Clinical Trials /

Genetically Modified T-cell Immunotherapy in Treating Patients With Relapsed/Refractory Acute Myeloid Leukemia and Persistent/Recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm

NCT02159495

Description:

This phase I trial studies the side effects and the best dose of genetically modified T-cells after lymphodepleting chemotherapy in treating patients with acute myeloid leukemia or blastic plasmacytoid dendritic cell neoplasm that has returned after a period of improvement or has not responded to previous treatment. An immune cell is a type of blood cell that can recognize and kill abnormal cells in the body. The immune cell product will be made from patient or patient's donor (related or unrelated) blood cells. The immune cells are changed by inserting additional pieces of deoxyribonucleic acid (DNA) (genetic material) into the cell to make it recognize and kill cancer cells. Placing a modified gene into white blood cells may help the body build an immune response to kill cancer cells.

Related Conditions:
  • Acute Biphenotypic Leukemia
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Blastic Plasmacytoid Dendritic Cell Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Genetically Modified T-cell Immunotherapy in Treating Patients With Relapsed/Refractory Acute Myeloid Leukemia and Persistent/Recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm
  • Official Title: Phase I Study of Cellular Immunotherapy Using T Cells Lentivirally Transduced to Express a CD123-Specific, Hinge-Optimized, CD28-Costimulatory Chimeric Antigen Receptor and a Truncated EGFR for Patients With CD123+ Relapsed/Refractory Acute Myeloid Leukemia and Persistent/Recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm

Clinical Trial IDs

  • ORG STUDY ID: 13272
  • SECONDARY ID: NCI-2014-01147
  • SECONDARY ID: 13272
  • NCT ID: NCT02159495

Conditions

  • Adult Acute Myeloid Leukemia in Remission
  • Acute Biphenotypic Leukemia
  • Early Relapse of Acute Myeloid Leukemia
  • Late Relapse of Acute Myeloid Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Secondary Acute Myeloid Leukemia
  • Blastic Plasmacytoid Dendritic Cell Neoplasm
  • Acute Myeloid Leukemia
  • Adult Acute Lymphoblastic Leukemia
  • Interleukin-3 Receptor Subunit Alpha Positive
  • Minimal Residual Disease
  • Refractory Acute Myeloid Leukemia
  • Untreated Adult Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
cyclophosphamideCPM, CTX, Cytoxan, Endoxan, EndoxanaTreatment (lymphodepletion, T-cell immunotherapy)
Autologous CD123CAR-CD28-CD3zeta-EGFRt-expressing T LymphocytesCD123R(EQ)28zeta/EGFRt+ T cells, Anti CD123-CAR/CD28-costimulatory Lentiviral Vector-transduced Autologous T LymphocytesTreatment (lymphodepletion, T-cell immunotherapy)
Allogeneic CD123CAR-CD28-CD3zeta-EGFRt-expressing T-lymphocytesAllogeneic CD123R(EQ)28zeta/EGFRt+ T CellsTreatment (lymphodepletion, T-cell immunotherapy)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, Oforta, SH T 586Treatment (lymphodepletion, T-cell immunotherapy)

Purpose

This phase I trial studies the side effects and the best dose of genetically modified T-cells after lymphodepleting chemotherapy in treating patients with acute myeloid leukemia or blastic plasmacytoid dendritic cell neoplasm that has returned after a period of improvement or has not responded to previous treatment. An immune cell is a type of blood cell that can recognize and kill abnormal cells in the body. The immune cell product will be made from patient or patient's donor (related or unrelated) blood cells. The immune cells are changed by inserting additional pieces of deoxyribonucleic acid (DNA) (genetic material) into the cell to make it recognize and kill cancer cells. Placing a modified gene into white blood cells may help the body build an immune response to kill cancer cells.

Detailed Description

      PRIMARY OBJECTIVES: I. To examine the anti-tumor activity and safety of administering ex vivo
      expanded T cells that are genetically modified using a self-inactivating (SIN) lentiviral
      vector to express a co-stimulatory CD123-specific chimeric antigen receptor (CAR) as well as
      a truncated EGFR (CD123CAR-CD28-CD3zeta-EGFRt+ T cells [CD123+ CAR T cells]) following
      lymphodepletion for patients with CD123+ relapsed or refractory acute myeloid leukemia (AML)
      (arm 1), or CD123+ persistent or recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm
      (BPDCN) (arm 2). II. To determine the recommended Phase II dose (RP2D) for both arms (AML and
      BPDCN). SECONDARY OBJECTIVES: I. To assess activity in the form of CD123+ CAR T cell
      persistence, 6 month progression free survival (PFS 6mo) rate, and 1 year overall survival
      (OS) rate, and describe the immunogenicity of CD123R(EQ)28zeta/EGFRt+ T cells. TERTIARY
      OBJECTIVES: I. To assess impact on hematopoiesis, change from baseline in numbers of CD123+
      blood cells, CD123 expression on malignant cells and hematopoietic cells, and the clinical
      efficacy of EGFRt mediated CAR T cell ablation.

