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T Cell Receptor Immunotherapy Targeting MAGE-A3 for Patients With Metastatic Cancer Who Are HLA-DP0401 Positive

Information source: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Metastatic Cancer That Express the MAGE-A3-DP4 Antigen

Intervention: Anti-MAGE-A3-DP4 TCR (Biological); Cyclophosphamide (Drug); Fludarabine (Drug); Aldesleukin (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Steven A Rosenberg, M.D., Principal Investigator, Affiliation: National Cancer Institute (NCI)

Overall contact:
Ellen Bodurian, Phone: (301) 594-2644, Email: ncisbirc@mail.nih.gov

Summary

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.

Clinical Details

Official title: 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

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

Primary outcome: Determine a safe dose of administration and determine if this approach will result in an objective tumor regression

Detailed description: Background:

- We have constructed a single retroviral vector that contains both and $ <= chains of

a T cell receptor (TCR) that recognizes the DP0401/0402 restricted MAGE-A3 tumor antigen, which can be used to mediate genetic transfer of this TCR with high efficiency.

- In co-cultures with HLA-DP0401/0402 and MAGE-A3 double positive tumors, the anti-

MAGE-A3- DP0401/0402 restricted (anti-MAGE-A3-DP4) TCR transduced T cells secreted significant amounts of IFN-y with high specificity. Objectives: Primary objectives:

- Determine a safe dose of the administration of autologous CD4 cells transduced with an

anti- MAGE-A3-DP0401/0402 restricted (MAGE-A3-DP4) TCR and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen.

- Determine if this approach will result in objective tumor regression in patients with

metastatic cancer expressing MAGE-A3-DP4.

- Determine the toxicity profile of this treatment regimen.

Secondary Objective:

- Determine the in vivo survival of TCR gene-engineered cells.

Eligibility: Patients who are HLA-DP0401/0402 positive and 18 years of age or older must have

- Metastatic cancer whose tumors express the MAGE-A3-DP4 antigen;

- Previously received and have been a non-responder to or recurred following at least one

first line treatment for metastatic disease; Patients may not have:

- Contraindications for high dose aldesleukin administration.

Design:

- PBMC obtained by leukapheresis will be enriched for CD4 cells and transduced with the

retroviral vector supernatant encoding the anti-MAGE-A3-DP4 TCR.

- The study will begin in a standard phase I dose escalation. After the MTD cell dose has

been determined, patients will be enrolled into the phase 2 portion of the trial at the MTD established during the phase I portion of the study. In the phase 2 portion, patients will be entered into two cohorts: cohort 1 will include patients with metastatic melanoma; cohort 2 will include patients with renal cancer and other types of metastatic cancer.

- Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen

consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo tumor reactive, TCR gene-transduced PBMC plus IV aldesleukin.

- Patients will undergo complete evaluation of tumor response every 1-6 months until off

study criteria are met.

- For each of the 2 strata evaluated in the phase 2 portion, the study will be conducted

using a phase II optimal design where initially 21 evaluable patients will be enrolled. For each of these two arms of the trial, if 0 or 1 of the 21 patients experiences a clinical response, then no further patients will be enrolled but if 2 or more of the first 21 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled in that stratum.

- For both strata, the objective will be to determine if the treatment regimen is able to

be associated with a clinical response rate that can rule out 5% (p0=0. 05) in favor of a modest 20% PR + CR rate (p1=0. 20).

Eligibility

Minimum age: 18 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

- INCLUSION CRITERIA

1. 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. 2. 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. 3. Patients must be HLA-DP4 positive. 4. 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. 5. Greater than or equal to 18 years of age and less than or equal to age 70. 6. Able to understand and sign the Informed Consent Document 7. Willing to sign a durable power of attorney 8. Clinical performance status of ECOG 0 or 1 9. Life expectancy of greater than three months 10. 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. 11. 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. 12. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus. 13. Hematology

- Absolute neutrophil count greater than 1000/mm3 without the support of

filgrastim

- WBC greater than or equal to 3000/mm3

- Platelet count greater than or equal to 100,000/mm3

- Hemoglobin > 8. 0 g/dl

14. 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. 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 must have progressing disease after prior treatment. 16. Six weeks must have elapsed from the time of any antibody therapy that could affect an anti cancer immune response, including anti-CTLA4 antibody therapy, so at the time the patient receives the preparative regimen to allow antibody levels to decline. Note: Patients who have previously received ipilimumab and have documented GI toxicity 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 treatment on the fetus or infant. 2. 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. 3. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease). 4. 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). 5. Concurrent systemic steroid therapy. 6. History of severe immediate hypersensitivity reaction to any of the agents used in this study. 7. History of any cardiac events including coronary revascularization or ischemic symptoms. 8. Documented LVEF of less than or equal to 45% testing is required in patients who aregreater than or equal to 60 years old

Locations and Contacts

Ellen Bodurian, Phone: (301) 594-2644, Email: ncisbirc@mail.nih.gov

National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States; Recruiting
For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center, Phone: 866-820-4505, Email: ncisbirc@mail.nih.gov
Additional Information

NIH Clinical Center Detailed Web Page

Related publications:

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. Review.

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.

Starting date: January 2014
Last updated: July 23, 2015

Page last updated: August 23, 2015

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