Clinical Trials /

Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients

NCT03745326

Description:

Background: A new cancer therapy takes white blood cells from a person, grows them in a lab, genetically changes them, then gives them back to the person. Researchers think this may help attack tumors in people with certain cancers. It is called gene transfer using anti-KRAS G12D mTCR cells. Objective: To see if anti-KRAS G12D mTCR cells are safe and cause tumors to shrink. Eligibility: Adults ages 18-70 who have cancer with a molecule on the tumors that can be recognized by the study cells Design: Participants will be screened with medical history, physical exam, scans, photography, and heart, lung, and lab tests. An intravenous (IV) catheter will be placed in a large vein in the chest. Participants will have leukapheresis. Blood will be removed through a needle in an arm. A machine will divide the blood and collect white blood cells. The rest of the blood will be returned to the participant through a needle in the other arm. A few weeks later, participants will have a hospital stay. They will: - Get 2 chemotherapy medicines by IV over 5 days. - Get the changed cells through the catheter. Get up to 9 doses of a medicine to help the cells. They may get a shot to stimulate blood cells. - Recover in the hospital for up to 3 weeks. They will provide blood samples. Participants will take an antibiotic for at least 6 months. Participants will have several follow-up visits over 2 years. They will repeat most of the screening tests and may have leukapheresis. Participants blood will be collected for several years.

Related Conditions:
  • Malignant Solid Tumor
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 G12D Variant of Mutated RAS in HLA-A*11:01 Patients
  • Official Title: Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients

Clinical Trial IDs

  • ORG STUDY ID: 190017
  • SECONDARY ID: 19-C-0017
  • NCT ID: NCT03745326

Conditions

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

Interventions

DrugSynonymsArms
Cyclophosphamide1/Phase I
Fludarabine1/Phase I
Aldesleukin1/Phase I
anti-KRAS G12D mTCR PBL1/Phase I

Purpose

Background: A new cancer therapy takes white blood cells from a person, grows them in a lab, genetically changes them, then gives them back to the person. Researchers think this may help attack tumors in people with certain cancers. It is called gene transfer using anti-KRAS G12D mTCR cells. Objective: To see if anti-KRAS G12D mTCR cells are safe and cause tumors to shrink. Eligibility: Adults ages 18-70 who have cancer with a molecule on the tumors that can be recognized by the study cells Design: Participants will be screened with medical history, physical exam, scans, photography, and heart, lung, and lab tests. An intravenous (IV) catheter will be placed in a large vein in the chest. Participants will have leukapheresis. Blood will be removed through a needle in an arm. A machine will divide the blood and collect white blood cells. The rest of the blood will be returned to the participant through a needle in the other arm. A few weeks later, participants will have a hospital stay. They will: - Get 2 chemotherapy medicines by IV over 5 days. - Get the changed cells through the catheter. Get up to 9 doses of a medicine to help the cells. They may get a shot to stimulate blood cells. - Recover in the hospital for up to 3 weeks. They will provide blood samples. Participants will take an antibiotic for at least 6 months. Participants will have several follow-up visits over 2 years. They will repeat most of the screening tests and may have leukapheresis. Participants blood will be collected for several years.

Detailed Description

      Background:

        -  We generated an HLA-A11:01-restricted murine T-cell receptor (mTCR) that specifically
           recognizes the G12D-mutated variant of KRAS (and other RAS family genes) expressed by
           many human cancers and constructed a single retroviral vector that contains alpha and
           beta chains that confer recognition of this antigen when transduced into PBL.

        -  In co-cultures with HLA-A11:01+ target cells expressing this mutated oncogene, mTCR
           transduced T-cells lyse target cells and secrete IFN-y with high specificity.

      Objectives:

      -Primary objectives:

        -  Phase I: Determine the safety of administering PBL transduced with anti-KRAS G12D mTCR
           in concert with preparative lymphodepletion and high-dose interleukin-2 (IL-2;
           aldesleukin).

        -  Phase II: Determine if anti-KRAS G12D mTCR-transduced PBL can mediate the regression of
           tumors harboring the RAS G12D mutation.

      Eligibility:

        -  Patients must be/have:

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

             -  HLA-A*11:01 positive

             -  Metastatic or unresectable RAS G12D-expressing cancer which has progressed after
                standard therapy (if available).

        -  Patients may not have:

             -  Allergies or hypersensitivities to high-dose aldesleukin, cyclophosphamide, or
                fludarabine.