      OUTLINE: This is a dose-escalation study of autologous or allogeneic (related or unrelated
      donor) CD123+ CAR T cells. Patients undergo a lymphodepleting regimen 3-10 days prior to
      CD123+ CAR T cell infusion as determined by the principal investigator and the protocol team.
      Patients receive either cyclophosphamide intravenously (IV) on days -4 and/or -3; fludarabine
      phosphate and cyclophosphamide IV on days -5 to -3; fludarabine phosphate IV on days -5 to -3
      and cyclophosphamide IV on days -4 and/or -3. Patients receive autologous or allogeneic
      CD123+ CAR T cells IV over 15 minutes on day 0. Patients with evidence of disease at > 28
      days, continuing expression of the CD123 antigen, and not having experienced a dose-limiting
      toxicity (DLT) may receive a second infusion of CD123+ CAR T cells after 28 days. After
      completion of study treatment, patients are followed up at 24 hours, then every 2 days for up
      to 14 days, every week for 1 month, every month for 1 year and then yearly for 15 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (lymphodepletion, T-cell immunotherapy)ExperimentalPatients undergo a lymphodepleting regimen 3-10 days prior to CD123+ CAR T cell infusion as determined by the principal investigator and the protocol team. Patients receive either cyclophosphamide IV on days -4 and/or -3; fludarabine phosphate and cyclophosphamide IV on days -5 to -3; fludarabine phosphate IV on days -5 to -3 and cyclophosphamide IV on days -4 and/or -3. Patients receive autologous or allogeneic CD123+ CAR Tcells IV over 15 minutes on day 0. Patients with evidence of disease at > 28 days, continuing expression of the CD123 antigen, and not having experienced a DLT may receive a second infusion of CD123+ CAR T cells after 28 days.
  • cyclophosphamide
  • Fludarabine Phosphate

Eligibility Criteria

        Inclusion Criteria:

          -  ARM 1 AML: Research patients enrolled are those patients with relapsed or refractory
             CD123+ AML de novo, or secondary OR participants who are at high risk for disease
             recurrence NOTE: CD123+ biphenotypic acute leukemia or CD123+ acute lymphoblastic
             leukemia (ALL) may also be considered but only after discussion with the study
             principal investigator (PI)

               -  Relapsed AML is defined as patients that had a first complete remission (CR)
                  before developing recurrent disease (increased bone marrow blasts)

               -  Refractory AML is defined as patients that have not achieved a first CR after 2
                  cycles of induction chemotherapy; for patients with AML evolving from
                  myelodysplastic syndrome, they should have completed at least one cycle of
                  induction chemotherapy

          -  ARM 2 BPDCN: Research participants with a diagnosis of BPDCN, according to World
             Health Organization (WHO) classification by hematopathology, who underwent at least 1
             line of systemic therapy for BPDCN and who have persistent or recurrent disease in at
             least one of the following are eligible: peripheral blood, bone marrow, lymph nodes,
             spleen, cutaneous lesions or other sites OR participants who are at high risk for
             disease recurrence

          -  FOR BOTH STUDY ARMS: Research participants must have bone marrow and/or peripheral
             blood samples available for confirmation of diagnosis of AML or BPDCN; CD123
             positivity must be confirmed by either flow cytometry or immunohistochemistry within
             90 days of study entry; cytogenetics, flow cytometry, and molecular studies (such as
             FMS-like tyrosine kinase-3 [FLT-3] status) will be obtained as per standard practice
             however, for research participants who are a high risk of recurrence, they must have
             historical bone marrow and/or peripheral blood samples available for confirmation of
             diagnosis of AML or BPDCN; CD123 positivity must be confirmed by either flow cytometry
             or immunohistochemistry prior to start of lymphodepletion

          -  Weight >= 50 kg

          -  Karnofsky performance status score >= 70

          -  Life expectancy >= 16 weeks at time of enrollment

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control or abstinence) prior to study entry and
             for six months following duration of study participation; should a woman become
             pregnant or suspect that she is pregnant while participating on the trial, she should
             inform her treating physician immediately

          -  Calculated creatinine clearance (absolute value) of >= 50 mL/minute or creatinine <
             2.0 mg/dl or < 2 times upper limit of normal for the research participant's age group

          -  Serum bilirubin =< 3.0 mg/dL

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 5 times the
             institutional upper limits of normal

          -  Ejection fraction measured by echocardiogram (ECHO) or multi gated acquisition scan
             (MUGA) >= 50%

