Genetically Engineered Lymphocyte Therapy in Treating Patients With B-Cell Leukemia or Lymphoma That is Resistant or Refractory to Chemotherapy

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Abramson Cancer Center of the University of Pennsylvania
ClinicalTrials.gov Identifier:
NCT01029366
First received: December 9, 2009
Last updated: October 16, 2013
Last verified: October 2013

December 9, 2009
October 16, 2013
July 2009
October 2013   (final data collection date for primary outcome measure)
Number of Adverse Events [ Designated as safety issue: Yes ]
  • New onset secondary malignancies [ Designated as safety issue: No ]
  • Occurrence of study related adverse events (defined as >= Grade 3 signs/symptoms, laboratory toxicities, and clinical events) that are possibly, likely, or definitely related to study treatment [ Time Frame: Until week 24 ] [ Designated as safety issue: Yes ]
  • Feasibility to manufacture CART-19 cells from patient apheresis products [ Designated as safety issue: No ]
  • Engraftment as defined by duration of in vivo survival of CART-19 cells [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01029366 on ClinicalTrials.gov Archive Site
Not Provided
  • Anti-tumor responses to CART-19 cell infusions [ Designated as safety issue: No ]
  • Overall survival and cause of death [ Designated as safety issue: No ]
  • Correlation of in vitro killing assays of CART-19 cells against patient tumor with clinical response in patients with stored or accessible tumor cells [ Designated as safety issue: No ]
  • Host immunity against the murine anti-CD19 or other elements of the transgene or vector such as VSV-G, and correlation with loss of detectable CART-19 (loss of engraftment) [ Designated as safety issue: No ]
  • General anti-tumor immunity [ Time Frame: Baseline and post-infusion ] [ Designated as safety issue: No ]
  • Relative survival of CART-19 TCR zeta and TCR zeta:4-1BB cells over time (in subjects infused with mixture of T cells) [ Designated as safety issue: No ]
  • Relative subsets of CART-19 T cells (Tcm, Tem, and Treg) [ Designated as safety issue: No ]
  • Relative engraftment of CART-19 cells expressing TCR zeta or TCR zeta:4-1BB domains [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Genetically Engineered Lymphocyte Therapy in Treating Patients With B-Cell Leukemia or Lymphoma That is Resistant or Refractory to Chemotherapy
Pilot Study of Redirected Autologous T-cells Engineered to Contain Anti-CD19 Attached to TCR and 4-1BB Signaling Domains in Patient With Chemotherapy Resistant or Refractory CD19+ Leukemia and Lymphoma

Adoptive immunotherapy has been successful in treatment of cancer due the graft versus tumor effect, but effective treatment is typically associated with graft versus host disease (GVHD). Autologous T cell transfer for cancer immunotherapy is an alternative approach that offers cancer specific immunotherapy without GVHD. To break immunological tolerance to tumors, autologous T cells have been modified with tumor-specific T cell receptors (TCRs)1,2. Studies using this approach have demonstrated the potent expansion, trafficking and antitumor activity of the redirected autologous T cells, but the approach is limited by MHC restriction and therefore is challenging for broad clinical application3,4. An alternative approach is to modify T cells with a chimeric immunoreceptor (CIR) which mimics the signaling of the natural TCR when encountering tumor antigen. This creates a universal tumor specific TCR that can be used across patients with a common tumor antigen5. Despite advances in current treatments, most patients with B cell malignancies remain incurable. Most B cell lymphomas, mantle cell lymphomas, ALLs, CLLs, hairy cell leukemias, and a subset of acute myelogenous leukemias express the CD19 antigen6-8. Expression of CD19 is highly restricted to B cells, and is not detected on other normal tissues, including hematopoietic stem cells, thus making it a safe tumor antigen for the CIR approach9. Previous clinical approaches have utilized the CD3 or Fc receptor signaling chain for T cell activation10. Costimulation via 4-1BB signaling has been shown to improve antitumor activity in vitro, and therefore incorporation of this signaling chain in the CIR may improve function of the T-bodies in vivo11-13. Our hypothesis is that CD19:4-1BB:CD3 modified cells will demonstrate improved engraftment and function over CD19-CD3 modified cells in patients with B cell malignancies.

Primary objectives:

1. To evaluate the safety and feasibility of a single target dose of 5 times 10e9 total cells, acceptable range of 1.5 times 10e7 to 5 times 10e9 total cells comprised of autologous CART-19 cells that express the TCR zeta and 4-1 BB costimulatory domain.

