Clinical Trials /

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

NCT02706392

Description:

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.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

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

  • ORG STUDY ID: 9330
  • SECONDARY ID: NCI-2015-01753
  • SECONDARY ID: 9330
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: P50CA138293
  • SECONDARY ID: RG9215045
  • NCT ID: NCT02706392

Conditions

  • Estrogen Receptor Negative
  • HER2/Neu Negative
  • Progesterone Receptor Negative
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Mantle Cell Lymphoma
  • Refractory Chronic Lymphocytic Leukemia
  • Stage IV Breast Cancer AJCC v6 and v7
  • Stage IV Non-Small Cell Lung Cancer AJCC v7
  • Triple-Negative Breast Carcinoma

Interventions

DrugSynonymsArms
ROR1 CAR-specific Autologous T-LymphocytesAutologous ROR1-CAR-T Cells, Chimeric Anti-ROR1 T-cell Receptor-expressing Autologous T-lymphocytes, ROR1-CAR-TTreatment (ROR1 CAR-specific autologous T-lymphocytes)

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 dose escalation study of ROR1 CAR-specific autologous T-lymphocytes.

      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

NameTypeDescriptionInterventions
Treatment (ROR1 CAR-specific autologous T-lymphocytes)ExperimentalPatients 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.
  • ROR1 CAR-specific Autologous T-Lymphocytes

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):

          -  Patients with non-small cell lung cancer that is metastatic or inoperable and who have
             been treated with at least one line of prior therapy or declined conventional therapy

          -  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)

          -  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

          -  ROR1 expression in > 20% of the primary tumor or metastasis by immunohistochemistry
             (IHC)

          -  Karnofsky performance status of >= 70%

          -  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

          -  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 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])

          -  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

          -  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

          -  Patients may receive agents to protect against skeletal related complications such as
             zoledronic acid or denosumab

          -  ROR1 expression in > 20% of the primary tumor or metastasis by IHC

          -  Karnofsky performance status of >= 70%

          -  Patients must be off chemotherapy for a minimum of 3 weeks prior to planned
             leukapheresis

          -  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

        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 =< 65% 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

          -  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

          -  Untreated 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):

          -  Absolute neutrophil count (ANC) < 1000/mm^3

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

          -  Platelet count < 75,000/mm^3

          -  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

          -  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 an
             FEV1 of =< 65% or 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 EF of
             45-49% must receive clearance by a cardiologist to be eligible for the trial

          -  Patients who are 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

          -  Women who are breastfeeding

          -  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

          -  Untreated 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:

          -  ANC < 1000/mm^3

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

          -  Platelet count < 75,000/mm^3

          -  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

          -  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 an
             FEV1 of =< 65% or 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 EF of
             45-49% must receive clearance by a cardiologist to be eligible for the trial

          -  Patients who are 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

          -  Breast-feeding women

          -  Patients who have contraindication to cyclophosphamide chemotherapy

          -  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

          -  Untreated 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Within 35 days of receptor tyrosine kinase-like orphan receptor 1 positive chimeric antigen receptor-T cell infusion
Safety Issue:
Description:Will be graded according to Common Terminology Criteria for Adverse Events.

Secondary Outcome Measures

Measure:Duration of persistence of adoptively transferred receptor tyrosine kinase-like orphan receptor 1 positive chimeric antigen receptor-T cells
Time Frame:Up to 365 days after the T cell infusion
Safety Issue:
Description:Data should be collected for persistence of transferred T cells and descriptive statistics will be used to summarize the changes from baseline where possible.
Measure:Identification of sites where receptor tyrosine kinase-like orphan receptor 1 positive chimeric antigen receptor-T cells migrate
Time Frame:Up to 15 years
Safety Issue:
Description:Samples of bone marrow, blood and other tissues (e.g. cerebral spinal fluid, tumor, thoracentesis fluid) will be collected from patients as clinically indicated. Receptor tyrosine kinase-like orphan receptor 1 positive chimeric antigen receptor-T cells and their frequency/persistence will be detected by flow cytometry, polymerase chain reaction, and immunohistochemistry as appropriate
Measure:Objective response rate of complete remission and partial remission
Time Frame:Up to 15 years
Safety Issue:
Description:Data should be collected for efficacy of transferred T cells and descriptive statistics will be used to summarize the changes from baseline where possible. For those patients with measurable disease at the time T cell therapy commences, responses will be evaluated using standard response criteria based on computed tomography or positron emission tomography imaging and histologic analysis of bone marrow or other tissue samples.
Measure:Overall survival
Time Frame:Up to 15 years
Safety Issue:
Description:Data should be collected for efficacy of transferred T cells and descriptive statistics will be used to summarize the changes from baseline where possible.
Measure:Progression free survival
Time Frame:Up to 15 years
Safety Issue:
Description:Data should be collected for efficacy of transferred T cells and descriptive statistics will be used to summarize the changes from baseline where possible.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

Last Updated

February 20, 2019