          -  Diffusion capacity of carbon monoxide (DLCO) or forced expiratory volume in one second
             (FEV1) > 45% predicted

          -  Research participants' last dose of prior chemotherapy or radiation must be >= 2 weeks
             before leukapheresis; Note: this criterion is not applicable if the research
             participant's donor is undergoing leukapheresis

          -  If a research participant has undergone prior allogeneic stem cell transplant, he/she
             must be off all immunosuppressants for graft versus host disease (GVHD) for at least 2
             weeks before undergoing leukapheresis

             *Note: the above is not applicable if the research participant's donor is undergoing
             leukapheresis

          -  Negative serum or urine pregnancy test

          -  All research participants must have the ability to understand and willingness to sign
             a written informed consent or age appropriate assent for pediatric patients *Note: For
             research participants who do not speak English, a short form consent may be used with
             a City of Hope (COH) certified interpreter/translator to proceed with screening and
             leukapheresis, while the request for a translated full consent is processed; however,
             the research participant is allowed to proceed with lymphodepletion and T cell
             infusion only after the translated full consent form is signed

        ELIGIBILITY TO UNDERGO LYMPHODEPLETION Note: evaluation should be performed no more than 7
        days prior to lymphodepletion

          -  Research participant with known central nervous system (CNS) leukemic involvement that
             is refractory to intrathecal chemotherapy and/or cranio-spinal radiation but
             effectively treated to complete remission (<5 white blood cell[WBC]/mm^3 and no blast
             in cerebrospinal fluid [CSF]) is eligible to proceed with lymphodepletion

          -  Research participants must have a donor or stem cells source identified for allogeneic
             transplantation, either related (7/8 or 8/8 allele matched or haploidentical),
             unrelated 7/8 or 8/8 allele match) donor, or cord blood stem cell source (at least 4/6
             matched)

          -  Research participants with a response less than a CR or complete response with
             incomplete hematopoietic recovery (CRi) or detectable minimal residual disease (MRD)
             positive disease

          -  Research participant has a released cryopreserved T cell product for CAR T cell
             infusion on approximately day 0

          -  Research participant must be at least 2 weeks out from having received the last dose
             of investigational agent

          -  Karnofsky performance status (KPS) >= 70

          -  Documented measurable or evaluable disease

          -  Non hematological toxicity related to prior therapy must either have returned to =<
             grade 2, baseline, or deemed irreversible

          -  Research participants of reproductive potential must agree to use and utilize and
             adequate method of contraception throughout treatment and for at least 8 weeks after T
             cell infusion

          -  If a research participant has undergone prior allogeneic stem cell transplant, he/she
             must be off all immunosuppressants for GVHD for at least 7 days before beginning
             lymphodepletion

          -  Pulmonary: not requiring supplemental oxygen or mechanical ventilation, oxygen
             saturation 90% or higher on room air

          -  Cardiovascular: not requiring pressor support, no symptomatic cardiac arrhythmias, no
             acute coronary syndrome, or uncontrolled hypertension

          -  Renal Function: calculated creatinine clearance (absolute value) of >= 50 mL/minute or
             creatinine < 2.0 mg/dl or < 2 times upper limit of normal for the research
             participant's age group

          -  Liver Function: adequate liver function defined as total bilirubin =< 3.0 mg/dl

          -  ALT and AST =< 5 times the institutional upper limits of normal

          -  Neurological: research participant without clinically significant encephalopathy/new
             focal deficits

          -  Infectious diseases: no clinical evidence of uncontrolled active infectious process

        ELIGIBILITY CRITERIA AT TIME OF INFUSION OF GENETICALLY MODIFIED T CELLS

          -  Research participants has undergone lymphodepletion

          -  Pulmonary: not requiring supplemental oxygen or mechanical ventilation, oxygen
             saturation 90% or higher on room air

          -  Cardiovascular: not requiring pressor support, no symptomatic cardiac arrhythmias, no
             acute coronary syndrome, or uncontrolled hypertension

          -  Renal Function: calculated creatinine clearance (absolute value) of >= 50 mL/minute or
             creatinine < 2.0 mg/dl or < 2 times upper limit of normal for the research
             participant's age group

          -  Liver Function: adequate liver function defined as total bilirubin =< 3.0 mg/dl

          -  ALT and AST =< 5 times the institutional upper limits of normal

          -  Neurological: research participant without clinically significant encephalopathy/new
             focal deficits

          -  Infectious diseases: no clinical evidence of uncontrolled active infectious process

          -  Research participant must be off all anti-leukemic drugs, with the exception of the
             lymphodepleting regimens, at least 7 days prior to CAR T cell infusion

