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

NCT02159495 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 13272NCI-2014-01147
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (3)

• 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

  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.

  28 days

• Incidence of adverse events as assessed by NCI CTCAE version 4.0

  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.

  Up to 15 years

• Disease response (CR or CRi)

  Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated. Analysis will be done separately for each disease arm.

  Up to 15 year post-treatment

Secondary Outcomes (5)

• Engraftment of transferred CD123+ CAR T cells

  Day 28

• CAR123-specific antibody level

  Up to 15 years

• Duration of response

  Up to 15 years

• Progression Free Survival (PFS)

  Up to 15 years

• Survival

  Up to 15 years

Other Outcomes (5)

• Number of CD123+ normal cells in peripheral blood and bone marrow

  Up to day 14

• Number of peripheral blood cell subsets in hematopoietic stem cell compartment

  Up to day 14

• Proof of elimination of CD123+ CAR T cells

  Up to day 14

Study Arms (1)

Treatment (lymphodepletion, T-cell immunotherapy)

EXPERIMENTAL

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.

Drug: cyclophosphamide; Biological: Autologous CD123CAR-CD28-CD3zeta-EGFRt-expressing T Lymphocytes; Other: laboratory biomarker analysis; Biological: Allogeneic CD123CAR-CD28-CD3zeta-EGFRt-expressing T-lymphocytes; Drug: Fludarabine Phosphate

Interventions

cyclophosphamide DRUG

Given IV

Also known as: CPM, CTX, Cytoxan, Endoxan, Endoxana

Treatment (lymphodepletion, T-cell immunotherapy)

Autologous CD123CAR-CD28-CD3zeta-EGFRt-expressing T Lymphocytes BIOLOGICAL

Given IV

Also known as: CD123R(EQ)28zeta/EGFRt+ T cells, Anti CD123-CAR/CD28-costimulatory Lentiviral Vector-transduced Autologous T Lymphocytes

Treatment (lymphodepletion, T-cell immunotherapy)

laboratory biomarker analysis OTHER

Correlative studies

Treatment (lymphodepletion, T-cell immunotherapy)

Allogeneic CD123CAR-CD28-CD3zeta-EGFRt-expressing T-lymphocytes BIOLOGICAL

Given IV

Also known as: Allogeneic CD123R(EQ)28zeta/EGFRt+ T Cells

Treatment (lymphodepletion, T-cell immunotherapy)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, Oforta, SH T 586

Treatment (lymphodepletion, T-cell immunotherapy)

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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%
• ONLY research participants experiencing hypoxia with oxygen saturation less than 92% are required to have 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator
• Mustang Bio, Inc.: collaborator

Study Sites (1)

City of Hope Medical Center

Duarte, California, 91010, United States

Location

MeSH Terms

Conditions

Leukemia, Biphenotypic, Acute; Leukemia, Myeloid, Acute; Blastic Plasmacytoid Dendritic Cell Neoplasm; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Neoplasm, Residual

Interventions

Cyclophosphamide; fludarabine phosphate

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Histiocytic Disorders, Malignant; Lymphoma; Hematologic Neoplasms; Neoplasms by Site; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Lihua E. Budde

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 6, 2014
• First Posted: June 10, 2014
• Study Start: December 15, 2015
• Primary Completion (Estimated): August 6, 2026
• Study Completion (Estimated): August 6, 2026
• Last Updated: September 16, 2025

Record last verified: 2025-09

Locations

US (1)