MAGE-A3/12 Metastatic Cancer Treatment With Anti-MAGE-A3/12 TCR-Gene Engineered Lymphocytes

Study Overview
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Brief Summary
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Background: - MAGE-A3/12 is a type of protein commonly found on certain types of cancer cells, particularly in metastatic cancer. Researchers have developed a process to take lymphocytes (white blood cells) from cancer patients, modify them in the laboratory to target cancer cells that contain MAGE-A3/12, and return them to the patient to help attack and kill the cancer cells. These modified white blood cells are an experimental treatment, but researchers are interested in determining their safety and effectiveness as a possible treatment for cancers that involve MAGE-A3/12. Objectives: - To evaluate the safety and effectiveness of anti-MAGE-A3/12 lymphocytes as a treatment for metastatic cancers that have not responded to standard treatment. Eligibility: - Individuals at least 18 years of age who have been diagnosed with metastatic melanoma, renal cell cancer, or another type of metastatic cancer that has not responded to standard treatment. Design: Participants will be screened with a full medical history and physical examination, as well as blood and urine tests, tumor samples, and imaging studies. Participants will have leukapheresis to collect enough white blood cells for modification in the laboratory. Seven days before the start of anti-MAGE-A3/12 treatment, participants will have chemotherapy with cyclophosphamide and fludarabine to suppress the immune system in preparation for the treatment. After the last dose of chemotherapy, participants will receive the anti-MAGE-A3/12 cells as an infusion for 20 to 30 minutes, followed by a dose of interleukin-2 to keep the anti-MAGE-A3/12 cells alive and active as long as possible. Participants will also receive filgrastim to encourage the production of blood cells. Participants will remain in the hospital to be monitored for possible side effects, and after release from the hospital will have regular followup exams with blood samples and imaging studies to evaluate the effectiveness of the treatment....

Detailed Description
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Background We have constructed a single retroviral vector that contains both alpha and beta chains of a T cell receptor (TCR) that recognizes the MAGE-A3/12 tumor antigen, which can be used to mediate genetic transfer of this TCR with high efficiency (> 30%) without the need to perform any selection. In co-cultures with human leukocyte antigen serotype within HLA-A serotype group (HLA-A2) and MAGE-A3/12 double positive tumors, anti-MAGE-A3/12 TCR transduced T cells secreted significant amounts of Interferon (IFN)-gamma with high specificity. Objectives: Primary objectives: Determine if the administration of anti-MAGE-A3/12 engineered peripheral blood lymphocytes and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic cancer that expresses the MAGE-A3/12 antigen. Determine the toxicity profile of this treatment regimen Secondary objectives: -Determine the in vivo survival of TCR gene-engineered cells. Eligibility: Patients who are human leukocyte antigen (HLA)-A*0201 positive and 18 years of age or older must have: metastatic cancer whose tumors express the MAGE-A3/12 antigen; previously received and have been a non-responder to or recurred following standard care for metastatic disease; Patients may not have: -contraindications for high dose aldesleukin administration. Design: PBMC obtained by leukapheresis (approximately 10^10) cells) will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth. Transduction is initiated by exposure of approximately 10^7 to 5 X 10^8 cells to retroviral vector supernatant containing the anti-MAGE-A3/12 TCR genes. The study will begin by evaluating the safety of two ranges of cells, 5 x 10^9 - 3 x 10^10, and greater than 3 x 10^10- 1 x 10^11 in a standard phase I dose escalation fashion using a 3+3 design. Once this safety has been confirmed, patients will be enrolled into the phase 2 portion of the trial using up to 1 x 10^11 cells. In the phase 2 portion, patients will be entered into two cohorts based on histology: cohort 1 will include patients with metastatic melanoma or renal cell cancer; cohort 2 will include patients with 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 (720,000 IU/kg every (q)8h for a maximum of 15 doses). 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. If the patient has stable disease (SD) or tumor shrinkage, repeat complete evaluations will be performed every 1-3 months. After the first year, patients continuing to respond will continue to be followed with this evaluation every 3-4 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 combination of high dose aldesleukin, lymphocyte depleting chemotherapy, and anti-MAGE-A3/12 TCR-gene engineered lymphocytes 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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Phase I/II Study of Metastatic Cancer That Expresses MAGE-A3/12 Using Lymphodepleting Conditioning Followed by Infusion of Anti-MAGE-A3/12 TCR-Gene Engineered Lymphocytes

Conditions
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Metastatic Cancer, Metastatic Renal Cancer, Metastatic Melanoma

