Clinical Trials /

Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Mutated Neoantigens in People With Metastatic Cancer

NCT03412877

Description:

Background: In gene transfer therapy, cells are taken from a person s tumor to isolate mutations. White blood cells are then taken from the person's body, changed with a type of virus to attack the tumor cells, and returned to the person. Objective: To see if gene transfer therapy shrinks tumors. Eligibility: People with certain metastatic cancer for which standard treatments have not worked Design: Participants will complete screening and stages 1-3 under another protocol. Screening includes: Undergoing a biopsy or surgery at the NIH to obtain pieces of tumor in order to grow tumor cells Medical history Physical exam Scans Blood, urine, heart, and lung tests The study has 7 stages: 1. Screening tests repeated over 1-2 weeks. Participants will have leukapheresis: Blood is removed by a needle in one arm. A machine removes white blood cells. The rest of the blood is returned by a needle in the other arm. An IV catheter will be placed in the chest. 2. Care at home over 6-12 weeks. 3. Stopping therapy for 4-6 weeks while their cells are changed in a lab. 4. Hospital stay for 1 week to get chemotherapy by IV. 5. Receiving changed cells by catheter. Then getting a drug over 1-5 days to help the cells live longer. 6. Recover in the hospital for 1 2 weeks. Participants will get drugs and have blood and urine tests. 7. Participants will take an antibiotic and maybe an antiviral for at least 6 months after treatment. They will have repeat screening tests at visits every few months for the first year, every 6 months for the second year, then as determined. ...

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Ampulla of Vater Carcinoma
  • Bladder Carcinoma
  • Breast Carcinoma
  • Esophageal Carcinoma
  • Gastrointestinal Stromal Tumor
  • Glioblastoma
  • Kidney Carcinoma
  • Malignant Esophagogastric Neoplasm
  • Malignant Gastric Neoplasm
  • Malignant Intestinal Neoplasm
  • Malignant Small Intestinal Neoplasm
  • Malignant Solid Tumor
  • Malignant Testicular Neoplasm
  • Non-Small Cell Lung Carcinoma
  • Ovarian Carcinoma
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Mutated Neoantigens in People With Metastatic Cancer
  • Official Title: Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Mutated Neoantigens in People With Metastatic Cancer

Clinical Trial IDs

  • ORG STUDY ID: 180049
  • SECONDARY ID: 18-C-0049
  • NCT ID: NCT03412877

Conditions

  • Glioblastoma
  • Non-Small Cell Lung Cancer
  • Ovarian Cancer
  • Breast Cancer
  • Gastrointestinal/Genitourinary Cancer

Interventions

DrugSynonymsArms
Cyclophosphamide1-Experimental Therapy
Fludarabine1-Experimental Therapy
Aldesleukin1-Experimental Therapy
Individual Patient TCR-Transduced PBL1-Experimental Therapy

Purpose

Background: In gene transfer therapy, cells are taken from a person s tumor to isolate mutations. White blood cells are then taken from the person's body, changed with a type of virus to attack the tumor cells, and returned to the person. Objective: To see if gene transfer therapy shrinks tumors. Eligibility: People with certain metastatic cancer for which standard treatments have not worked Design: Participants will complete screening and stages 1-3 under another protocol. Screening includes: Undergoing a biopsy or surgery at the NIH to obtain pieces of tumor in order to grow tumor cells Medical history Physical exam Scans Blood, urine, heart, and lung tests The study has 7 stages: 1. Screening tests repeated over 1-2 weeks. Participants will have leukapheresis: Blood is removed by a needle in one arm. A machine removes white blood cells. The rest of the blood is returned by a needle in the other arm. An IV catheter will be placed in the chest. 2. Care at home over 6-12 weeks. 3. Stopping therapy for 4-6 weeks while their cells are changed in a lab. 4. Hospital stay for 1 week to get chemotherapy by IV. 5. Receiving changed cells by catheter. Then getting a drug over 1-5 days to help the cells live longer. 6. Recover in the hospital for 1 2 weeks. Participants will get drugs and have blood and urine tests. 7. Participants will take an antibiotic and maybe an antiviral for at least 6 months after treatment. They will have repeat screening tests at visits every few months for the first year, every 6 months for the second year, then as determined. ...

Detailed Description

      Background:

        -  The administration of autologous tumor-infiltrating lymphocytes (TIL) can mediate
           complete, durable regressions in 20-25% of patients with metastatic melanoma. Recent
           studies have shown that these TIL predominantly recognize unique mutated neoantigens
           expressed by the cancer not shared by other melanomas.

        -  Administration of bulk autologous TIL to patients with a variety of other solid cancers,
           including cancers of the gastrointestinal tract and genitourinary tract, have little if
           any therapeutic impact.

