Clinical Trials /

Genetically Modified T-Cell Therapy in Treating Patients With Advanced ROR1+ Malignancies

NCT02602821

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Breast Carcinoma
  • Chronic Lymphocytic Leukemia
  • Mantle Cell Lymphoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Closed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Genetically Modified T-Cell Therapy in Treating Patients With Advanced ROR1+ Malignancies

Title

  • Brief Title: Genetically Modified T-Cell Therapy in Treating Patients With Advanced ROR1+ Malignancies
  • Official Title: Phase I Study of Adoptive Immunotherapy for Advanced ROR1+ Malignancies With Defined Subsets of Autologous T Cells Engineered to Express a ROR1-Specific Chimeric Antigen Receptor
  • Clinical Trial IDs

    NCT ID: NCT02706392

    ORG ID: 9330

    NCI ID: NCI-2015-01753

    Trial Conditions

    Estrogen Receptor Negative

    HER2/Neu Negative

    Progesterone Receptor Negative

    Recurrent Adult Acute Lymphoblastic Leukemia

    Recurrent Breast Carcinoma

    Recurrent Chronic Lymphocytic Leukemia

    Recurrent Mantle Cell Lymphoma

    Recurrent Non-Small Cell Lung Carcinoma

    Refractory Chronic Lymphocytic Leukemia

    Stage IV Breast Cancer

    Stage IV Non-Small Cell Lung Cancer

    Triple-Negative Breast Carcinoma

    Trial Interventions

    Drug Synonyms Arms

    Trial Purpose

    This phase I trial studies the side effects and best dose of genetically modified T-cell
    therapy in treating patients with receptor tyrosine kinase-like orphan receptor 1 positive
    (ROR1+) chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), acute lymphoblastic
    leukemia (ALL), stage IV non-small cell lung cancer (NSCLC), or triple negative breast
    cancer (TNBC) that has spread to other places in the body and usually cannot be cured or
    controlled with treatment (advanced). Genetically modified therapies, such as ROR1 specific
    chimeric antigen receptor (CAR) T-cells, are taken from a patient's blood, modified in the
    laboratory so they specifically may kill cancer cells with a protein called ROR1 on their
    surfaces, and safely given back to the patient after conventional therapy. The "genetically
    modified" T-cells have genes added in the laboratory to make them recognize ROR1.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To evaluate the safety of adoptive T cell therapy using ex vivo expanded autologous
    cluster of differentiation (CD)8+ and CD4+ ROR1 CAR-T cells for patients with advanced ROR1+
    hematologic (Cohort A) and epithelial (Cohort B) malignancies.

    SECONDARY OBJECTIVES:

    I. To determine duration of in vivo persistence of adoptively transferred T cells, and the
    phenotype of persisting T cells.

    II. To determine trafficking of adoptively transferred T cells traffic to the bone marrow or
    other tumor site and function in vivo.

    III. To determine preliminary antitumor activity of the adoptive transfer of ROR1 CAR-T
    cells in patients with measurable tumor burden prior to T cell transfer.

    OUTLINE: This is a phase I, dose escalation study of ROR1 CAR-specific autologous
    T-lymphocytes followed by a phase II study.

    Patients receive chemotherapy comprising fludarabine phosphate and cyclophosphamide as
    determined by the referring physician in consultation with the protocol principal
    investigator (PI). Beginning within 36-96 hours after completion of lymphodepleting
    chemotherapy, patients receive ROR1 CAR-specific autologous T-lymphocytes intravenously (IV)
    over 20-30 minutes. Patients may receive a second infusion of ROR1 CAR-specific autologous
    T-lymphocytes with or without additional cytoreductive therapy at the same (for those that
    received the highest cell dose) or up to the next highest dose level and there is persistent
    disease, there were no toxicities attributed to the first infusion, and the patient is at
    least 21 days from the first T cell infusion.

    After completion of study treatment, patients are followed up for at least 15 years.

    Trial Arms

    Name Type Description Interventions
    Treatment (ROR1 CAR-specific autologous T-lymphocytes) Experimental Patients receive chemotherapy comprising fludarabine phosphate and cyclophosphamide as determined by the referring physician in consultation with the protocol PI. Beginning within 36-96 hours after completion of lymphodepleting chemotherapy, patients receive ROR1 CAR-specific autologous T-lymphocytes IV over 20-30 minutes. Patients may receive a second infusion of ROR1 CAR-specific autologous T-lymphocytes with or without additional cytoreductive therapy at the same (for those that received the highest cell dose) or up to the next highest dose level and there is persistent disease, there were no toxicities attributed to the first infusion, and the patient is at least 21 days from the first T cell infusion.

