T Cell Receptor Gene Therapy Targeting KK-LC-1 for Gastric, Breast, Cervical, Lung and Other KK-LC-1 Positive Epithelial Cancers

Study Overview
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Brief Summary
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Background: Researchers have found a new way to treat cancer using T cell therapy. The therapy used in this study is T Cell Receptor (TCR) Gene Therapy Targeting KK-LC-1, a cancer germline antigen that is expressed by certain cancers. This therapy is a type of treatment in which a participant s T cells (a type of immune system white blood cell) are changed in the laboratory to attack cancer cells and given back to the participant. This treatment might help people with KK-LC-1 positive cancers which may include gastric, breast, cervical, lung and other epithelial Cancers. Epithelial cancers are cancers that begin in the cells that line an organ. Objective: The purpose of this study is to determine the safety of different doses of KK-LC-1 TCR T cells plus aldesleukin to treat metastatic or refractory/recurrent KK-LC-1 positive cancers. Eligibility: Adults aged 18 and older with metastatic or refractory/recurrent KK-LC-1 positive epithelial cancer. Design: Participants will be screened with HLA typing (a blood test needed for eligibility) and KK-LC-1 testing of the cancer tumor (to determine if the cancer is KK-LC-1 positive). A new biopsy may be needed if tumor from an outside location is not available for KK-LC-1 testing. Eligible participants will come to the NIH campus to have a screening evaluation which will include physical exam, review of medical history and current medications, blood and heart tests, imaging (X-ray, CT scan, MRI or PET scan), and evaluation of participant s veins that are used for drawing blood. If the participant is eligible for the study based on the screening evaluation, they will have a baseline evaluation prior to receiving the experimental treatment which may include additional laboratory or imaging tests. Participants will have a large IV catheter inserted into a vein to undergo a procedure called leukapheresis. Leukapheresis is the removal of the blood by a machine to collect specific white blood cells. The remaining blood is returned to the body. This procedure is needed to collect the cells that will be modified to target the cancer. The cells are grown in the lab and given back to the participant through an injection into the participant's tumor. It takes 11-15 days to grow the cells. While the cells are growing, the participant will be admitted to the hospital about one week before the cell infusion to receive 2 types of chemotherapy through an IV catheter over 5 days. The main purpose of the chemotherapy is to make the cells more effective in fighting the cancer tumors. The cells will be given 1-2 days after the last dose of chemotherapy. Within 24 hours after the cell infusion, participants will be given a cell growth factor called aldesleukin through an IV for up to 4 days. Aldesleukin is thought to help the cells live longer in the participant s body. Participants will recover in the hospital until they are well enough to go home, which is usually about 7-12 days after the cell infusion or last dose of aldesleukin. Participants will have a follow-up visit at approximately 40 days after the date of cell infusion. This visit will be to evaluate the safety of the cell therapy and the response of the cancer to the treatment which will include physical examination, lab tests, and imaging studies. If a participant has stable disease or their cancer has responded to the treatment, they will be seen again at 12 weeks post cell infusion, every 3 months x 3 visits, and then every 6 months x 5 years. If a participant s cancer progresses after this therapy, they will be return to their home doctor for further management. After receiving cell therapy, participants will be followed on a long-term gene therapy protocol. Participants will have blood drawn periodically to test if the cells have grown or changed. These blood tests will take place immediately before the cells, and then at 3, 6, and 12 months for the first year and possibly annually thereafter based on the results. These tests can be drawn locally and sent to the NIH. After a participant is off the study, they will be contacted by telephone or mailed questionnaire for a total of 15 years after cell therapy....

Detailed Description
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Background: KK-LC-1 is a cancer germline (CG) antigen with expression restricted to germ cells (which lack MHC class I expression) in adults and epithelial cancers including lung, breast and gastric. This limited expression pattern makes it an ideal target for T Cell Receptor (TCR) gene therapy. TCR T cell therapy targeting CG antigens has been shown to induce objective responses without autoimmunity or off-target toxicity in participants with melanoma, synovial sarcoma and cervical cancer T cells genetically engineered with a TCR targeting KK-LC-1 display specific reactivity against HLA-A01:01, KK-LC-1 target cells. KK-LC-1 TCR T cells can mediate tumor regression in pre-clinical mouse models of cancer Objective: To determine the maximally tolerated dose of KK-LC-1 TCR T cells plus aldesleukin for the treatment of metastatic KK-LC-1 positive epithelial cancers. Eligibility: Participants greater than or equal to 18 years old with metastatic or refractory/recurrent KK-LC-1 positive epithelial cancer. Prior first line systemic therapy is required unless the participant declines standard treatment. Participants must be HLA-A-01:01-positive. Design: This is a phase I clinical trial that will test the safety and efficacy of escalating doses of KK-LC-1 TCR T cells. Participants will receive a non-myeloablative lymphocyte-depleting preparative regimen of cyclophosphamide and fludarabine followed by a single infusion of KK-LC-1 TCR T cells and high-dose aldesleukin. Re-treatment will be allowed for a small number of subjects

