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T Cell Receptor Immunotherapy Targeting MAGE-A3 for Patients With Metastatic Cancer Who Are HLA-A*01 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; Metastatic Melanoma

Intervention: Aldesleukin (Drug); Fludarabine (Drug); Cyclophosphamide (Drug); Anti-MAGE-A3 HLAA* 01-restricted TCR (Biological)

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:
Jessica G Yingling, R.N., Phone: (866) 820-4505, Email: ncisbirc@mail.nih.gov

Summary

Background: The NCI Surgery Branch has developed an experimental therapy for treating patients with 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 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 cells) cause tumors to shrink and to be certain the treatment is safe Eligibility:

- Adults age 18-66 with 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 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 cells and aldesleukin. They will stay in the hospital for about 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. Follow up visits take up to 2 days.

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 Anti-MAGE-A3 HLA-A*01 Restricted 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 safety and objective response rate of administration of autologous T cells transduced with an anti- MAGE-A3 HLA-A*01-restricted TCR (MAGE-A3-01) TCR and aldesleukin

Detailed description: Background:

- We have constructed a single retroviral vector that contains both alpha and beta chains

of a T cell receptor (TCR) that recognizes the HLA-A 01 restricted MAGE-A3 tumor antigen, which can be used to mediate genetic transfer of this TCR with high efficiency.

- In co-cultures with HLA-A 01 and MAGE-A3 double positive tumors, the anti-MAGE-A3- A 01

restricted (anti-MAGE-A3-01) TCR transduced T cells secreted significant amounts of IFN- >= with high specificity. Objectives: Primary objectives:

- Determine a safe dose of administration of autologous T cells transduced with an anti-

MAGE-A3 HLA-A 01-restricted TCR (MAGE-A3-01) 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.

- 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-A 01 positive and 18 years of age or older must have:

- Metastatic cancer whose tumors express the MAGE-A3 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 transduced with the retroviral vector

supernatant encoding the anti-MAGE-A3 HLA-A 01-restricted TCR.

- The study will begin with a 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 modes 20% PR + CR rate (p1=0. 20).

- In order to complete the dose escalation phase and both phase 2 cohorts, a total of up

to 20+82=102 patients may be required (20 + 2 strata with a maximum of 41 apiece). Up to 6 patients enrolled at the MTD will count towards the accrual in the appropriate phase 2 strata if they are evaluable for response and if they would be fully eligible for enrollment in the phase 2 portion of the trial. Provided that about 4-5 patients per month will be able to be enrolled onto this trial, approximately 2 to 3 years may be needed to accrue the maximum number of required patients.

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 106 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-A*01 positive. 4. Greater than or equal to 18 years of age and less than or equal to age 70. 5. Able to understand and sign the Informed Consent Document 6. Willing to sign a durable power of attorney 7. Clinical performance status of 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 treatment. 10. 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. 11. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus. 12. 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

13. Chemistry:

- Serum ALT/AST less than or equal to to 2. 5 times the upper limit of normal

- Serum creatinine less than or equal to to 1. 6 mg/dl

- Total bilirubin less than or equal to to 1. 5 mg/dl, except in patients with

Gilbert s Syndrome who must have a total bilirubin less than 3. 0 mg/dl. 14. 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. 15. 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, 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 are:

- - Age greater than or equal to 60 years old

9. Patients with CNS metastases or symptomatic CNS involvement (including cranial neuropathies or mass lesions). 10. Patients presenting with lesions that may harbor an occult infectious source.

Locations and Contacts

Jessica G Yingling, R.N., Phone: (866) 820-4505, 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.

Johnson LA, Morgan RA, Dudley ME, Cassard L, Yang JC, Hughes MS, Kammula US, Royal RE, Sherry RM, Wunderlich JR, Lee CC, Restifo NP, Schwarz SL, Cogdill AP, Bishop RJ, Kim H, Brewer CC, Rudy SF, VanWaes C, Davis JL, Mathur A, Ripley RT, Nathan DA, Laurencot CM, Rosenberg SA. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood. 2009 Jul 16;114(3):535-46. doi: 10.1182/blood-2009-03-211714. Epub 2009 May 18.

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: May 2014
Last updated: August 5, 2015

Page last updated: August 23, 2015

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