Secondary objectives:

  1. Proof of mechanism: determine if 2nd generation CAR expressing 4-1BB costimulation domains have improved persistence in patients.
  2. Proof of concept: determine the effects of CART-19 on CD19 expression in vivo.
  3. Proof of bioactivity: Evaluate changes in systemic soluble immune factors in patients
  4. Proof of bioactivity: Evaluate impact of CART19 treatment on tumor burden
  5. Explore whether CART-19 cells retain anti-tumor activity in vivo.
  6. Determine if host immunity develops against CART-19.
  7. Characterize the relative subsets of CART-19 T cells (Tcm, Tem, and Treg).
  8. Describe survival and response rates
Interventional
Not Provided
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Hematopoietic/Lymphoid Cancer
  • Adult Acute Lymphoblastic Leukemia in Remission
  • B-cell Adult Acute Lymphoblastic Leukemia
  • B-cell Chronic Lymphocytic Leukemia
  • Prolymphocytic Leukemia
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Refractory Chronic Lymphocytic Leukemia
  • Stage III Adult Diffuse Large Cell Lymphoma
  • Stage III Chronic Lymphocytic Leukemia
  • Stage III Grade 1 Follicular Lymphoma
  • Stage III Grade 2 Follicular Lymphoma
  • Stage III Grade 3 Follicular Lymphoma
  • Stage III Mantle Cell Lymphoma
  • Stage IV Adult Diffuse Large Cell Lymphoma
  • Stage IV Chronic Lymphocytic Leukemia
  • Stage IV Grade 1 Follicular Lymphoma
  • Stage IV Grade 2 Follicular Lymphoma
  • Stage IV Grade 3 Follicular Lymphoma
  • Stage IV Mantle Cell Lymphoma
  • Other: laboratory biomarker analysis
  • Genetic: polymerase chain reaction
    Other Name: PCR
  • Genetic: reverse transcriptase-polymerase chain reaction
    Other Name: RT-PCR
  • Biological: anti-CD19-CAR retroviral vector-transduced autologous T cells
    Given IV
  • Biological: genetically engineered lymphocyte therapy
Experimental: Arm I
Patients receive CART-19 cells transduced with a lentiviral vector to express anti-CD19 scFv TCRζ:41BB administered on days 0, 1, 2 and 11 in the absence of disease progression or unacceptable toxicity
Interventions:
  • Other: laboratory biomarker analysis
  • Genetic: polymerase chain reaction
  • Genetic: reverse transcriptase-polymerase chain reaction
  • Biological: anti-CD19-CAR retroviral vector-transduced autologous T cells
  • Biological: genetically engineered lymphocyte therapy
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
14
Not Provided
October 2013   (final data collection date for primary outcome measure)

Inclusion

  • Male and female subjects with CD19+ B cell malignancies in patients with no available curative treatment options (such as autologous or allogeneic SCT) who have limited prognosis (several months to < 2 year survival) with currently available therapies will be enrolled
  • CD19+ leukemia or lymphoma
  • ALL in CR2 or CR3 and not eligible for allogeneic SCT because of age, comorbid disease, or lack of available family member or unrelated donor
  • Follicular lymphoma, previously identified as CD19+:
  • At least 2 prior combination chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy
  • Stage III-IV disease
  • Less than 1 year between last chemotherapy and progression (i.e. most recent progression free interval < 1 year)
  • Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc)
  • CLL:
  • At least 2 prior chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy. Patients with high risk disease manifested by deletion chromosome 17p will be eligible if they fail to achieve a CR to initial therapy or progress within 2 years of 1 prior
  • Less than 2 years between last chemotherapy and progression (i.e. most recent progression free interval < 2 years)
  • Not eligible or appropriate for conventional allogeneic SCT
  • Patients who achieve only a partial response to FCR as initial therapy will be eligible.
  • Mantle cell lymphoma:
  • Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT
  • Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc...)
  • Relapsed after prior autologous SCT
  • B-cell prolymphocytic leukemia (PLL) with relapsed or residual disease after at least 1 prior therapy and not eligible for allogeneic SCT
  • Diffuse large cell lymphoma, previously identified as CD19+:
  • Residual disease after primary therapy and not eligible for autologous SCT
  • Relapsed after prior autologous SCT
  • Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate of conventional allogeneic or autologous SCT
  • Expected survival > 12 weeks
  • Creatinine < 2.5 mg/dl
  • ALT/AST < 3x normal
  • Bilirubin < 2.0 mg/dl
  • Any relapse after prior autologous SCT will make patient eligible regardless of other prior therapy
  • Adequate venous access for apheresis, and no other contraindications for leukapheresis
  • Voluntary informed consent is given

Exclusion

  • Pregnant or lactating women
  • The safety of this therapy on unborn children is not known
  • Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion
  • Uncontrolled active infection
  • Active hepatitis B or hepatitis C infection
  • Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary
  • Previously treatment with any gene therapy products
  • Feasibility assessment during screening demonstrates < 30% transduction of target lymphocytes, or insufficient expansion (< 5-fold) in response to CD3/CD28 costimulation
  • Any uncontrolled active medical disorder that would preclude participation as outlined
  • HIV infection
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01029366
UPCC 04409, NCI-2009-01357
Yes
Abramson Cancer Center of the University of Pennsylvania
Abramson Cancer Center of the University of Pennsylvania
Not Provided
Principal Investigator: Noelle Frey, MD Abramson Cancer Center of the University of Pennsylvania
Abramson Cancer Center of the University of Pennsylvania
October 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP