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
Overview
- Phase
- Phase 1
- Intervention
- cyclophosphamide
- Conditions
- Adult Acute Myeloid Leukemia in Remission
- Sponsor
- City of Hope Medical Center
- Enrollment
- 31
- Locations
- 1
- Primary Endpoint
- 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
- Status
- Active, not recruiting
- Last Updated
- 7 months ago
Overview
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 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.
Investigators
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 participant 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 at 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
- •Karnofsky performance status score \>= 70
- •A life expectancy \>= 16 weeks at time of enrollment
- •Pediatric research participants must weigh \> 50 kg
- •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
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; such social situations include but are not limited to lack of reliable means of transportation for follow up, inability to make time for required clinic visits due to work or family needs, or lack of reliable ways of communication with the study team in the event that the participant is seriously ill
- •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
Arms & Interventions
Treatment (lymphodepletion, T-cell immunotherapy)
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 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.
Intervention: cyclophosphamide
Treatment (lymphodepletion, T-cell immunotherapy)
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 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.
Intervention: Autologous CD123CAR-CD28-CD3zeta-EGFRt-expressing T Lymphocytes
Treatment (lymphodepletion, T-cell immunotherapy)
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 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.
Intervention: laboratory biomarker analysis
Treatment (lymphodepletion, T-cell immunotherapy)
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 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.
Intervention: Allogeneic CD123CAR-CD28-CD3zeta-EGFRt-expressing T-lymphocytes
Treatment (lymphodepletion, T-cell immunotherapy)
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 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.
Intervention: Fludarabine Phosphate
Outcomes
Primary Outcomes
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 arm.
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 arm.
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 arm.
Secondary Outcomes
- Survival(Up to 15 years)
- CAR123-specific antibody level(Up to 15 years)
- Engraftment of transferred CD123+ CAR T cells(Day 28)
- Duration of response(Up to 15 years)
- Progression Free Survival (PFS)(Up to 15 years)