This Research study is being done to characterize the safety, tolerability, and preliminary
antitumor activity of the NEXI-001 T cell product (a new experimental therapy), which
contains populations of CD8+ T cells targeting multiple leukemia associated antigen peptides
in patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) who have
relapsed disease after an allogeneic hematopoietic cell transplant (HCT).
The study will enroll AML or MDS patients who have either Minimal Residual Disease (MRD) or
relapsed disease after a human leukocyte antigen (HLA)-matched allogeneic HCT. Patients who
have had an HLA-mismatched or haploidentical allogeneic HCT will not be eligible to
participate in this study. Eligible patients for this study must also have ≥ 50% T-cell
chimerism from the original donor at the time study entry.
The enrolled patients will undergo bridging therapy for the purposes of disease control while
the NEXI-001 T cell product is being manufactured. Choice of bridging therapy administered
will be per the Investigator's discretion, but is limited to acceptable agents as specified
in the protocol. Bridging therapy will be administered prior to lymphodepleting (LD) therapy,
with the last dose of the bridging therapy administered ≥ 14 days prior to initiation of LD
therapy. Within 72 hours after completing LD therapy, patients will receive a single IV
infusion of the NEXI-001 T cell product.
The NEXI-001 is an adoptive cellular therapy product which contains populations of
antigen-specific CD8+ T cells. The antigen-specific CD8+ T cells in the NEXI-001 T cell
product are derived from Peripheral Blood Mononuclear Cells (PBMC) obtained from the original
stem cell donor. During the manufacturing process, these cells are primed and expanded ex
vivo using nano-size artificial Antigen Presenting Cells (aAPC) loaded with five leukemia
associated antigen peptides in combination with a proprietary T cell enrichment and expansion
process.
The NEXI-001 T cell product is restricted to patients that are HLA-A2.01 allele positive for
this study.
There are two parts to this study, a Safety Evaluation Phase and a Dose Expansion Phase. The
Safety Evaluation Phase will determine the safety and tolerability of a single dose of
NEXI-001 T cell product, and will consist of Dose Escalation at two dose levels - each with
cohorts of three patients.
When all three patients at Dose Level 1 have dosed and cleared the DLT period, three
additional patients will be enrolled at Dose Level 2. When three patients have cleared the
DLT period at the highest dose level, that dose will be advanced to the Dose Expansion Phase.
The Dose Expansion Phase will enroll up to 16 additional patients to further define the
safety and evaluate the initial anti-tumor efficacy of the NEXI- 001 T cell product at the
dose established from the Safety Evaluation Phase.
All patients will enter a Post-Treatment Follow-Up period after infusion of the NEXI- 001 T
cell product. During this phase, all patients will be monitored for AEs and followed for
anti-leukemia response until the end of study visit is complete (up to one year).
Additional assessments for safety, disease status, and other secondary and exploratory
endpoints will also be monitored during the follow-up period.
All patients will be followed for overall survival (OS) from time of disease progression
until the last visit of the last patient. During this time, patients will be followed via
telephone or other electronic contact at 12 week intervals for monitoring of OS.
Inclusion Criteria:
General
1. Ability to provide informed consent and documentation of informed consent prior to
initiation of any study-related tests or procedures that are not part of
standard-of-care for the patient's disease. Patients must also be willing and able to
comply with study procedures, including the acquisition of specified research
specimens
2. Age ≥ 18 years old
3. Expression of HLA-A*0201 as determined by high resolution sequence-based typing method
(e.g. TruSight HLA v2 Sequence Panel)
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Patients must have a confirmed diagnosis of AML (according to World Health
Organization (WHO) classification) or MDS with evidence of MRD or morphological
relapse after HLA-matched allogeneic HCT
MRD includes:
1. Detection of blasts <5% in bone marrow
2. Detection of a clonal abnormal blast population via multi-color flow cytometry
3. Detection of known or new myeloid gene mutations
6. Donor match at 10 of 10 loci for HLA-A, -B, -C, -DRB1 and DQB1, with each typed at
high resolution by DNA-based methods.