        -  Recent studies in the National Cancer Institute Surgery Branch, (NCI-SB), have shown
           that TIL from non-melanoma solid cancers can also contain T-cells reactive against
           non-shared unique mutated neoantigens expressed in the cancer. The frequency of these
           T-cells is very low (often < 0.1%) and it is thus difficult to isolate and grow mutation
           reactive T-cells to levels required for effective therapy.

        -  In a single patient with chemo-refractory metastatic cholangiocarcinoma we were able to
           grow a relatively pure population of neoantigen reactive TIL and administration of these
           cells mediated a near-complete regression of all metastatic disease now lasting 2.5
           years.

        -  We have developed approaches to identify these rare neoantigen reactive T-cells from
           common non-melanoma cancers, to isolate their T-cell receptors (TCR), and to genetically
           engineer autologous peripheral blood lymphocytes (PBL) to express these TCRs with high
           efficiency. The neoantigen TCR gene-modified cells can recognize and destroy the
           autologous cancer in vitro.

        -  With these techniques, we have isolated a number of TCRs selectively recognizing shared
           mutated oncogenes (e.g., KRAS, TP53) in the context of several major histocompatibility
           complexes (MHC-I and MHC-II). For patients with the appropriate MHC restriction, whose
           tumors express these shared mutated oncogenes, these TCRs represent an additional option
           for broadening the patient s anti-tumor repertoire with autologous gene-modified cells.

        -  This clinical protocol will treat patients with refractory solid cancers using the
           adoptive transfer of autologous PBL transduced with genes encoding TCRs that recognize
           unique mutated neoantigens expressed by the cancer.

      Objectives:

      -Primary objective:

      --Determine the rate of objective response (using RECIST v1.1 criteria) of patients with
      solid cancers who receive autologous PBL that have been transduced with genes encoding T-cell
      receptors that recognize mutated neoantigens in the autologous cancer.

      Eligibility:

      -Patients must be/have:

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

        -  Solid cancer with at least one lesion that can be measured, that falls into one of four
           cohorts: (1) gastrointestinal and genitourinary cancers; (2) breast, ovarian, and other
           solid cancers; (3) non-small cell lung cancer (NSCLC); and, (4) glioblastoma. Metastatic
           disease is required for cohorts 1-3, but not for cohort 4.

        -  Evaluable solid cancer that has recurred following standard chemotherapy or standard
           systemic therapy

        -  Normal basic laboratory values.

        -  No allergies or hypersensitivity to high-dose aldesleukin administration

        -  No concurrent major medical illnesses or any form of immunodeficiency.

      Design:

        -  Patients will have already undergone resection or biopsy to obtain tumor for generation
           of autologous TIL cultures. This will have been conducted under the NCI-SB cell harvest
           protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell
           Therapy Protocols).

        -  Exomic sequencing, and often RNA-Seq will be performed to identify the mutations
           expressed in the patient s cancer. Multiple autologous TIL cultures will be grown and
           tested for reactivity against mutations from the autologous tumor using assays we have
           developed that involve the exposure of autologous antigen-presenting cells to long
           peptides containing the mutation or tandem mini-genes encoding the mutation.

        -  T-cell cultures with reactivity against mutations will be identified and the individual
           T-cell receptors that recognize the mutation will be synthesized and used to create a
           retrovirus for transduction of the TCR into the patient s autologous PBL.

        -  Patients that present with tumors expressing mutated shared oncogenes (KRAS or TP53)
           that also express the appropriate restriction element may be treated with autologous
           PBLs retrovirally -transduced with TCR(s) previously isolated in the Surgery Branch
           targeting the shared mutated antigen. These patients will be administered a cell
           infusion product of TCRs targeting mutated shared oncogenes (KRAS or TP53). Their cell
           infusion product will not include PBL transduced with unique (i.e., non-shared) TCR(s).

        -  Patients will be entered into four cohorts: (1) gastrointestinal and genitourinary
           cancers; (2) breast, ovarian, and other solid cancers; (3) non-small cell lung cancer
           (NSCLC); and, (4) glioblastoma. Autologous PBL (transduced with either TCR(s) targeting
           mutated shared oncogenes TP53 or KRAS, or, TCR(s) targeting individual neoantigens) will
           then be expanded to large numbers using our standard rapid expansion protocol and
           administered to the patient following a non-myeloablative, lymphodepleting preparative
           regimen of cyclophosphamide and fludarabine. Patients will then begin high-dose
           aldesleukin after the infusion of autologous transduced PBL. At the discretion of the
           Principal Investigator (PI), patients enrolled in Cohort 3 may receive low-dose
           aldesleukin.

        -  Clinical and immunologic response will be evaluated about 4-6 weeks after cell infusion
           and periodically thereafter.

        -  It is anticipated that approximately one patient per month may enroll on the trial for
           each of the four histologic groups. Thus, accrual of up to 4 x 50=200 total evaluable
           patients may be completed in approximately 2-4 years. In order to allow for a small
           number of inevaluable patients, the accrual ceiling will be set to 210.
    

