KK-LC-1 TCR-T Cell Therapy for Gastric, Breast, Cervical, and Lung Cancer

Study Overview
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Brief Summary
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This is a phase I clinical trial to determine the maximum tolerated dose (MTD) of KK-LC-1 TCR-T cells for the treatment of metastatic cancers that express KK-LC-1. Participants will receive a conditioning regimen, KK-LC-1 TCR-T cells, and aldesleukin. The safety profile and clinical response to treatment will be determined.

Detailed Description
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This study will determine the MTD of KK-LC-1 TCR-T cells for the treatment of metastatic cancers that express KK-LC-1 and will assess clinical tumor response to treatment. KK-LC-1 is an abnormal protein that is expressed by certain types of cancer. The cancers that most commonly express KK-LC-1 include gastric, lung, breast, and cervix cancer. KK-LC-1 TCR-T cells are autologous T cells that are genetically engineered to target the KK-LC-1 antigen. Tumor targeting by the KK-LC-1 TCR requires that subjects have the the HLA-A*01:01 allele. Participants will receive a conditioning regimen consisting of cyclophosphamide and fludarabine. They will then receive a single infusion of KK-LC-1 TCR-T cells, which will be followed by administration of aldesleukin. Adverse events, dose limiting toxicity, tumor response, and tumor response duration will be determined.

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

Conditions
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Breast Cancer, Gastric Cancer, Cervical Cancer, Lung Cancer

Intervention / Treatment
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* Drug: KK-LC-1 TCR-T cells
* Drug: Aldesleukin 720,000 IU/kg IV every eight hours


Participation Criteria
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Eligibility Criteria
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Signed, written informed consent obtained prior to any study procedures. Age > 18 years at the time of informed consent. Metastatic solid tumor with ≥ 25% of tumor cells positive for KK-LC-1 by IHC assay. Due to the low frequency of KK-LC-1 expression in most cancers, screening will focus on gastric, NSCLC, TNBC, and cervix cancers. The IHC test will be performed by the Rutgers Cancer Institute of New Jersey, Department of Biorepository Services. HLA-A*01:01 allele by HLA haplotype test. Measureable disease per RECIST Criteria Version 1.1 at time of enrollment. Prior treatment with cancer type-specific stand of care systemic cancer therapy is required. Standard treatment options must be considered and declined. Documentation of rationale is required if a subject is deemed unsuitable for standard therapy. Subjects with < 3 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. Patients with surgically resected brain metastases are eligible. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening. Negative pregnancy test for women under 55 and all women who have had a menstrual period in the last 12 months. A pregnancy tests is not required for women who have had a bilateral oophorectomy or hysterectomy. Women of child-bearing potential must agree to use adequate contraception (i.e., intrauterine device, hormonal barrier method of birth control; abstinence; tubal ligation or vasectomy) prior to study entry and for four months after treatment. Should a women become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately. Participants must have 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 except in participants with Gilbert's Syndrome who must have a total bilirubin < 3.0 mg/dL. Serum AST (SGOT)/ALT (SGPT) < 2.5 x ULN Calculated creatinine clearance (CrCl) >50 mL/min/1.73 m2for participants with creatinine levels above institutional normal (by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation). INR or a PTT ≤1.5 X ULN unless the subject is receiving anticoagulant therapy. Subjects on anticoagulant therapy must have a PT or PTT within therapeutic range and no history of severe hemorrhage. Serology: HIV antibody negative Hepatitis B antigen negative Hepatitis C antibody negative or HCV RNC negative (i.e., no current HCV infection) More than four weeks must have elapsed since any prior systemic therapy or radiotherapy at the time the patient receives the KK-LC-1 TCR T cells. Adverse events from prior therapy must have resolved to≤ grade 1 according to CTCAE Version 5 or have demonstrated clinical stability and meet the eligibility criteria for the protocol. Oxygen saturation ≥ 92% on room air. Left ventricular ejection fraction ≥45% by echocardiogram or MUGA for patients 50 years of age or older.

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
Intervention Model: Sequential Assignment
Interventional Model Description: This is a phase I clinical trial that will determine the maximum tolerated dose and clinical tumor responses for escalating doses of KK-LC-1 TCR-T cells.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KK-LC-1 TCR-T cells<br>Subjects will receive a conditioning regimen, KK-LC-1 TCR-T cells, and aldesleukin. | Drug: KK-LC-1 TCR-T cells<br>* Participants will receive a conditioning regimen consisting of cyclophosphamide and fludarabine. KK-LC-1 TCR-T cells will be administered as a single intravenous infusion.<br>Drug: Aldesleukin 720,000 IU/kg IV every eight hours<br>* Aldesleukin 720,000 IU/kg IV every eight hours after KK-LC-1 TCR-T cell infusion for up to six doses. Aldesleukin dosing will be stopped for aldesleukin-related grade 3 or greater toxicity other than flushing, fever, chills, or hemodynamic changes (tachycardia or hypotension) that respond to crystalloid infusion. Aldesleukin may also be stopped at any time at investigator discretion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of KK-LC-1 TCR-T cells | The highest dose level achieved according to the protocol-defined criteria for DLTs and determination of MTD. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events of KK-LC-1 TCR T cells | Adverse event determination as measured by National Cancer Institute (NCI) Common 5.0Terminology Criteria for Adverse Events (CTCAE) Criteria Version 5.0 | 30 days | 
| Tumor response rate | Tumor response will be determined by RECIST criteria as per the protocol description | 6 weeks | 
| Tumor response duration | Tumor response duration will be determined by RECIST criteria as per the protocol description | Through study completion, up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TIL, CAR-T, immunotherapy, stomach cancer, lung cancer, breast cancer, triple negative, cervical cancer, cell therapy, gene therapy, tumor infiltrating lymphocytes, T cells, immune