Clinical Trials /

Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients

NCT03190941

Description:

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.

Related Conditions:
  • Cancer
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*1101 Patients
  • Official Title: 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 1101 Patients

Clinical Trial IDs

  • ORG STUDY ID: 170113
  • SECONDARY ID: 17-C-0113
  • NCT ID: NCT03190941

Conditions

  • Pancreatic Cancer
  • Gastric Cancer
  • Gastrointestinal Cancer
  • Colon Cancer
  • Rectal Cancer

Interventions

DrugSynonymsArms
CyclophosphamidePhase I
FludarabinePhase I
anti-KRAS G12V mTCRPhase I
AldesleukinPhase I

Purpose

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.

Detailed Description

      Background:

        -  We generated an HLA-A1101-restricted murine T-cell receptor (mTCR) that specifically
           recognizes the G12V-mutated variant of KRAS (and other RAS family genes), expressed by
           many human cancers and constructed a single retroviral vector that contains its alpha
           and beta chains that confers recognition of this antigen when transduced into PBL.

        -  In co-cultures with HLA-A1101+ target cells expressing this mutated oncogene, mTCR
           transduced T cells lyse target cells and secrete IFN-gamma with high specificity.

      Objectives:

      Primary objectives:

        -  To determine the safety of administering PBL transduced with anti-KRAS G12V mTCR in
           concert with preparative lymphodepletion and high dose interleukin-2 (IL-2;
           aldesleukin).

        -  To determine if anti-KRAS G12V mTCR-transduced PBL can mediate the regression of tumors
           with the RAS G12V mutation.

      Eligibility:

      Patients who are HLA-A 1101 positive and 18 years of age or older must have:

      -A metastatic or unresectable RAS G12V-expressing cancer which has progressed after standard
      therapy (if available).

      Patients may not have:

      -Contraindications for high dose aldesleukin, cyclophosphamide or fludarabine
      administration.

      Design:

        -  PBMC obtained by leukapheresis 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 these cells to retroviral vector supernatant
           containing replication-incompetent virus encoding the anti-KRAS G12V mTCR.

        -  All patients will receive a non-myeloablative lymphocyte depleting preparative regimen
           of cyclophosphamide and fludarabine.

        -  On day 0 patients will receive their PBL transduced with the anti-KRAS G12V mTCR and
           will then begin high dose aldesleukin.

        -  A complete evaluation of lesions will be conducted approximately 4-6 weeks after
           treatment.

        -  The study will be conducted using a Phase I/II optimal design, with two separate
           cohorts for the phase II component: Cohort 1- pancreatic cancers; Cohort 2: all other
           RAS G12V cancers.

        -  A total of 110 patients may be required; approximately 24 patients in the phase I
           portion of the study and 86 (41, plus an allowance of up to 2 non-evaluable per phase
           II cohort) patients in the phase II portion of the study.
    

Trial Arms

NameTypeDescriptionInterventions
Phase IExperimentalNon-myeloablative lymphocyte delpleting regimen followed by anti-KRAS G12V mTCR and high dose aldesleukin.
  • Cyclophosphamide
  • Fludarabine
  • Aldesleukin
Phase IIExperimentalNon-myeloablative lymphocyte delpleting regimen followed by anti-KRAS G12V mTCR and high dose aldesleukin.
  • Cyclophosphamide
  • Fludarabine
  • Aldesleukin

Eligibility Criteria

        -INCLUSION CRITERIA:

          1. Measurable malignancy expressing KRAS G12V 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.

          2. Confirmation of KRAS G12V by the Laboratory of Pathology of the NCI.

          3. Patients must be HLA-A 1101 positive.

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

          5. Patients must have previously received standard systemic therapy for their advanced
             cancer and have been either non-responders (progressive disease) 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 have contraindications to receiving those
                  medications.

               -  For pancreatic cancer, they must have received gemcitabine, 5FU and oxaliplatin
                  or have contraindications to receiving those medications.

          6. 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.

          7. Greater than or equal to 18 years of age and less than or equal to 70 years of age.

          8. Willing to sign a durable power of attorney

          9. Able to understand and sign the Informed Consent Document

         10. Clinical performance status of ECOG 0 or 1

         11. 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.

         12. 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 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.

         13. Women of child-bearing potential must have a negative pregnancy test because of the
             potentially dangerous effects of the treatment on the fetus.

         14. Hematology

               -  Absolute neutrophil count greater than 1000/mm3 without the support of
                  filgrastim

               -  WBC greater than or equal to 3000/mm3

               -  Platelet count greater than or equal to 100,000/mm3

               -  Hemoglobin > 8.0 g/dl

         15. Chemistry:

               -  Serum ALT/ASTless than or equal to to 2.5 times the upper limit of normal

               -  Serum creatinine less than or equal to to 1.6 mg/dl

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

         16. 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).

         17. More than 3 weeks must have elapsed since minor surgical procedures or limited field
             radiotherapy at the time the patient receives the preparative regimen, and patients
             toxicities must have recovered to grade 1 or less.

         18. Subjects must be co-enrolled in protocol 03-C-0277.

        EXCLUSION CRITERIA:

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

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

          3. Active systemic infections (e.g.: requiring anti-infective treatment), coagulation
             disorders or any other major medical illnesses.

          4. 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).

          5. Concurrent systemic steroid therapy.

          6. History of severe immediate hypersensitivity reaction to cyclophosphamide or
             fludarabine.

          7. History of coronary revascularization or ischemic symptoms

          8. Documented LVEF of less than or equal to 45%. Testing is required in patients 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 or chest pain

               -  Age greater than or equal to 60 years old

          9. Documented FEV1 less than or equal to 50% 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

         10. Patients who are receiving any other investigational agents
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response rate
Time Frame:6 weeks (+/- 2 weeks) after cell infusion, then at week 12, every 3 months x3, every 6 months x2 years.
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Survival and persistence of mTCR gene-engineered cells.
Time Frame:approximately 4-5 years
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • KRAS
  • HRAS
  • NRAS
  • Cell Therapy
  • Immunotherapy

Last Updated

June 17, 2017