a. Patients who have had prior HLA-mismatched or haploidentical allogeneic HCT will
not be eligible
7. T-cell chimerism ≥ 50% to donor (by PCR analysis)
8. Acceptable laboratory parameters as follows:
1. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × upper
limit of normal (ULN)
2. Total bilirubin ≤ 1.5 × ULN, except patients with Gilbert's syndrome, who may
enroll if the conjugated bilirubin is within normal limits
3. Creatinine < 1.5 mg/dL or a calculated or measured creatinine clearance (CL) ≥ 50
mL/min per standard calculation
9. Recovery to Grade 1 or baseline of non-hematologic toxicities from prior treatments,
excluding alopecia
10. Female patients of childbearing potential must test negative for pregnancy at
enrollment and during the study. Sexually active women of child-bearing potential,
unless surgically sterile, must be willing to use a highly effective method of birth
control defined as those which result in a low failure rate (i.e., less than 1% per
year) such as implants, injectables, combined oral contraceptives, intra-uterine
devices (IUDs) or vasectomized partner
11. Male patients with partners of childbearing potential must be either vasectomized or
agree to use a condom in addition to having their partners use another method of
contraception resulting in a highly effective method of birth control defined as those
which result in a low failure rate (i.e., less than 1% per year) such as implants,
injectables, combined oral contraceptives, or IUDs. Patients should not have sexual
intercourse with females who are either pregnant or lactating without double-barrier
contraception Is not pregnant or breastfeeding, or expecting to conceive or father
children within the projected duration of the trial, starting with the prescreening or
screening visit through one year from administration of NEXI-001 cells
Exclusion Criteria:
1. Active acute or chronic graft versus host disease (GvHD)
1. Eligible patients will not be on any steroids ≥10 mg per day prednisone or
equivalent or other immunosuppressants such as tacrolimus, cyclosporine, etc.
2. Intermittent topical, inhaled or intranasal corticosteroids are allowed
2. Have active or uncontrolled infections with positive cultures and/or requiring
treatment with IV anti-infective agents
3. History of clinically significant cardiovascular disease including but not limited to:
1. Myocardial infarction or unstable angina within the 6 months prior to the
initiation of study
2. Stroke or transient ischemic attack within 6 months prior to initiation of study
3. Clinically significant cardiac arrhythmia
4. Uncontrolled hypertension: systolic blood pressure (SBP) > 180 mmHg, diastolic
blood pressure (DBP) > 100 mmHg
5. Congestive heart failure (New York Heart Association [NYHA] class III-IV)
6. Pericarditis or clinically significant pericardial effusion
7. Myocarditis
4. Clinically significant pulmonary compromise, including a requirement for supplemental
oxygen use to maintain adequate oxygenation
5. History of autoimmune disease (e.g. Crohn's, rheumatoid arthritis, systemic lupus
erythematosus, etc.) resulting in end organ injury or requiring systemic
immunosuppression / systemic disease modifying agents within the last 2 years prior to
enrollment. Subjects with a history of autoimmune-related hypothyroidism on a stable
dose of thyroid replacement hormone and subjects with controlled Type 1 diabetes
mellitus on a stable insulin regimen may be eligible for the study
6. Human immunodeficiency virus (HIV) seropositive; HIV testing within 2 years of
enrollment
7. Seropositive for and with evidence of active viral infection with hepatitis B virus
(HBV). Patients who are hepatitis B surface antigen (HBsAg) negative and HBV viral DNA
negative are eligible
1. Patients who had HBV but have received an antiviral treatment and show
non-detectable viral DNA for 6 months are eligible
2. Patients who are seropositive because of HBV vaccine are eligible
8. Seropositive for and with active viral infection with hepatitis C virus (HCV)
a. Patients who had HCV but have received an antiviral treatment and show no
detectable HCV viral DNA for 6 months are eligible
9. Second primary invasive malignancy that has not been in remission for greater than 2
years. Exceptions that do not require a 2-year remission include: resected
non-melanoma skin cancer; carcinoma in situ (cervix, bladder, breast, etc.) or
squamous intraepithelial lesion on Pap smear; localized prostate cancer (Gleason score
< 6); or resected melanoma in situ
10. History of trauma or major surgery within 4 weeks prior to the study enrollment
11. Any serious underlying medical or psychiatric condition that would impair the ability
of the patient to receive or tolerate the planned treatment and follow up
12. Known hypersensitivity to any component of NEXI-001 T cells, cyclophosphamide,
fludarabine or tocilizumab
13. Vaccination with any live virus vaccine is not permitted prior to the initiation of
study treatment. Inactivated annual influenza vaccination is allowed.
14. Dementia or altered mental status that would preclude understanding and rendering of
informed consent
15. History of seizures, aphasia, psychosis or other chronic clinically significant
neurologic disorders
a. Patients with remote history of seizures that are well controlled on anti-seizure
medications and without any seizure episode for 6 months are eligible
16. Any issue that in the opinion of the investigator, would contraindicate the patient's
participation in the study or confound the results of the study
