Clinical trial NCT01869166: Treatment of Chemotherapy Refractory EGFR(Epidermal Growth Factor Receptor) Positive Advanced Solid Tumors (CART-EGFR)
Official title: Clinical Study of Chimeric EGFR Antigen Receptor-modified T Cells in Chemotherapy Refractory Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Advanced EGFR-positive Solid Tumors
Keywords: chemotherapy and/or EGFR-antibody/kinase inhibitor therapy refractory solid tumors
Lead sponsor: Chinese PLA General Hospital
Sponsor class: OTHER
First posted: 2013-06-05
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Placing a tumor antigen chimeric receptor that has been created in the laboratory into patient autologous T cells may make the body build immune response to kill cancer cells.

PURPOSE: This clinical trial is to study genetically engineered lymphocyte therapy in treating patients with EGFR positive advanced/unresectable operation solid tumors, such as lung cancer, colorectal cancer，ovary cancer，cholangiocarcinoma，pancreatic cancer，renal carcinoma and other relapsed/metastatic tumors.

Detailed description: PRIMARY OBJECTIVES:

I. Determine the safety and feasibility of the chimeric antigen receptor T cells transduced with the anti-EGFR Lentivirus vector (referred to as CART-EGFR cells).

II. Determine duration of in vivo survival of CART-EGFR cells. RT-PCR (reverse transcription polymerase chain reaction) analysis of whole blood will be used to detect and quantify survival of CART-EGFR CD3zeta:CD137 over time.

SECONDARY OBJECTIVES:

I. For patients with advanced， relapsed/metastatic cancers, measure anti-tumor response due to CART-EGFR cell infusions.

II. Estimate relative trafficking of CART-EGFR cells in tumor bed.

III. Determine if cellular or humoral host immunity develops against the murine anti-EGFR, and assess correlation with loss of detectable CART-EGFR (loss of engraftment).

IV. Determine the relative subsets of CART-EGFR T cells (Tcm, Tem, and Treg).

OUTLINE: Patients are assigned to 1 group according to order of enrollment.

Patients receive anti-EGFR-CAR (coupled with CD137 and CD3 zeta signalling domains)Lentivirus vector-transduced autologous T cells for 3-5 days in the absence of unacceptable toxicity.

After completion of study treatment, patients are followed intensively for 6 months, every 3 months for 2 years, and annually thereafter for 13 years.

Estimate relative trafficking of CART-EGFR cells in peripheral blood.

Eligibility criteria: Inclusion Criteria:

1. Chemotherapy refractory EGFR-positive non-small cell lung cancer, colorectal cancer with liver metastasis,and chemotherapy resistant or relapsed ovary cancerlung cancer,cholangiocarcinoma，pancreatic cancer，renal carcinoma and other relapsed/metastatic/unresectable operation tumors.the expression of EGFR in tumor is more than 50%.
2. Relapsed patients after anti-EGFR using antibody or kinase inhibitor therapy.
3. Patients must be 18 years of age or older.
4. Patients must have an ECOG (Eastern Cooperative Oncology Group )performance status of 0-2.
5. Patients must have evidence of adequate hepatic and renal function as evidenced by the following laboratory parameters:

   Absolute neutrophil count greater than 1500/mm3. Platelet count greater than 100,000/mm3. Hemoglobin greater than 10g/dl (patients may receive transfusions to meet this parameter).

   Total bilirubin \< 1.5 times upper limits of normal. Serum creatinine less than or equal to 1.6 mg/ml or the creatinine clearance must be greater than 70 ml/min/1.73m(2).
6. Seronegative for HIV antibody.
7. Seronegative for active hepatitis B, and seronegative for hepatitis C antibody.
8. Patients must be willing to practice birth control during and for four months following treatment.NOTE:women of child-bearing age must have evidence of negative pregnancy test.
9. Patients must be willing to sign an informed consent.

Exclusion Criteria:

1. Patients with life expectancy less than 12 months will be excluded.
2. Patients with uncontrolled hypertension (\> 160/95), unstable coronary disease evidenced by uncontrolled arrhythmias, unstable angina, decompensated congestive heart failure (\> New York Heart Association Class II), or myocardial infarction within 6 months of study will be excluded.
3. Patients with any of the following pulmonary function abnormalities will be excluded: FEV(forced expiratory volume), \< 30% predicted; DLCO (diffusing capacity of lung for carbon monoxide) \< 30% predicted (post-bronchodilator); Oxygen Saturation less than 90% on room air.
4. Patients with severe liver and kidney dysfunction or consciousness disorders will be excluded.
5. Pregnant and/or lactating women will be excluded.
6. Patients with active infections, including HIV, will be excluded, due to unknown effects of the vaccine on lymphoid precursors.
7. Patients with any type of primary immunodeficiencies will be excluded from the study.
8. Patients requiring corticosteroids (other than inhaled) will be excluded.
9. Patients with history of T cell tumors will be excluded.
10. Patients who are participating or participated any other clinical trials in latest 30 days will be excluded.

Primary outcomes:
measure: Occurrence of study related adverse events
timeFrame: Until week 24
Secondary outcomes:
measure: Anti-tumor responses to CART-EGFR cell infusions
timeFrame: up to 24 weeks
Other outcomes:
measure: in vivo existence of CART-EGFR
timeFrame: 1 year
Locations:
city: Beijing
country: China
facility: Chinese PLA General Hospital
state: Beijing
Study officials:
affiliation: Chinese PLA General Hospital
name: weidong han, Dr.
role: STUDY_CHAIR
References:
citation: Liu Y, Guo Y, Wu Z, Feng K, Tong C, Wang Y, Dai H, Shi F, Yang Q, Han W. Anti-EGFR chimeric antigen receptor-modified T cells in metastatic pancreatic carcinoma: A phase I clinical trial. Cytotherapy. 2020 Oct;22(10):573-580. doi: 10.1016/j.jcyt.2020.04.088. Epub 2020 Jun 9.
citation: Guo Y, Feng K, Liu Y, Wu Z, Dai H, Yang Q, Wang Y, Jia H, Han W. Phase I Study of Chimeric Antigen Receptor-Modified T Cells in Patients with EGFR-Positive Advanced Biliary Tract Cancers. Clin Cancer Res. 2018 Mar 15;24(6):1277-1286. doi: 10.1158/1078-0432.CCR-17-0432. Epub 2017 Nov 14.
citation: Feng KC, Guo YL, Liu Y, Dai HR, Wang Y, Lv HY, Huang JH, Yang QM, Han WD. Cocktail treatment with EGFR-specific and CD133-specific chimeric antigen receptor-modified T cells in a patient with advanced cholangiocarcinoma. J Hematol Oncol. 2017 Jan 5;10(1):4. doi: 10.1186/s13045-016-0378-7.