Trial Arms

NameTypeDescriptionInterventions
1-Experimental TherapyExperimentalNon-myeloablative lymphocyte depleting chemotherapy regimen of cyclophosphamide and fludarabine + Individual Patient TCR-Transduced PBL + high or low-dose aldesleukin
  • Cyclophosphamide
  • Fludarabine
  • Aldesleukin
  • Individual Patient TCR-Transduced PBL

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Solid cancer that can be measured, that falls into one of four cohorts: (1)
             gastrointestinal and genitourinary cancers; (2) breast, ovarian, and other solid
             cancers; (3) non-small cell lung cancer (NSCLC); and, (4) glioblastoma.

             --Note: Metastatic disease is required for Cohorts 1-3, but not required for cohort 4.
             NSCLC includes but is not limited to squamous cell carcinoma, adenosquamous carcinoma
             or adenocarcinomas. Neuroendocrine tumors are not eligible.

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

          -  Refractory to approved standard systemic therapy. Specifically:

               -  Patients with metastatic colorectal cancer must have received oxaliplatin or
                  irinotecan.

               -  Patients with breast and ovarian cancer must be refractory to both first and
                  second line treatments.

               -  Patients with NSCLC must have received at least one platinum-based chemotherapy
                  regimen and at least one FDA approved targeted treatment (when appropriate).

               -  Patients with glioblastoma must have progression of disease after radiotherapy
                  (including patients that undergo surgery for recurrent disease and are rendered
                  NED). This includes recurrent glioblastoma after receiving all standard
                  first-line treatment, including surgery (if feasible due to neurosurgical and
                  neuro-anatomical considerations) and adjuvant radiotherapy +/- chemotherapy.

          -  For Cohorts 1-3: patients with 3 or fewer brain metastases that are less than or equal
             to 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.

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

          -  For Cohorts 1-3: clinical performance status of ECOG 0 or 1.

          -  For cohort 4: Patients must have Karnofsky performance status greater than or equal to
             60.

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

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

          -  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.

          -  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.

          -  Chemistry:

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

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

               -  Total bilirubin less than or equal to 2.0 mg/dl, except in patients with
                  Gilbert's Syndrome, who must have a total bilirubin less than or equal to 3.0
                  mg/dl.

          -  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.

        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.

          -  For cohort 3: more than two weeks must have elapsed since any prior palliation for
             major bronchial occlusion or bleeding at the time the patient receives the preparative
             regimen, and patient s toxicities must have recovered to a grade 1 or less.

          -  For cohort 4: patients must be at least four weeks from radiation therapy.
             Additionally, patients must be at least six weeks from nitrosoureas, four weeks from
             temozolomide, three weeks from procarbazine, two weeks from vincristine and four weeks
             from last bevacizumab administration. Patients must be at least four weeks from other
             cytotoxic therapies not listed above and two weeks for non-cytotoxic agents (e.g.,
             interferon) including investigative agents.

          -  For Cohort 4: Patients must either not be receiving steroids, or be on a stable dose
             of steroids, for at least five days prior to registration.

          -  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 protocol 03-C-0277.

        EXCLUSION CRITERIA:

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

          -  Concurrent systemic steroid therapy, except for patients with glioblastoma (cohort 4).

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

          -  For cohort 3: Any major bronchial occlusion or bleeding not amenable to palliation.

          -  For cohort 4: Clinically significant hemorrhagic or ischemic stroke, including
             transient ischemic attacks and other central nervous system bleeding in the preceding
             six months that were not related to glioma surgery.

        Note: History of prior intratumoral bleeding is not an exclusion criterion; however,
        patients with a history of prior intratumoral bleeding, will need to undergo a non-contrast
        head CT to exclude acute bleeding.

          -  Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease
             and AIDS).

          -  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.)

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

          -  For Cohorts 1, 2, or 4: Clinically significant patient history which in the judgment
             of the Principal Investigator (PI) would compromise the patients' ability to tolerate
             high-dose aldesleukin.

        Note: At the discretion of the PI, patients enrolled in cohort 3 may receive low-dose
        aldesleukin.

          -  History of coronary revascularization or ischemic symptoms.

          -  Any patient known to have an LVEF less than or equal to 45%.

          -  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

          -  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, within the past two years).

               -  Symptoms of respiratory dysfunction

          -  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 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x 2 years, then per PI discretion
Safety Issue:
Description:Percentage of patients who have a clinical response to treatment (objective tumor regression)

Secondary Outcome Measures

Measure:Phenotypic and functional characteristics of PBL
Time Frame:2-4 years post cell infusion
Safety Issue:
Description:Phenotypic and functional characteristics of PBL
Measure:In vivo survival of TCR gene-engineered cells
Time Frame:6 weeks post-treatment and then as indicated
Safety Issue:
Description:TCR and vector presence will be quantitated in PBMC samples using established PCR techniques

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Gene Therapy
  • Immunotherapy
  • Cell Therapy
  • Adoptive Cell Therapy

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