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Protocol Details

A Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced with a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

17-C-0113

Sponsoring Institute

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 18
Max Age: 70

Referral Letter Required

No

Population Exclusion(s)

Pregnant Women and Fetuses;
Children

Special Instructions

Currently Not Provided

Keywords

KRAS;
HRAS;
NRAS;
Cell Therapy;
Immunotherapy

Recruitment Keyword(s)

None

Condition(s)

Pancreatic Cancer;
Gastric Cancer;
Gastrointestinal Cancer;
Colon Cancer;
Rectal Cancer

Investigational Drug(s)

Anti-KRAS G12V murine TCR transduced PBL

Investigational Device(s)

None

Intervention(s)

Drug: Cyclophosphamide
Drug: Fludarabine
Biological/Vaccine: Anti-KRAS G12V mTCR PBL
Drug: Aldesleukin

Supporting Site

National Cancer Institute

Background:

A new cancer therapy involves taking white blood cells from a person, growing them in the lab, genetically modifying them, then giving them back to the person. This therapy is called gene transfer using anti-KRAS G12V mTCR cells.

Objective:

To see if anti-KRAS G12 V mTCR cells are safe and can shrink tumors.

Eligibility:

Adults at least 18 years old with cancer that has the KRAS G12V molecule on the surface of tumors.

Design:

In another protocol, participants will:

Be screened

Have cells harvested and grown

Have leukapheresis

In this protocol, participants will have the procedures below.

Participants will be admitted to the hospital.

Over 5 days, participants will get 2 chemotherapy medicines as an infusion via catheter in the upper chest.

A few days later, participants will get the anti-KRAS G12V mTCR cells via catheter.

For up to 3 days, participants will get a drug to make the cells active.

A day after getting the cells, participants will get a drug to increase their white blood cell count. This will be a shot or injection under the skin.

Participants will recover in the hospital for 1-2 weeks. They will have lab and blood tests.

Participants will take an antibiotic for at least 6 months.

Participants will have visits every few months for 2 years, and then as determined by their doctor.

Visits will be 1-2 days. They will include lab tests, imaging studies, and physical exam. Some visits may include leukapheresis or blood drawn.

Participants will have blood collected over several years.

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Eligibility

INCLUSION CRITERIA:

- Measurable metatstatic unresectable malignancy expressing G12V mutated KRAS as assessed by one of the following methods: RT-PCR on tumor tissue, tumor DNA sequencing or any other CLIA certified laboratory test on resected tissue. Patients shown to have tumors expressing G12V mutated NRAS and HRAS will also be eligible as these oncogenes share complete amino acid homology with G12V mutated KRAS for their first 80 N-terminal amino acids, completely encompassing the target epitope.

- Patients must be HLA-A*11:01 positive as confirmed by the NIH Department of Transfusion Medicine.

- Confirmation of the diagnosis of cancer by the Laboratory of Pathology of the NCI.

- Patients must:

-have previously received standard systemic therapy for their advanced cancer and have been either non-responders or have recurred. Specifically:

-- For patients with metastatic colorectal cancer, they must have had at least two systemic chemotherapy regimens that include 5FU, leucovorin, bevacizumab, oxaliplatin and irinotecan (or similar agents) or have contraindications to receiving those medications.

-- Patients with pancreatic cancer must have received gemcitabine, 5FU, and oxaliplatin (or similar agents), or have contraindications to receiving those medications.

-- Patients with non-small cell lung cancer (NSCLC) must have had appropriate targeted therapy as indicated by abnormalities in ALK, EGFR or expression of PDL- 1. Other patients must have had platinum-based chemotherapy.

-- Patients with ovarian cancer or prostate cancer must have had approved first line chemotherapy

OR

-have declined standard treatment

- Patients with 3 or fewer brain metastases that are less than 1 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.

- Age greater than or equal to 18 years and less than or equal to 70 years.

- Clinical performance status of 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 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 may 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 HCV RNA negative.

- Hematology:

-ANC greater than or equal to 1000/mm^3 without the support of filgrastim

-WBC greater than or equal to 3000/mm^3

-Platelet count greater than or equal to 100,000/mm^3

-Hemoglobin > 8.0 g/dL

- Chemistry:

-- Serum ALT/AST less than or equal to 5.0 x ULN

-- Total bilirubin less tha or equal to 1.5 mg/dL, except in patients with Gilbert s Syndrome who must have a total bilirubin less than or equal to 3.0 mg/dL.

- Patients must have either an eGFR > 60 mL/m (based on serum creatinine and lab nomogram) or a formal 6-24h CrCl > 60 mL/m.

- More than four weeks must have elapsed since completion of any prior systemic therapy and enrollment.

Note: Patients may have undergone minor surgical procedures or limited field radiotherapy within the four weeks before enrollment, as long as related major organ toxicities have recovered to grade 1 or less.

-Ability of subject to understand and the willingness to sign a written informed consent document.

-Willing to sign a durable power of attorney.

- Subjects must be co-enrolled on NCI-SB cell harvest protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols).

EXCLUSION CRITERIA:

a) Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.

b) Concurrent systemic steroid therapy.

c) Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses.

d) Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).

e) 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).

f) History of severe immediate hypersensitivity reaction to cyclophosphamide, aldesleukin, or fludarabine.

g) History of coronary revascularization or ischemic symptoms

h) Documented LVEF less than or equal to 45% tested in patients:

-Age greater than or equal to 65 years

-With 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 and/or chest pain

i) Documented FEV1 less than or equal to 50% predicted tested in patients with:

-A prolonged history of cigarette smoking (approximately 20 packs/year within the past two years).

-Symptoms of respiratory dysfunction

j) Patients who are receiving any other investigational agents


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Citations:

Davis JL, Theoret MR, Zheng Z, Lamers CH, Rosenberg SA, Morgan RA. Development of human anti-murine T-cell receptor antibodies in both responding and nonresponding patients enrolled in TCR gene therapy trials. Clin Cancer Res. 2010 Dec 1;16(23):5852-61. doi: 10.1158/1078-0432.CCR-10-1280.

Wang QJ, Yu Z, Griffith K, Hanada K, Restifo NP, Yang JC. Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors. Cancer Immunol Res. 2016 Mar;4(3):204-14. doi: 10.1158/2326-6066.CIR-15-0188. Epub 2015 Dec 23.

Abrams SI, Khleif SN, Bergmann-Leitner ES, Kantor JA, Chung Y, Hamilton JM, Schlom J. Generation of stable CD4+ and CD8+ T cell lines from patients immunized with ras oncogene-derived peptides reflecting codon 12 mutations. Cell Immunol. 1997 Dec 15;182(2):137-51.

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Contacts:

Principal Investigator

Referral Contact

For more information:

James C. Yang, M.D.
National Cancer Institute (NCI)



For more information NCI/Surgery Branch Recruitment Center
National Cancer Institute (NCI)
National Institutes of Health
Building 10
Room 2-1730
10 Center Drive
Bethesda, Maryland 20892
(866) 820-4505
IRC@nih.gov

Recruitment Center - SB
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Building 10, Room 2-1730, Bethesda, Maryland 20892, United States
(866) 820-4505
ncisbirc@mail.nih.gov

Clinical Trials Number:

NCT03190941

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