Trial Title:
Safety of Myeloablative Conditioning, Orca-T, and Allogeneic, Donor-Derived CD19/CD22-CAR (Chimeric Antigen Receptor) T Cells in Adults With B-cell Acute Lymphoblastic Leukemia (ALL)
NCT ID:
NCT05507827
Condition:
Lymphoid Leukemia
Conditions: Official terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Allogeneic donor-derived T-cells transduced with bivalent lentiviral vector (CD19/CD22-BBz) chimeric antigen receptor (CAR)
Description:
CD19/C22CAR T cells will be administered at a dose of CAR+ cells/kg body weight via IV
administration
Arm group label:
Dose escalation
Intervention type:
Drug
Intervention name:
Treg CD34+HSPC (Orca-T)
Description:
Purified donor-derived regulatory T-cell (Treg) plus CD34 + hematopoietic progenitor
cells
Arm group label:
Dose escalation
Summary:
To assess the safety of administering allogenic, donor-derived CD19/CD22-CAR T cells that
meet established release specifications in adults with B-cell ALL following a
myeloablative conditioning regimen and Orca-T to determine if this will augment graft
versus leukemia without increasing acute GVHD or graft failure.
Criteria for eligibility:
Criteria:
Patient Inclusion Criteria:
- Subjects in CR must have a history of chemotherapy refractory disease defined as
progression or stable disease after one line of chemotherapy, or relapsed disease
after achieving prior CR OR must have other high risk ALL features including: CRLF2
rearrangement, Ph-like phenotype, MLL/KMT2a rearrangement, or hypodiploid karyotype.
- Subjects with persistent or relapsed minimal residual disease (MRD) (by flow
cytometry, PCR, FISH, or next generation sequencing) require verification of MRD in
the peripheral blood or bone marrow on two occasions at least 2 weeks apart.
- Subjects with active ALL (defined as >=5% bone marrow blasts, circulating blasts, or
extramedullary disease) are eligible.
- Age ≥ 18 and ≤ 65 years (i.e., from age 18 to < 66 years old) at the time of
enrollment
- Eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2; or
Karnofsky ≥ 60%
- CD19 expression is required any time since diagnosis. CD19 expression may be
detected by immunohistochemistry or by flow cytometry. The choice of whether to use
flow cytometry or immunohistochemistry will be determined by what is the most easily
available tissue sample in each subject. In general, immunohistochemistry will be
used for lymph node biopsies, flow cytometry will be used for peripheral blood and
bone marrow samples. Patients receiving prior CD19 CAR T cell or blinatumomab are
eligible if there is no documented history of CD19 negativity on the malignant
cells.
- Subjects must have an HLA matched related donor willing to undergo unstimulated
apheresis for T cell collection for CAR T cell generation followed by GCSF mobilized
apheresis for HSC/Treg graft.
- Matched related donor who is an 8/8 match for HLA-A, -B, -C, and -DRB1, all typed
using DNA-based high-resolution methods
- Subjects must have adequate organ function measured by:
- Cardiac: Cardiac ejection fraction at rest ≥ 45%
- Hepatic:
- Total bilirubin < 2 times upper limit of normal (ULN) (patients with Gilbert's
syndrome may be included where hemolysis has been excluded and with approval of
the study PI)
- ALT/AST <= 3 times ULN
- Renal: Calculated creatinine clearance ≥ 50 mL/min or serum creatinine < 2.0
mg/dL
- Pulmonary: Diffusing capacity of the lung for carbon monoxide (DLCO) (adjusted
for hemoglobin) ≥ 50%
- CNS: Subjects with CNS involvement are eligible as long as there are no overt
signs or symptoms that in the evaluation of the investigator would mask or
interfere with the neurological assessment of toxicity.
- Negative serum or urine beta-HCG test in females of childbearing potential within 3
weeks of registration
- Subjects of childbearing or child fathering potential must be willing to practice
birth control from the time of enrollment on this study and for twelve (12) months
after receiving the preparative conditioning regimen.
- Must be able to give informed consent. Legal authorized representative (LAR) is
permitted if subject is cognitively able to provide verbal assent.
Donor Inclusion Criteria
- Age ≥ 18 and ≤ 75 years at time of enrollment
- Karnofsky performance status of ≥ 70% defined by institutional standards
- Willing to donate for two separate apheresis collections (T cells and PBSC)
- Matched related donor who is an 8/8 match for HLA-A, -B, -C, and -DRB1, all typed
using DNA-based high-resolution methods
- Negative serum or urine beta-HCG test in females of childbearing potential within 2
weeks of first apheresis
- Seronegative for HIV-1 RNA PCR; HIV 1 and HIV 2 Ab (antibody); HTLV-1 and HTLV-2 Ab;
PCR negative or sAg (surface antigen) negative for hepatitis B; negative for the
Treponema pallidum antibody Syphilis screen; and negative for HIV-1 and hepatitis C
by nucleic acid testing (NAT) within 40 days of donor apheresis procedures.
- In the case that T pallidum antibody tests are positive, donors must:
- Be evaluated and show no evidence of syphilis infection of any stage by
physical exam and history
- Have completed effective antibiotic therapy to treat syphilis
- Have a documented negative non-treponemal test (such as RPR) or in the case of
a positive non-treponemal test must be evaluated by an infectious disease
expert to evaluate for alternative causes of test positivity and confirm no
evidence of active syphilitic disease
Patient Exclusion Criteria:
- History of other malignancy unless disease free for at least 3 years. At the
discretion of the Principal Investigator, subjects in remission for 1-2 years prior
to enrollment may be deemed eligible after considering the nature of other
malignancy, likelihood of recurrence for one year following therapy, and impact of
prior treatment on risk of CD19/CD22-CAR T cells and Treg graft. Subjects in
remission <1 year are not eligible. The following exceptions apply:
- Nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) is
eligible.