      Design:

        -  This is a phase I/II, single center study of PBL transduced with anti-KRAS G12D mTCR in
           HLA-A*11:01 positive patients with advanced solid tumors expressing G12D mutated RAS.

        -  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 G12D mTCR.

        -  All patients will receive a non-myeloablative, lymphodepleting preparative regimen of
           cyclophosphamide and fludarabine.

        -  On Day 0, patients will receive PBL transduced with the anti-KRAS G12D mTCR and will
           then begin high-dose aldesleukin.

        -  A complete evaluation of lesions will be conducted approximately 6 weeks (plus-minus 2
           weeks) after treatment.

        -  The study will be conducted using a phase I/II Simon minimax design, with two separate
           cohorts for the Phase II component: Cohort 2a, patients with RAS G12D pancreatic cancer,
           and Cohort 2b, patients with RAS G12D non-pancreatic cancer.

        -  A total of up to 70 patients may be required; approximately 24 patients in the Phase I
           portion of the study and 46 (21, 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
1/Phase IExperimentalNon-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12D mTCR PBL + highdose aldesleukin
  • Cyclophosphamide
  • Fludarabine
  • Aldesleukin
  • anti-KRAS G12D mTCR PBL
2/Phase IIExperimentalNon-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12D mTCR PBL + high-dose aldesleukin
  • Cyclophosphamide
  • Fludarabine
  • Aldesleukin
  • anti-KRAS G12D mTCR PBL

Eligibility Criteria

        -  INCLUSION CRITIERIA:

               1. Measurable (per RECIST v1.1 criteria), metastatic, or unresectable malignancy
                  expressing G12D 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 G12D mutated NRAS and
                  HRAS will also be eligible as these oncogenes share complete amino acid homology
                  with G12D mutated KRAS for their first 80 N-terminal amino acids, completely
                  encompassing the target epitope.

               2. Confirmation of G12D mutated KRAS, NRAS, or HRAS by the NCI Laboratory of
                  Pathology.

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

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

               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:

                    -  Patients with metastatic colorectal cancer must have had at least two
                       systemic chemotherapy regimens that include 5FU, leucovorin, bevacizumab,
                       oxaliplatin, and irinotecan, or have contraindications to receiving those
                       medications.

                    -  Patients with pancreatic cancer must have received gemcitabine, 5FU, and
                       oxaliplatin, 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.

               6. Patients with 3 or fewer brain metastases that are < 1 cm in diameter and
                  asymptomatic are eligible. Lesions that have been treated with stereotactic
                  radiosurgery must be clinically stable for one month after treatment for the
                  patient to be eligible. Patients with

                  surgically resected brain metastases are eligible.

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

               8. Clinical performance status of ECOG 0 or 1

               9. Patients of both genders must be willing to practice birth control from the time
                  of enrollment on this study and for four months after treatment.

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

              11. Serology

                  --Seronegative for HIV antibody. (The experimental treatment being evaluated in
                  this protocol depends on an intact immune system. Patients who are HIV
                  seropositive may 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.

              12. Hematology

                    -  ANC > 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. Subjects may be transfused to reach this cut-off.

              13. Chemistry

                    -  Serum ALT/AST less than or equal to 3.0 x ULN

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

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

              14. 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).

              15. 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. Note: Patients may
                  have undergone minor surgical procedures within the past three weeks, as long as
                  all toxicities have recovered to grade 1 or less.

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

              17. Willing to sign a durable power of attorney.

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

        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. Concurrent systemic steroid therapy.

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

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

          5. Concurrent opportunistic infections (The experimental treatment being evaluated in
             this protocol depends on an intact immune system. Patients who have decreased
             immunecompetence may be less responsive to the experimental treatment and more
             susceptible

             to its toxicities.)

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

          7. History of coronary revascularization or ischemic symptoms.

          8. 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.

          9. Documented FEV1 less than or equal to 50% predicted tested in patients with:

               -  A prolonged history of cigarette smoking (greater than or equal to 20 pack-year
                  smoking history, with cessation within the past two 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:Frequency and severity of treatment-related adverse events
Time Frame:5 years following cell infusion
Safety Issue:
Description:Aggregate of all adverse events, as well as their frequency and severity

Secondary Outcome Measures

Measure:In vivo survival of mTCR geneengineered cells
Time Frame:Batched and assayed at the conclusion of the study
Safety Issue:
Description:TCR and vector presence will be quantified in PBMC samples using established PCR techniques

Details

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

Trial Keywords

  • Immunotherapy
  • Cell Therapy
  • KRAS
  • HRAS
  • NRAS

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