Official Title
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A Phase I Trial of T Cell Receptor Gene Therapy Targeting KK-LC-1 for Gastric, Breast, Cervical, Lung and Other KK-LC-1 Positive Epithelial Cancers

Conditions
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Kita-kyushu Lung Cancer Antigen 1, Human

Intervention / Treatment
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* Drug: IL-2 (Aldesleukin)
* Drug: Cyclophosphamide
* Biological: KK-LC-1 TCR
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Participants must have histologically or cytologically confirmed KK-LC-1 positive epithelial cancer (KK-LC-1 positivity assay performed at Rutgers Cancer Institute of New Jersey). KK-LC-1 expression will be determined by immunohistochemistry (IHC). KK-LC- 1 score of 25% or greater will be considered positive. Participants must be HLA-A 01 by low resolution typing, and HLA-A 01:01 by one of the high resolution type results Measurable metastatic or refractory/recurrent KK-LC-1+ epithelial cancer (determined by ISH). All participants must have received prior first line standard therapy or be ineligible to receive available therapies with known survival benefit. Participants with three or fewer brain metastases that have been treated with surgery or stereotactic radiosurgery are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month before protocol treatment. Participants with surgically resected brain metastases are eligible. Age >18 years of age. Because no dosing or adverse event data are currently available on the use of KK-LC-1 TCR in participants <18 years of age, children are excluded from this study. ECOG performance status <1. Participants must have adequate organ and marrow function as defined below: leukocytes >=3,000/mcL absolute neutrophil count >=1,500/mcL platelets >=100,000/mcL hemoglobin >=9.0 g/dL total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT) =<2.5 X institutional upper limit of normal creatinine within normal institutional limits OR --creatinine clearance >=60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal. Serology: Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Participants who are HIV seropositive can have decreased immune-competence and thus are 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 the participant must be tested for the presence of antigen by RT-PCR and be HCV RNA negative. The effects of the study agent on the developing human fetus are unknown. For this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and up to four months after treatment. Women of childbearing potential must have a negative pregnancy test. Women of childbearing potential are defined as all women except women who are postmenopausal or who have had a hysterectomy. Postmenopausal will be defined as women over the age of 55 who have not had a menstrual period in at least one year or a participant that has received a treatment (i.e. chemotherapy or pelvic radiation) that has resulted in them becoming postmenopausal. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with KK-LC-1 TCR transduced PBL, breastfeeding should be discontinued if the mother is treated with KK-LC-1 TCR transduced PBL. These potential risks may also apply to other agents used in this study. More than four weeks must have elapsed since any prior systemic therapy at the time the participant receives the KK-LC-1 TCR T cells. Participants may have undergone minor surgical procedures within the past three weeks, as long as all toxicities have recovered to Grade 1 or less Ability of subject to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: Participants who are receiving any other investigational agents. History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine or aldesleukin. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Participants with abnormal pulmonary function tests but stable obstructive or restrictive pulmonary disease may be eligible. 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. Participants who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities). Participants with autoimmune diseases such as Crohn s disease, ulcerative colitis, rheumatoid arthritis, autoimmune hepatitis or pancreatitis, and systemic lupus rythematosus. Hypothyroidism, vitiligo and other minor autoimmune disorders are not exclusionary. Participants on active systemic immunosuppressive therapy that cannot be safely withheld. Participants with a history of coronary revascularization or ischemic symptoms unless participant has a normal cardiac stress test. Any condition which would, in the opinion of the Principal Investigator, indicate that the subject is a poor candidate for the clinical trial or would jeopardize the subject or the integrity of the data obtained. Documented LVEF <= 45%

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment at dose levels 1 through 7<br>Non-myeloablative, lymphocyte depleting preparative regimen, followed by KK-LC-1 TCR T cells plus aldesleukin at escalating doses | Drug: IL-2 (Aldesleukin)<br>* dose of 720,000 IU/kg (based on total body weight) as an intravenous bolus over a 15 minute period beginning within 24 hours of cell infusion and continuing for up to four days (maximum 12 doses).<br>Drug: Cyclophosphamide<br>* 30 mg/kg IV infusion over 1 hour (+ 10 min) Once daily x 2 doses (Days -6 and -5)<br>Biological: KK-LC-1 TCR<br>* 1 x 108 transduced KK-LC-1 TCR T cells<br>Drug: Fludarabine<br>* 25 mg/m2 IV infusion over 30 minutes (+ 10 min) To be administered following completion of cyclophosphamide. Once daily x 5 doses (Days -6, -5, -4, -3, -2)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the maximally tolerated dose of KK-LC-1 TCR T cells plus aldesleukin for the treatment of KK-LC-1 plus cancers. | The fraction of patients who experience a DLT will be identified at a given dose level, with information reported about the number and grade of each type of DLT identified. | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vaccine, Gene Therapy, Cell Therapy, T Cell Therapy, Immunotherapy, CAR T, Tumor infiltrating lymphocyte, Triple Negative Breast Cancer, Metastatic Solid Tumor, Metastatic carcinoma