronegative for 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 antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.

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

l.Hematology

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

- WBC greater than or equal to 3000/mm^3

- Platelet count greater than or equal to 100,000/mm^3

- Hemoglobin > 8.0 g/dl

m. Chemistry:

- Serum ALT/AST less than 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 1.5 mg/dl, except in patients with Gilbert s Syndrome who must have a total bilirubin less than 3.0 mg/dl.

n. 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 must have

progressing disease after prior treatment. Note: Patients who have previously received ipilimumab and have documented GI toxicity must have a normal colonoscopy with normal colonic biopsies.

o. Subjects must be co-enrolled in protocol 03-C-0277.

EXCLUSION CRITERIA:

a. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.

b. Active systemic infections, (e.g.: requiring anti-infective treatment), coagulation disorders or any other active major medical illnesses

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

d. Concurrent 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).

e. Concurrent systemic steroid therapy.

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

g. History of any cardiac events including coronary revascularization or ischemic symptoms.

h. Documented LVEF of less than or equal to 45% testing is required in patients who are

--greater than or equal to 65 years old

--Clinically significant atrial and or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or have a history of ischemic heart disease, or chest pain.

i. Documented FEV1 less than or equal to 60% predicted tested in patients with:

-- A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2 years).

-- Symptoms of respiratory dysfunction

j. Patients who are receiving any other investigational agents.


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Citations:

Morgan RA, Dudley ME, Yu YY, Zheng Z, Robbins PF, Theoret MR, Wunderlich JR, Hughes MS, Restifo NP, Rosenberg SA. High efficiency TCR gene transfer into primary human lymphocytes affords avid recognition of melanoma tumor antigen glycoprotein 100 and does not alter the recognition of autologous melanoma antigens. J Immunol. 2003 Sep 15;171(6):3287-95.

Suri A. Cancer testis antigens--their importance in immunotherapy and in the early detection of cancer. Expert Opin Biol Ther. 2006 Apr;6(4):379-89.

Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, Wunderlich JR, Nahvi AV, Helman LJ, Mackall CL, Kammula US, Hughes MS, Restifo NP, Raffeld M, Lee CC, Levy CL, Li YF, El-Gamil M, Schwarz SL, Laurencot C, Rosenberg SA. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011 Mar 1;29(7):917-24. doi: 10.1200/JCO.2010.32.2537. Epub 2011 Jan 31.

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Contacts:

Principal Investigator

Referral Contact

For more information:

Steven A. Rosenberg, M.D.
National Cancer Institute (NCI)
BG 10-CRC RM 3-3940
10 CENTER DR
BETHESDA MD 20814
(866) 820-4505
sar@mail.nih.gov

Abigail R. Johnson, R.N.
National Cancer Institute (NCI)
National Institutes of Health
Building 10
Room 2-1730
10 Center Drive
Bethesda, Maryland 20892
(301) 496-2132
ncisbirc@mail.nih.gov

Recruitment Center - SB
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Building 10, Room 2-1730, Bethesda, Maryland 20892, United States
(866) 820-4505
ncisbirc@mail.nih.gov

Clinical Trials Number:

NCT02111850

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