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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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 Patien

Brief Summary: 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 Summary:

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 adult 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, estimate duration of response, 6 month progression free survival (PFS 6mo) rate, and 1 year overall survival (OS) rate, and describe the immunogenicity of CD123+ CAR 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 3-7 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 (D
Sponsor: City of Hope Medical Center

Current Primary Outcome:

  • 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 ]
    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.
  • Incidence of adverse events as assessed by NCI CTCAE version 4.0 [ Time Frame: Up to 15 years ]
    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.
  • Disease response (CR or CRi) [ Time Frame: Up to 15 year post-treatment ]
    Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated. Analysis will be done separately for each disease.


Original Primary Outcome:

  • 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 ]
    Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated. Tables will summarized all toxicities and side effects by attribution of treatment, dose, time-post treatment, organ and severity.
  • Incidence of adverse events as assessed by NCI CTCAE version 4.0 [ Time Frame: Up to 15 years ]
    Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated. Tables will summarized all toxicities and side effects by attribution of treatment, dose, time-post treatment, organ and severity.


Current Secondary Outcome:

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


Original Secondary Outcome:

  • Disease response (CR, CRi, or PR) [ Time Frame: Up to 15 year post-treatment ]
    Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated.
  • Engraftment of transferred T-cell [ Time Frame: Day 28 ]
    Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated.
  • Anti-CAR123 antibody levels [ Time Frame: Up to 15 years ]
    Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated.


Information By: City of Hope Medical Center

Dates:
Date Received: June 6, 2014
Date Started: December 1, 2015
Date Completion: December 2017
Last Updated: March 13, 2017
Last Verified: March 2017