    Eligibility Criteria

    Inclusion Criteria:

    - INCLUSION CRITERIA FOR PATIENTS WITH CLL, MCL OR ALL (COHORT A)

    - CLL who are beyond first remission and who have failed combination chemoimmunotherapy
    with regimens containing a purine analogue and anti-CD20 antibody, or who have failed
    tyrosine kinase or phosphatidylinositol 3 (PI3) kinase inhibitors, or who were not
    eligible for or declined such therapy; patients with fludarabine refractory disease
    are eligible

    - Mantle cell lymphoma patients who are beyond first remission and previously treated
    with chemoimmunotherapy; patients who have relapsed following autologous
    hematopoietic cell transplant (HCT) are eligible

    - ALL patients who have relapsed or have residual disease following treatment with
    curative intent; ALL patients must have ROR1 expressed on > 90% of the leukemia
    blasts to be eligible

    - Confirmation of diagnosis by internal pathology review of initial or subsequent
    biopsy or other pathologic material at the Fred Hutchinson Cancer Research Center
    (FHCRC)/Seattle Cancer Care Alliance (SCCA)

    - Evidence of ROR1 expression by immunohistochemistry or flow cytometry on any prior or
    current tumor specimen

    - Karnofsky performance status >= 70%

    - Negative pregnancy test for women of childbearing potential; subjects of childbearing
    potential are those who have not been surgically sterilized or have not been free
    from menses for > 1 year

    - Fertile male and female patients must be willing to use a contraceptive method
    before, during, and for at least two months after the T cell infusion

    - Ability to understand and provide informed consent

    - INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B):

    - INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients with stage IV
    non-small cell lung cancer who have been treated with at least one line of prior
    therapy or declined conventional therapy

    - INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients with known
    epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations
    must have been treated on at least one line of molecularly targeted therapy (e.g.,
    erlotinib, crizotinib)

    - INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients must have
    measurable disease by at least one of the criteria below:

    - Extra skeletal disease that can be accurately measured in at least one dimension
    as >= 10 mm with conventional computed tomography (CT) techniques as defined by
    Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

    - Skeletal or bone-only disease measurable by fludeoxyglucose F 18 (FDG) positron
    emission tomography (PET) imaging

    - INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): ROR1 expression in >
    20% of the primary tumor or metastasis by immunohistochemistry (IHC)

    - INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Karnofsky performance
    status of >= 70%

    - INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients must be off
    chemotherapy for a minimum of 3 weeks prior to start of treatment; targeted therapies
    must be stopped at least 3 days prior to start of lymphodepletion

    - INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Negative pregnancy
    test for women of childbearing potential; subjects of childbearing potential are
    those who have not been surgically sterilized or have not been free from menses for >
    1 year

    - INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Fertile male and
    female patients must be willing to use a contraceptive method before, during and for
    at least two months after the T cell infusion

    - INCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Ability to understand
    and provide informed consent

    - INCLUSION CRITERIA FOR TNBC

    - INCLUSION CRITERIA FOR TNBC: Histologically confirmed diagnosis of metastatic TNBC;
    i.e. breast cancer that is estrogen receptor (ER) negative (=< 10%), progesterone
    receptor (PR) negative (=< 10%), and human epidermal growth factor receptor 2 (HER2)
    negative (0 or 1+ by immunohistochemistry or negative for gene amplification by
    fluorescence in situ hybridization [FISH])

    - INCLUSION CRITERIA FOR TNBC: Patients must have measurable disease by at least one of
    the criteria below:

    - Extra skeletal disease that can be accurately measured in at least one dimension
    as >= 10 mm with conventional CT techniques as defined by RECIST 1.1

    - Skeletal or bone-only disease measurable by FDG PET imaging

    - INCLUSION CRITERIA FOR TNBC: Patients must have received standard adjuvant,
    neoadjuvant, and/or metastatic chemotherapy per National Comprehensive Cancer Network
    (NCCN) or institutional practice; no maximum on number of prior systemic treatment
    regimens

    - INCLUSION CRITERIA FOR TNBC: Patients may receive agents to protect against skeletal
    related complications such as zolendronic acid or denosumab

    - INCLUSION CRITERIA FOR TNBC: ROR1 expression in > 20% of the primary tumor or
    metastasis by IHC

    - INCLUSION CRITERIA FOR TNBC: Karnofsky performance status of >= 70%

    - INCLUSION CRITERIA FOR TNBC: Patients must be off chemotherapy for a minimum of 3
    weeks prior to planned leukapheresis

    - INCLUSION CRITERIA FOR TNBC: Negative pregnancy test for women of childbearing
    potential; subjects of childbearing potential are those who have not been surgically
    sterilized or have not been free from menses for > 1 year

    - INCLUSION CRITERIA FOR TNBC: Fertile male and female patients must be willing to use
    a contraceptive method before, during and for at least two months after the T cell
    infusion

    - INCLUSION CRITERIA FOR TNBC: Ability to understand and provide informed consent

    Exclusion Criteria:

    - EXCLUSION CRITERIA FOR PATIENTS WITH CLL, MCL, OR ALL (COHORT A)

    - Treatment with other investigational agent(s) within 30 days of planned
    lymphodepletion

    - Patients requiring ongoing daily corticosteroid therapy at a dose of > 15 mg of
    prednisone per day (or equivalent); pulsed corticosteroid use for disease control is
    acceptable

    - Active autoimmune disease requiring immunosuppressive therapy

    - Serum creatinine > 2.5 mg/dL

    - Serum glutamic oxaloacetic transaminase (SGOT) > 5 x upper limit of normal

    - Bilirubin > 3.0 mg/dL

    - Patients with clinically significant pulmonary dysfunction, as determined by medical
    history and physical exam should undergo pulmonary function testing; those with a
    forced expiratory volume in 1 second (FEV1) of < 2.0 L or diffusion capacity of the
    lung for carbon monoxide (DLCO) (corrected) < 40% will be excluded

    - Significant cardiovascular abnormalities as defined by any one of the following:
    congestive heart failure, clinically significant hypotension, symptomatic coronary
    artery disease, or a documented ejection fraction of < 45%; any patient with an
    ejection fraction (EF) of 45-49% must receive clearance by a cardiologist to be
    eligible for the trial

    - Patients who are human immunodeficiency virus (HIV) seropositive

    - Uncontrolled active infection (bacterial, viral, fungal, mycobacterial) not
    responding to treatment with intravenous antibiotics, antiviral or antifungal agents,
    or long-term treatment with oral agents

    - Anticipated survival of < 3 months

    - Women who are breast-feeding

    - Patients who have contraindication to cyclophosphamide chemotherapy

    - Known additional malignancy that is progressing or requires active treatment;
    exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
    skin, or in situ cervical cancer that has undergone potentially curative therapy

    - Active central nervous system (CNS) metastases and/or carcinomatous meningitis;
    subjects with previously treated brain metastases may participate provided they are
    stable (without evidence of progression by imaging for at least four weeks prior to
    enrollment and any neurologic symptoms have returned to baseline), have no evidence
    of new or enlarging brain metastases

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B)

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Absolute neutrophil
    count (ANC) < 1000/mm^3

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Hemoglobin (Hgb) < 9
    mg/dl (transfusion permitted to achieve this)

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Platelet count <
    75,000/mm^3

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Treatment with other
    investigational agent(s) within 30 days of planned lymphodepletion

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients requiring
    ongoing daily corticosteroid therapy at a dose of > 15 mg of prednisone per day (or
    equivalent); pulsed corticosteroid use for disease control is acceptable

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Active autoimmune
    disease requiring immunosuppressive therapy

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Serum creatinine > 2.5
    mg/dL

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): SGOT > 5 x upper limit
    of normal

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): bilirubin > 3.0 mg/dL

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients with
    clinically significant pulmonary dysfunction, as determined by medical history and
    physical exam should undergo pulmonary function testing; those with an FEV1 of < 2.0
    L or DLCO (corrected) < 40% will be excluded

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Significant
    cardiovascular abnormalities as defined by any one of the following: congestive heart
    failure, clinically significant hypotension, symptomatic coronary artery disease, or
    a documented ejection fraction of < 45%; any patient with an EF of 45-49% must
    receive clearance by a cardiologist to be eligible for the trial

