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

Study Overview
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Brief Summary
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Background: The National Cancer Institute (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-Melanoma antigen family A, 3 (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: - Adult's age 18-70 with metastatic cancer expressing the MAGE-A3 molecule. Design: Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (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.

Detailed Description
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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 Melanoma antigen family A, 3 (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 Interferon gamma (IFN-y) with high specificity. Objectives: Primary objectives: Determine a safe dose of the administration of autologous cluster of differentiation 4 (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. Eligibility: Patients who are human leukocyte antigens (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 1 dose escalation. After the maximum tolerated dose (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 1 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 peripheral blood mononuclear cells (PBMC) plus intravenous (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 2 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% partial response (PR) + complete response (CR) rate (p1=0.20).

Official Title
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A 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

Conditions
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Melanoma, Cervical Cancer, Renal Cancer, Urothelial Cancer, Breast Cancer

Intervention / Treatment
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* Biological: Anti-MAGE-A3-DP4 T Cell Receptor (TCR) Peripheral Blood Lymphocytes (PBL)
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Aldesleukin


Participation Criteria
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Eligibility Criteria
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-INCLUSION CRITERIA: Metastatic or locally advanced refractory/recurrent cancer that expresses Melanoma antigen family A, 3 (MAGE-A3) as assessed by one of the following methods: Reverse transcription polymerase chain reaction (RT-PCR) on tumor tissue defined as 30,000 copies of MAGE-A3 per 10^6 glyceraldehyde 3-phosphate dehydrogenase (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 National Cancer Institute (NCI). 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. Patients must be human leucocyte antigen (HLA)-DP4 positive. Patients with 3 or fewer brain metastases that are less than 1 centimeter (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. Greater than or equal to 18 years of age and less than or equal to age 70. Ability of subject to understand and the willingness to sign the Informed Consent Document. Willing to sign a durable power of attorney Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1 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. 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 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 hepatitis C hepatitis C virus (HCV) ribonucleic acid (RNA) negative. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus. Hematology Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim White blood cell (WBC) greater than or equal to 3000/mm^3 Platelets count greater than or equal to 100,000/mm^3 Hemoglobin > 8.0 g/dl Chemistry: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (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. 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 gastrointestinal (GI) toxicity must have a normal colonoscopy with normal colonic biopsies. Subjects must be co-enrolled in protocol 03-C-0277. EXCLUSION CRITERIA: Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant. Active systemic infections, (e.g.: requiring anti-infective treatment), coagulation disorders or any other active major medical illnesses Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease). 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). Concurrent systemic steroid therapy. History of severe immediate hypersensitivity reaction to any of the agents used in this study. History of any cardiac events including coronary revascularization or ischemic symptoms. Documented left ventricular ejection fraction (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. Documented forced expiratory volume (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 Patients who are receiving any other investigational agents.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/Phase I Experimental Therapy<br>Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Anti-Melanoma antigen family A, 3 (MAGE-A3)-DP4 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + high-dose aldesleukin | Biological: Anti-MAGE-A3-DP4 T Cell Receptor (TCR) Peripheral Blood Lymphocytes (PBL)<br>* Day 0: cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes<br>Drug: Cyclophosphamide<br>* Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5 % in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hour.<br>* Other names: Cytoxan;Drug: Fludarabine<br>* Days -7 to -3: Fludarabine 25 mg/m^2 /day intravenous piggy-back (IVPB) daily over 30 minutes for 5 days.<br>* Other names: Fludara;Drug: Aldesleukin<br>* Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).<br>* Other names: Proleukin;|
| Experimental: 2/Phase II Experimental Therapy<br>Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Anti-Melanoma antigen family A, 3 (MAGE-A3)-DP4 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + high-dose aldesleukin | Biological: Anti-MAGE-A3-DP4 T Cell Receptor (TCR) Peripheral Blood Lymphocytes (PBL)<br>* Day 0: cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes<br>Drug: Cyclophosphamide<br>* Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5 % in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hour.<br>* Other names: Cytoxan;Drug: Fludarabine<br>* Days -7 to -3: Fludarabine 25 mg/m^2 /day intravenous piggy-back (IVPB) daily over 30 minutes for 5 days.<br>* Other names: Fludara;Drug: Aldesleukin<br>* Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).<br>* Other names: Proleukin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Cell Dose (MTD) of Cluster of Differentiation 4 (CD4) Cells Transduced With an Anti-MAGE-A3-DP0401/0402 Restricted (MAGE-A3-DP4) T Cell Receptor and Aldesleukin | Highest dose at which less than or equal to 1 of 6 patients experienced a dose-limiting toxicity (DLT) (all grade 3 and greater toxicities with the exception of myelosuppression and grade 3 fever, for example) or the highest dose level studied if DLTs are not observed at any of the dose levels. | Before progression to next-higher dose level, at least two weeks | 
| Percentage of Participants Who Have a Clinical Response to Treatment (Objective Tumor Regression) | Percentage of participants who have a clinical response to treatment (objective tumor regression) measured by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.0. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter of target lesions. Progression is at least a 20% increase in the sum of longest diameter of target lesions or the appearance of one or more new lesions. And stable disease is neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. | 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x2 years, then per principal investigator discretion, approximately 6 years | 
| Number of Adverse Events With Grades ≥1 That Are Possibly, Probably, and/or Definitely Related to Treatment | Aggregate of all adverse events with Grades ≥1 that are possibly, probably, and/or definitely related to treatment. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse events. | 6 weeks after cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Engineered T Cell Receptor (TCR) Cells That Survived at 4 Weeks | T cell receptor (TCR) and vector presence was quantitated in peripheral blood mononuclear cells (PBMC) samples using flow cytometry. It is a process by which cells are suspended in a liquid so they can be counted. | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gene Therapy, Tumor Regression, Immunotherapy, Adoptive Cell Therapy