- Hormonal therapy in subjects in remission >1 year will be allowed.
- Patients who have undergone a prior allogeneic or autologous stem cell transplant.
- Recipient positive anti-donor HLA antibodies against a mismatched allele in the
selected donor determined by either:
- a positive crossmatch test of any titer (by complement-dependent cytotoxicity
or flow cytometric testing), or
- the presence of anti-donor HLA antibody to any of the following HLA loci:
HLA-A, -B, -C, -DRB1, -DQB1, -DQA1, -DPB1, or -DPA1, with mean fluorescence
intensity (MFI) >1000 by solid phase immunoassay
- Presence of fungal, bacterial, viral, or other infection that is uncontrolled.
Simple UTI and uncomplicated bacterial pharyngitis are permitted if responding to
active treatment.
- Known history of infection with any of the following:
- HIV
- Hepatitis B (HBsAg positive) **
- Hepatitis C virus (anti HCV positive) **
** A history of hepatitis B or hepatitis C is permitted if the viral load is
undetectable per quantitative PCR and/or nucleic acid testing.
- Currently receiving corticosteroids or other immunosuppressive therapy. Topical
corticosteroids or oral systemic corticosteroid doses less than or equal to 10
mg/day are allowed.
- Planned pharmaceutical in vivo or ex vivo T cell depletion, e.g., post-transplant
cyclophosphamide (Cy), peri-transplant anti-thymocyte globulin (ATG), or
alemtuzumab. For patients that have previously been exposed to a T cell-depleting
agent, a 5-half-life washout of the agent must occur prior to planned Transplant Day
0.
- Hyperleukocytosis (≥ 50,000 blasts/μL) or rapidly progressive disease that in the
estimation of the investigator and sponsor would compromise ability to complete
study therapy.
- History of myocardial infarction, cardiac angioplasty or stenting, unstable angina,
or other clinically significant cardiac disease within 12 months of enrollment.
- Pregnant or breast feeding
- Patients with known autoimmune disease requiring the use of systemic
immunosuppressive therapy within the last year
- Presence of a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia,
cerebellar disease, or any autoimmune disease with CNS involvement that in the
judgment of the investigator may impair the ability to evaluate neurotoxicity.
- Any medical condition that in the judgement of the investigator is likely to
interfere with assessment of safety or efficacy of study treatment
Donor Exclusion Criteria
- Evidence of active infection
- Seropositive for HIV-1 or -2, HTLV-1 or -2
- Positive PCR test results indicating acute or chronic HBV infection. Patients with
isolated HBV core antibody positivity will not be excluded. Donors whose HBV
infection status cannot be determined conclusively by serologic test results
(www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf) must be negative for HBV by
PCR to be eligible for study participation.
- Potential for Zika virus infection as defined as any of the following:
- Medical diagnosis of Zika virus infection in the past 6 months
- Residence in, or travel to, an area with active Zika virus transmission within
the past 6 months.
- Unprotected sex within the past 6 months with a person who is known to have
either of the risk factors listed above (donor exclusion criterion 5.a or 5.b)
- Donors determined to be ineligible based on the results of Zika virus screening may
be determined to be eligible if:
o The donor has no signs or symptoms consistent with active Zika virus infection and
o Either of the following is true: i. The donor is a first-degree or second-degree
blood relative of the recipient ii. Urgent medical need, meaning no comparable human
cell product is available and the recipient is likely to suffer death or serious
morbidity without the human cell product, as attested by the Investigator.
- Pregnant or breastfeeding female
- Medical, physical, or psychological reason that would place the donor at increased
risk for complications from growth factor or leukapheresis.
Gender:
All
Minimum age:
18 Years
Maximum age:
65 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Stanford Cancer Center
Address:
City:
Palo Alto
Zip:
94305
Country:
United States
Status:
Recruiting
Contact:
Last name:
Lindsay Danley
Phone:
650-721-2372
Email:
lindsmd@stanford.edu
Investigator:
Last name:
Lori Muffly, MD, MS
Email:
Principal Investigator
Investigator:
Last name:
David Miklos, MD, PhD
Email:
Sub-Investigator
Investigator:
Last name:
Sally Arai, MD
Email:
Sub-Investigator
Investigator:
Last name:
Laura Johnston, MD
Email:
Sub-Investigator
Investigator:
Last name:
Robert Lowsky, MD
Email:
Sub-Investigator
Investigator:
Last name:
Robert Negrin, MD
Email:
Sub-Investigator
Investigator:
Last name:
Andrew Rezvani, MD
Email:
Sub-Investigator
Investigator:
Last name:
Judith Shizuru, MD, PhD
Email:
Sub-Investigator
Investigator:
Last name:
Wen-Kai Weng, MD, PhD
Email:
Sub-Investigator
Investigator:
Last name:
Praveen Shiraz, MD
Email:
Sub-Investigator
Investigator:
Last name:
Matthew Frank, MD, PhD
Email:
Sub-Investigator
Investigator:
Last name:
Sushma Bharadwaj, MD
Email:
Sub-Investigator
Investigator:
Last name:
Melody Smith, MD
Email:
Sub-Investigator
Start date:
August 18, 2022
Completion date:
January 2037
Lead sponsor:
Agency:
Dr. Melody Smith, MD, MS
Agency class:
Other
Collaborator:
Agency:
Orca Biosystems, Inc.
Agency class:
Industry
Source:
Stanford University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05507827