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients who are HIV
    seropositive

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Uncontrolled active
    infection (bacterial, viral, fungal, mycobacterial) not responding to treatment with
    intravenous antibiotics, antiviral or antifungal agents, or long-term treatment with
    oral agents

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Women who are
    breastfeeding

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Anticipated survival
    of < 3 months

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Patients who have
    contraindication to cyclophosphamide chemotherapy

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Known additional
    malignancy that is progressing or requires active treatment; exceptions include basal
    cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical
    cancer that has undergone potentially curative therapy

    - EXCLUSION CRITERIA FOR PATIENTS WITH NSCLC OR TNBC (COHORT B): Active central nervous
    system (CNS) metastases and/or carcinomatous meningitis; subjects with previously
    treated brain metastases may participate provided they are stable (without evidence
    of progression by imaging for at least four weeks prior to enrollment and any
    neurologic symptoms have returned to baseline), have no evidence of new or enlarging
    brain metastases

    - EXCLUSION CRITERIA FOR TNBC

    - EXCLUSION CRITERIA FOR TNBC: ANC < 1000/mm^3

    - Hgb < 9 mg/dl (transfusion permitted to achieve this)

    - EXCLUSION CRITERIA FOR TNBC: Platelet count < 75,000/mm^3

    - EXCLUSION CRITERIA FOR TNBC: Treatment with other investigational agent(s) within 30
    days of planned lymphodepletion

    - EXCLUSION CRITERIA FOR TNBC: Patients requiring ongoing daily corticosteroid therapy
    at a dose of > 15 mg of prednisone per day (or equivalent); pulsed corticosteroid use
    for disease control is acceptable

    - EXCLUSION CRITERIA FOR TNBC: Active autoimmune disease requiring immunosuppressive
    therapy

    - EXCLUSION CRITERIA FOR TNBC: Serum creatinine > 2.5 mg/dL

    - EXCLUSION CRITERIA FOR TNBC: SGOT > 5 x upper limit of normal

    - EXCLUSION CRITERIA FOR TNBC: Bilirubin > 3.0 mg/dL

    - EXCLUSION CRITERIA FOR TNBC: Patients with clinically significant pulmonary
    dysfunction, as determined by medical history and physical exam should undergo
    pulmonary function testing; those with an FEV1 of < 2.0 L or DLCO (corrected) < 40%
    will be excluded

    - EXCLUSION CRITERIA FOR TNBC: Significant cardiovascular abnormalities as defined by
    any one of the following: congestive heart failure, clinically significant
    hypotension, symptomatic coronary artery disease or a documented ejection fraction of
    < 45%; any patient with an EF of 45-49% must receive clearance by a cardiologist to
    be eligible for the trial

    - EXCLUSION CRITERIA FOR TNBC: Patients who are HIV seropositive

    - EXCLUSION CRITERIA FOR TNBC: Uncontrolled active infection (bacterial, viral, fungal,
    mycobacterial) not responding to treatment with intravenous antibiotics, antiviral or
    antifungal agents, or long-term treatment with oral agents

    - EXCLUSION CRITERIA FOR TNBC: Anticipated survival of < 3 months

    - EXCLUSION CRITERIA FOR TNBC: Breast-feeding women

    - EXCLUSION CRITERIA FOR TNBC: patients who have contraindication to cyclophosphamide
    chemotherapy

    - EXCLUSION CRITERIA FOR TNBC: Has a known additional malignancy that is progressing or
    requires active treatment; exceptions include basal cell carcinoma of the skin,
    squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone
    potentially curative therapy

    - EXCLUSION CRITERIA FOR TNBC: Has known active central nervous system (CNS) metastases
    and/or carcinomatous meningitis; subjects with previously treated brain metastases
    may participate provided they are stable (without evidence of progression by imaging
    for at least four weeks prior to enrollment and any neurologic symptoms have returned
    to baseline) and have no evidence of new or enlarging brain metastases

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum tolerated dose of ROR1 CAR-specific autologous T lymphocytes defined as a true dose limiting toxicity rate of 25% probably or definitely attributed to T cell infusion

    Secondary Outcome Measures

    Duration of persistence of adoptively transferred ROR1 CAR-T cells

    Identification of sites where ROR1 CAR-T cells migrate

    Objective response rate of complete remission and partial remission

    Overall survival

    Progression free survival

    Trial Keywords