Clinical Trials /

Administering Peripheral Blood Lymphocytes Transduced With a CD70-Binding Chimeric Antigen Receptor to People With CD70 Expressing Cancers

NCT02830724

Description:

Background: In a new cancer therapy, researchers take a person s blood, select a certain white blood cell to grow in the lab, and then change the genes of these cells using a virus. The cells are then given back to the person. This is called gene transfer. For this study, researchers will modify the person s white blood cells with anti-CD70. Objectives: To see if a gene transfer with anti-CD70 cells can safely shrink tumors and to be certain the treatment is safe. Eligibility: Adults age 18 and older diagnosed with cancer that has the CD70-expressing cancer. Design: Participants will be screened with medical history, physical exam, scans, and other tests. They may by admitted to the hospital. Leukapheresis will be performed. For this, blood is removed through a needle in the arm. A machine separates the white blood cells. The rest of the blood is returned through a needle in the other arm. Eligible participants will have an intravenous catheter placed in their upper chest. Over several days, they will get chemotherapy drugs and the anti-CD70 cells. They will recover in the hospital. Participants will take an antibiotic for 6 months after treatment. They will repeat leukapheresis. Participants will visit the clinic every 1-3 months for the first year after treatment, every 6 months for the second year, and then as determined by their physician. Follow-up visits will take 1-2 days. At each visit, participants will have lab tests, imaging studies, and a physical exam. Throughout the study, blood will be taken and participants will have many tests to determine the size and extent of their tumor and the treatment s impact.

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 CD70-Binding Chimeric Antigen Receptor to People With CD70 Expressing Cancers
  • Official Title: A Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a CD70-Binding Chimeric Antigen Receptor to Patients With CD70 Expressing Cancers

Clinical Trial IDs

  • ORG STUDY ID: 160131
  • SECONDARY ID: 16-C-0131
  • NCT ID: NCT02830724

Conditions

  • Pancreatic Cancer
  • Renal Cell Cancer
  • Breast Cancer
  • Melanoma
  • Ovarian Cancer

Interventions

DrugSynonymsArms
Cyclophosphamide1/Phase I
Fludarabine1/Phase I
Aldesleukin1/Phase I
Anti-hCD70 CAR transduced PBL1/Phase I

Purpose

Background: In a new cancer therapy, researchers take a person s blood, select a certain white blood cell to grow in the lab, and then change the genes of these cells using a virus. The cells are then given back to the person. This is called gene transfer. For this study, researchers will modify the person s white blood cells with anti-CD70. Objectives: To see if a gene transfer with anti-CD70 cells can safely shrink tumors and to be certain the treatment is safe. Eligibility: Adults age 18 and older diagnosed with cancer that has the CD70-expressing cancer. Design: Participants will be screened with medical history, physical exam, scans, and other tests. They may by admitted to the hospital. Leukapheresis will be performed. For this, blood is removed through a needle in the arm. A machine separates the white blood cells. The rest of the blood is returned through a needle in the other arm. Eligible participants will have an intravenous catheter placed in their upper chest. Over several days, they will get chemotherapy drugs and the anti-CD70 cells. They will recover in the hospital. Participants will take an antibiotic for 6 months after treatment. They will repeat leukapheresis. Participants will visit the clinic every 1-3 months for the first year after treatment, every 6 months for the second year, and then as determined by their physician. Follow-up visits will take 1-2 days. At each visit, participants will have lab tests, imaging studies, and a physical exam. Throughout the study, blood will be taken and participants will have many tests to determine the size and extent of their tumor and the treatment s impact.

Detailed Description

      Background:

        -  We generated a chimeric antigen receptor (CAR) that engages CD70 using its natural
           ligand CD27, as the binding moiety. Transducing peripheral blood lymphocytes (PBL) with
           this CAR conveys major histocompatibility complex (MHC)-independent recognition of
           CD70-expressing target cells, which include renal cell carcinoma and other cancers.

        -  In co-cultures with CD70+ target cells, anti-hCD70 CAR transduced T cells secrete
           significant amounts of IFN-gamma with high specificity.

      Objectives:

      Primary objectives:

        -  Phase I: Determine the safety of administering PBL transduced with anti-hCD70 CAR in
           concert with preparative lymphodepletion and high dose interleukin-2 (IL-2;
           aldesleukin).

        -  Phase II: Determine if anti-hCD70 CAR-transduced PBL can mediate the regression of CD70
           expressing tumors.

      Eligibility:

        -  Patients must be/have:

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

             -  CD70-expressing tumors

             -  Measurable metastatic disease that has progressed after standard therapy

        -  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-hCD70 CAR in
           patients with measurable, unresectable cancer expressing CD70.

        -  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-hCD70 CAR.

        -  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-hCD70 CAR 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 - clear cell renal cell carcinoma (RCC): Cohort 2 -
           non-RCC malignancies (solid tumors only).

        -  A total of up to 113 patients may be required; approximately 27 patients in the Phase I
           portion of the study and 43 (41, plus an allowance of up to 2 non-evaluable) patients in
           each cohort of the Phase II portion of the study.
    

Trial Arms

NameTypeDescriptionInterventions
1/Phase IExperimentalNon-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + anti-hCD70 CAR transduced PBL + high-dose aldesleukin
  • Cyclophosphamide
  • Fludarabine
  • Aldesleukin
  • Anti-hCD70 CAR transduced PBL
2/Phase IIExperimentalNon-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + anti-hCD70 CAR transduced PBL + high-dose aldesleukin
  • Cyclophosphamide
  • Fludarabine
  • Aldesleukin
  • Anti-hCD70 CAR transduced PBL

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Measurable, unresectable cancer expressing CD70 as assessed by immunohistochemistry of
             resected tissue (> 2+ CD70 positive on > 50% of cancer cells, or >1+ CD70 positive on
             >75% of cancer cells).

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

          -  Patients must have previously received at least one standard therapy for their cancer
             (if available) and have been either non-responders (progressive disease) or have
             recurred.

          -  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 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 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 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 greater than 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 2.5 times 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 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 (except for toxicities such as alopecia or
                  vitiligo). Note: Patients may have undergone minor surgical procedures within the
                  past 3 weeks, as long as all toxicities 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.

          -  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 the NCI-SB cell harvest protocol 03-C-0277 (Cell
             Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols).

        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.

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

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

          -  History of major organ autoimmune disease.

          -  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.

          -  History of coronary revascularization or ischemic symptoms.

          -  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.

               -  Who have had prior treatment with significant exposure to anthracyclines or
                  cyclophosphamide.

          -  Documented FEV1 less than or equal to 60% 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 2 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:Maximum tolerated cell dose (MTD)
Time Frame:Before progression to next-higer dose level
Safety Issue:
Description:Highest dose at which less than or equal to 1 of 6 patients experienced a DLT or the highest dose level studied if DLTs are not observed at any of the dose levels

Secondary Outcome Measures

Measure:In vivo survival of anti-hCD70 CAR transduced cells
Time Frame:3 and 6 months, and 1 year post cell administration
Safety Issue:
Description:CAR and vector presence will be quantitated in PBMC samples using established PCR techniques
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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Metastatic Solid Cancers
  • Renal Cell Cancer
  • Cell Therapy
  • CAR T Cells

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