        ELIGIBILITY CRITERIA TO UNDERGO OPTIONAL T CELL ABLATION

          -  Research participant has >= 1% CD123+ CAR T cells in the peripheral blood

          -  Pulmonary: not requiring supplemental oxygen or mechanical ventilation, oxygen
             saturation 90% or higher on room air

          -  Cardiovascular: not requiring pressor support, no symptomatic cardiac arrhythmias, no
             acute coronary syndrome, or uncontrolled hypertension

          -  Renal Function: serum creatinine did NOT increase by more than 2.5 fold from baseline
             (at time of screening)

          -  Liver Function: adequate liver function defined as total bilirubin =< 3.0 mg/dl

          -  AST =< 5 x ULN, ALT =< 5 x ULN

          -  Neurological: research participant without clinically significant encephalopathy/new
             focal deficits

          -  Infectious diseases: no clinical evidence of uncontrolled active infectious process

        ALLOGENEIC DONOR CRITERIA FOR APHERESIS DONATION:

          -  Related donor selection will be conducted in accordance with City of Hope's Department
             of Hematology & Hematopoietic Cell Transplantation criteria and, in the case of
             unrelated donor from a transplant center, will comply with the National Marrow Donor
             Program's (NMDP) donor selection standards; when a potentially eligible recipient of
             an unrelated donor product from an NMDP Center is identified, the recipient will
             complete an NMDP search transfer request to allow City of Hope (COH) NMDP staff to
             contact the NMDP Coordinating Center, who in turn, will contact the donor's prior
             Donor Center; the search will follow the NMDP Policy for subsequent donation requests;
             any form deemed appropriate and necessary by the NMDP, including the Subsequent
             Donation Request Form, Therapeutic T Cell Collection Prescription and Therapeutic Stem
             Cell Collection Prescription, will be submitted as required

          -  In the case of a related donor: The identified donor must be the original donor whose
             stem cells were used for the research participant's alloSCT

          -  For both related and unrelated donors: The donor's hepatitis B surface antigen must be
             negative and the hepatitis C antibody must be nonreactive; in the case of a positive
             hepatitis C antibody result, the hepatitic C virus (HCV) viral polymerase chain
             reaction (PCR) will have to be performed and the results should be negative

        Exclusion Criteria:

          -  Research participants with uncontrolled intercurrent illness including, but not
             limited to ongoing or active or poorly controlled infection, symptomatic congestive
             heart failure, unstable angina pectoris, cardiac arrhythmia, poorly controlled
             pulmonary disease or psychiatric illness/social situations that would limit compliance
             with study requirements

          -  Research participants who have tested human immunodeficiency virus (HIV) positive, or
             have active hepatitis B or C infection based on testing performed within 4 weeks of
             enrollment

          -  Research participants with presence of other active malignancy. However, research
             participants with history of prior malignancy treated with curative intent and in
             complete remission are eligible

          -  Pregnant and lactating women are excluded from this study

        Study-Specific Exclusion

          -  Failure of research participant to understand the basic elements of the protocol
             and/or the risks/benefits of participating in this phase I study

          -  History of allergic reactions attributed to compounds of similar chemical or
             biological composition to cetuximab

          -  Dependence on corticosteroids:

               -  If the participant is undergoing leukapheresis: physiological replacement doses
                  of steroids are allowed - prednisone no more than 7.5 mg, hydrocortisone less
                  than 12 mg/m^2/day

                    -  However, all participants must be able to reduce steroid requirement to no
                       more than physiological replacement doses prior to start of lymphodepletion

          -  Active autoimmune disease requiring systemic immunosuppressive therapy

          -  Research participants will be excluded, who in the opinion of the investigator, may
             not be able to comply with the safety monitoring requirements of the study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-limiting toxicity (DLT) defined as any grade 3 or higher toxicity as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame:28 days
Safety Issue:
Description:Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated. Tables will summarize all toxicities and side effects by attribution of treatment, dose, time-post treatment, organ and severity. Analysis will be done separately for each disease arm.

Secondary Outcome Measures

Measure:Engraftment of transferred CD123+ CAR T cells
Time Frame:Day 28
Safety Issue:
Description:Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated. Analysis will be done separately for each disease arm.
Measure:CAR123-specific antibody level
Time Frame:Up to 15 years
Safety Issue:
Description:Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated. Analysis will be done separately for each disease arm.
Measure:Duration of response
Time Frame:Up to 15 years
Safety Issue:
Description:Will provide descriptive statistics. Analysis will be done separately for each disease arm.
Measure:Progression Free Survival (PFS)
Time Frame:Up to 15 years
Safety Issue:
Description:Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated for PFS 6mo. Analysis will be done separately for each disease arm.
Measure:Survival
Time Frame:Up to 15 years
Safety Issue:
Description:Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated for 1 year OS. Analysis will be done separately for each disease arm.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

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