Intervention / Treatment
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* Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes
* Drug: Aldesleukin
* Drug: Cyclophosphamide
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Metastatic cancer that expresses MAGE-A3/12 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-A3/12 per 106 GAPDH copies, or by immunohistochemistry of resected tissue defined as 10% or greater of cells being 2-3+, or serum antibody reactive with MAGE-A3/12. Metastatic cancer diagnosis will be confirmed by the Laboratory of Pathology at the National Cancer Institute (NCI). Patients with melanoma or renal cell cancer must have previously received high dose aldesleukin and have been either non-responders (progressive disease) or have recurred. Patients with other histologies, must have previously received at least one systemic standard care (or effective salvage chemotherapy regimens) for metastatic disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurred. Greater than or equal to 18 years of age. Willing to sign a durable power of attorney Able to understand and sign the Informed Consent Document Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1. Life expectancy of greater than three months. Patients of both genders must be willing to practice birth control for four months after receiving the preparative regimen. Patients must be human leukocyte antigen (HLA)-A*0201 positive 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 hepatitis C antibody unless antigen negative. Hematology: Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim. White blood cell (WBC) (> 3000/mm^3). Platelet count greater than 100,000/mm^3. Hemoglobin greater than 8.0 g/dl. Chemistry: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less 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). EXCLUSION CRITERIA: 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. 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. 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 coronary revascularization or ischemic symptoms Any patient known to have an left ventricular ejection fraction (LVEF) less than or equal to 45%. Documented LVEF of less than or equal to 45% tested in patients with: History of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block Age greater than or equal to 60 years old Documented forced expiratory volume 1 (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

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ph I:Anti-MAGE A3/12 TCR PBL 5x10e9<br>Cyclophosphamide : 60 mg/kg/day x 2 days intravenous (IV) Aldesleukin : 720,000 IU/kg every 8 hours for a maximum of 15 doses PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes : Fludarabine : 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days. Note for phase I: The study will begin by evaluating the safety of two ranges of cells, 5x10^9-3x10^10, and greater than 3x10^10-1x10^11 in a standard phase I dose escalation fashion using a 3+3 design. | Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes<br> <br> Drug: Aldesleukin<br>* 720,000 IU/kg every 8 hours for a maximum of 15 doses<br>* Other names: IL-2;Drug: Cyclophosphamide<br>* 60 mg/kg/day x 2 days intravenous (IV)over 1 hour.<br>Drug: Fludarabine<br>* 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.<br>|
| Experimental: Ph I:Anti-MAGE A3/12 TCR PBL 3x10e10<br>Cyclophosphamide : 60 mg/kg/day x 2 days intravenous (IV) Aldesleukin : 720,000 IU/kg every 8 hours for a maximum of 15 doses PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes : Fludarabine : 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days. Note for phase I: The study will begin by evaluating the safety of two ranges of cells, 5x10^9-3x10^10, and greater than 3x10^10-1x10^11 in a standard phase I dose escalation fashion using a 3+3 design. | Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes<br> <br> Drug: Aldesleukin<br>* 720,000 IU/kg every 8 hours for a maximum of 15 doses<br>* Other names: IL-2;Drug: Cyclophosphamide<br>* 60 mg/kg/day x 2 days intravenous (IV)over 1 hour.<br>Drug: Fludarabine<br>* 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.<br>|
| Experimental: Ph II:Anti-MAGE TCR PBL MTD+HD IL-2<br>Phase II:Anti-MAGE A3/12 TCR PBL MTD + HD IL-2, Melanoma, RCC Cyclophosphamide : 60 mg/kg/day x 2 days intravenous (IV) Aldesleukin : 720,000 IU/kg every 8 hours for a maximum of 15 doses PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes : Fludarabine : 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days. Note for phase II:patients will be entered into two cohorts based on histology:cohort 1 will include patients with metastatic melanoma or renal cell cancer; cohort 2 will include patients with other types of metastatic cancer. | Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes<br> <br> Drug: Aldesleukin<br>* 720,000 IU/kg every 8 hours for a maximum of 15 doses<br>* Other names: IL-2;Drug: Cyclophosphamide<br>* 60 mg/kg/day x 2 days intravenous (IV)over 1 hour.<br>Drug: Fludarabine<br>* 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.<br>|
| Experimental: Ph II:Anti-MAGE A3/12 TCR PBL MTD<br>Phase II: Anti-MAGE A3/12 TCR PBL MTD + HD-IL2 Other Cancer Cyclophosphamide : 60 mg/kg/day x 2 days intravenous (IV) Aldesleukin : 720,000 IU/kg every 8 hours for a maximum of 15 doses PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes : Fludarabine : 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days. Note for phase II:patients will be entered into two cohorts based on histology:cohort 1 will include patients with metastatic melanoma or renal cell cancer; cohort 2 will include patients with other types of metastatic cancer. | Biological: PG13-MAGE-A3 TCR9W11 (anti-MAGE-A3/12 TCR) Transduced Autologous Peripheral Blood Lymphocytes<br> <br> Drug: Aldesleukin<br>* 720,000 IU/kg every 8 hours for a maximum of 15 doses<br>* Other names: IL-2;Drug: Cyclophosphamide<br>* 60 mg/kg/day x 2 days intravenous (IV)over 1 hour.<br>Drug: Fludarabine<br>* 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity Profile | Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module. | 2 years | 
| Clinical Tumor Regression (Complete Response (CR) + Partial Response (PR)) in Patients With Metastatic Cancer | Tumor regression response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is a disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, Gene Therapy, Metastatic Cancer, Clinical Response, Metastatic Melanoma, Metastatic Renal Cell Cancer