Acute Myeloid Leukemia Clinical Trial
CD33-CAR T Cell Therapy for the Treatment of Recurrent or Refractory Acute Myeloid Leukemia
This phase I trial tests the safety, side effects, and the best dose of anti-CD33 chimeric antigen receptor (CAR) T-Cell therapy in treating patients with acute myeloid leukemia that has come back (recurrent) or does not respond to treatment (refractory). CAR T-cell therapy is a type of treatment in which a patient or donor's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's or donor's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers.
I. Examine the anti-tumor activity and safety of administering patient-specific donor-derived (allogeneic) CD33-CAR T cells following lymphodepletion in research participants with CD33+ recurrent/refractory (r/r) acute myeloid leukemia (AML).
I. Assess activity in the form of CAR T cell expansion and persistence, to assess impact on hematopoiesis, 6-month progression free survival (PFS 6mo) rate, duration of response, and 1-year overall survival (OS) rate.
I. Change from baseline in numbers of CD33+ blood cells, CD33 expression on leukemia cells and hematopoietic cells.
II. For subjects who receive cetuximab for CAR T cell ablation, assess the activity of infusional cetuximab to eliminate transferred CD33R(CD8h)BBzeta/EGFRt+ T cells.
OUTLINE: This is a dose-escalation study.
Patients undergo lymphodepletion therapy 3-5 days prior to CAR T cell infusion and receive anti-CD33 CAR T-cells intravenously (IV) on day 0. Patients with persistent CD33+ AML who are > 28 days past the initial CAR T infusion, have additional product available and did not experience a dose-limiting toxicity, may optionally receive anti-CD33 CAR T-cells IV.
Documented informed consent of the participant and/or legally authorized representative
Assent, when appropriate, will be obtained per institutional guidelines
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, while the request for a translated full consent is processed
Agreement to allow the use of archival tissue from diagnostic tumor biopsies
If unavailable, exceptions may be granted with Study principal investigator (PI) approval
Age: >= 18 years
Karnofsky Performance Scale (KPS) >= 70
Life expectancy >= 16 weeks at the time of enrollment
Prior allogeneic transplant allowed if > 6 months prior to study enrollment
Participant must have a confirmed diagnosis of active CD33+ AML de novo, or secondary OR participants who are at a high risk for disease recurrence
Relapsed AML is defined as patients that had a first complete response (CR) before developing recurrent disease (increased bone marrow blasts)
Refractory AML is defined as patients that have not achieved a first CR after induction chemotherapy. For patients with AML evolving from myelodysplastic syndrome, they should have completed at least one cycle of induction chemotherapy
Research participants must have bone marrow and/or peripheral blood samples available for confirmation of diagnosis of AML
CD33 positivity must be confirmed by either flow cytometry or immunohistochemistry within 90 days of study entry. Cytogenetics, flow cytometry, and molecular studies (such as FLT-3 status) will be obtained as per standard practice
Research participants who are at a high risk of disease recurrence, they must have historical bone marrow and/or peripheral blood samples available for confirmation of diagnosis of AML
No known contraindications to lymphodepleting agents, steroids, tocilizumab and/or cetuximab, or the investigational agent
Total serum bilirubin =< 2.0 mg/dL
Participants with Gilbert syndrome may be included if their total bilirubin is =< 3.0
Aspartate aminotransferase (AST) =< 3 x the upper limit of normal (ULN)
Alanine aminotransferase (ALT) =< 3 x ULN
Estimated creatinine clearance of >= 60 mL/min per the Cockcroft-Gault formula, and the participant is not on hemodialysis
Left ventricular ejection fraction >= 50% within 8 weeks before enrollment
Oxygen (O2) saturation > 92% not requiring oxygen supplementation
Women of childbearing potential (WOCBP): negative urine or serum pregnancy test
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy
Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)
Research participants must have a potential donor or stem cell source identified for allogeneic transplantation, either related (7/8 or 8/8 allele matched or haploidentical)
DONOR: The identified donor must be the original donor whose stem cells were used for the research participant's allogeneic hematopoietic stem cell transplantation (alloSCT)
DONOR: The donor must be HIV negative
DONOR: KPS >= 70
DONOR: Documented body weight
Prior allogeneic transplant if < 6 months prior to enrollment
Concurrent use of systemic steroids or chronic use of immunosuppressant medications should be stopped 28-days prior to enrollment. Recent or current use of inhaled or topical steroids in standard doses is not exclusionary. Physiologic replacement of steroids (prednisone =< 7.5 mg/day, or equivalent doses of other corticosteroids) is allowed
Participants with active autoimmune disease, including graft versus host disease (GvHD), requiring systemic immune suppressive should be stopped 28-days prior to enrollment
Participants may not be receiving any other investigational agents and are not dependent on concurrent biological therapy, chemotherapy, or radiation therapy
With exception to Hydrea which must be stopped prior to initiation of lymphodepletion
Research participants on active systemic antifungal treatment within 8 weeks of enrollment are not eligible. However, participants on antifungal prophylaxis are eligible
Not applicable at the time of enrollment if the research participant's donor is undergoing leukapheresis
Subjects with >= Grade 2 myelofibrosis on bone marrow biopsy
Subjects with clinically significant arrhythmia or arrhythmias not stable on medical management within two weeks of screening if the patient is undergoing leukapheresis. Patients with controlled atrial arrythmia is allowed
Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
History of stroke or intracranial hemorrhage within 6 months prior to screening
Subjects with presence of other active malignancy, however, research participants with history of prior malignancy treated with curative intent and in complete remission are eligible
Clinically significant uncontrolled illness
Active infection requiring antibiotics
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
Active viral hepatitis
Females only: Pregnant or breastfeeding
Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures
Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
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