A Phase 1 Study of cytokine-induced memory-like (CIML) NK cells with venetoclax as consolidation therapy in AML

The purpose of this research study is to test the safety and to explore the effectiveness
of infusing cytokine- induced memory-like (CIML) natural killer (NK) cells in combination
with Interleukin-2 (IL-2) and standard-of-care venetoclax as a treatment for Acute
Myeloid Leukemia (AML).

Names of the study therapies involved in this study are:

- Lymphodepleting therapy with Fludarabine and Cyclophosphamide prior to CIML NK cell
infusion

- CIML NK (a cellular therapy)

- IL-2 (a recombinant, human glycoprotein)

- Venetoclax (a selective inhibitor of BCL-2 protein)

Inclusion Criteria for Trial Enrollment (Screening Visit #1):

- Acute myeloid leukemia (AML)

- Age ≥ 18 years old

- At time of screening patient is being treated with HMA(azacitidine or decitabine) +
venetoclax therapy and has received at least 1 cycle of HMA (azacitidine or
decitabine) + venetoclax. Patients can have received other lines of therapy prior to
HMA + venetoclax therapy including prior chemotherapy but cannot have received a
prior allogeneic stem cell transplant.

- Last bone marrow biopsy within 2 months (60 days) prior to the screening date showed
a complete remission (CR) or complete remission with incomplete count recovery (CRi)
or morphologic leukemia free state (MLFS) (< 5% blasts). Bone marrow biopsy does NOT
need to be repeated at screening visit #1 and a historic bone marrow biopsy report
can be used if it was obtained within 2 months (60 days) of screening visit #1. A
bone marrow biopsy will be repeated at screening visit #2.

- Last bone marrow biopsy within 2 months (60 days) prior to the screening date showed
measurable residual disease (MRD+) by either flow cytometry, next generation
sequencing or PCR. Patients with persistent DNMTA, TET2 or ASXL1 mutations will not
qualify as MRD+ as these DTA mutations are associated with clonal hematopoiesis.
Bone marrow biopsy does NOT need to be repeated at screening visit #1 and a historic
bone marrow biopsy report can be used if it was obtained within 2 months (60 days)
of screening visit #1. A bone marrow biopsy will be repeated at screening visit #2.

- Presence of molecular risk factors for relapse with continued HMA + venetoclax
therapy as defined by any of the following present at the time of diagnosis or start
of HMA + venetoclax therapy (these do not need to be present at the time the
screening BM biopsy):

- 2022 ELN adverse risk karyotype: t(6;9)(p23.3;q34.1)/DEK::NUP214;
t(v;11q23.3)/KMT2A-rearranged; t(9;22)(q34.1;q11.2)/BCR::ABL1;
t(8;16)(p11.2;p13.3)/KAT6A::CREBBP; inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/
GATA2, MECOM(EVI1), t(3q26.2;v)/MECOM(EVI1)-rearranged; -5 or del(5q); -7;
Complex karyotype, monosomal karyotype

- 2022 ELN adverse risk mutations: Any one of the following mutations: Mutated
TP53, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2

- Additional mutations associated with acquired resistance to venetoclax: Mutated
NRAS, KRAS, FLT3 ITD/TKD

- At the time of screening, the patient is considered not a good enough candidate to
undergo allogeneic hematopoietic stem cell transplantation (HSCT) in the opinion of
the treating physician. This could be either due to advanced age, significant
comorbidities or high risk of disease relapse after HSCT without additional therapy
prior to HSCT. The patient could potentially become eligible for a HSCT in the
future if the situation changes in the future (e.g., performance status improves
with therapy, MRD is eradicated with therapy).

- ECOG performance status ≤2 (see Appendix A)

- Available haploidentical or fully HLA-matched related donor that is willing and
eligible for non-mobilized collection.

- Participants must meet the following organ function as defined below:

- Total bilirubin: ≤1.5 x institutional upper limit of normal (ULN) (except
Gilbert's or disease-related hemolysis, then < 3 x ULN)

- AST(SGOT)/ALT(SGPT): ≤3 x institutional ULN

- creatinine clearance ≥ 45 mL/min; calculated by the Cockcroft Gault formula

- oxygen saturation ≥ 90% on room air

- left ventricular ejection fraction > 40%

- Negative pregnancy test for women of childbearing potential only.

- The effects of CIML NK cells and IL-2 on the developing human fetus are unknown. For
this reason, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in
this study, she should inform her treating physician immediately. Men treated or
enrolled on this protocol must also agree to use adequate contraception prior to the
study and until 4 months after the last IL-2 dose administration.

- Participants with known history or current symptoms of cardiac disease, or history
of treatment with cardiotoxic agents, should have a clinical risk assessment of
cardiac function using the New York Heart Association Functional Classification. To
be eligible for this trial, participants should be class 2B or better.

- Participants with a prior or concurrent malignancy whose natural history or
treatment does not have the potential to interfere with the safety or efficacy
assessment of the investigational regimen are eligible for this trial.

- Ability to understand and the willingness to sign a written informed consent
document. (Providing consents in as many languages as possible is encouraged)

- Subjects must be able to swallow pills.

- No laboratory evidence of ongoing hemolysis in opinion of investigator

Exclusion Criteria for Trial Enrollment (Screening visit #1)

- Prior allogeneic stem cell transplant, organ transplant or donor lymphocyte infusion
(DLI), CAR-T cell or NK cell therapy

- Persisting Grade > 1 non hematologic toxicity related to prior therapy; however,
alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety
risk based on investigator's judgment are acceptable.

- Autoimmune disease: Patients with a history of inflammatory bowel disease, including
ulcerative colitis and Crohn's Disease, are excluded from this study, as are
patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic
progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune
vasculitis [e.g., Wegener's Granulomatosis]) and motor neuropathy considered of
autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis). Patients
with Hashimoto's thyroiditis are eligible to go on study.

- Systemic corticosteroid therapy (> 10 mg of prednisone or equivalent dose of
systemic steroids for non-autoimmune indications for at least 4 weeks prior to CIML
NK cell infusion)

- Pregnant women are excluded from this study because of the unknown teratogenic risk
of CIML NK cells and IL-2 and with the potential for teratogenic or abortifacient
effects by Flu/Cy chemotherapy regimen. Because there is an unknown but potential
risk for adverse events in nursing infants secondary to treatment of the mother with
CIML NK cells and IL-2, breastfeeding should be discontinued if the mother is
treated on this study.

- HIV-positive participants are ineligible because of the potential for
pharmacokinetic interactions with anti-retroviral agents used in this study. In
addition, these participants are at increased risk of lethal infections when treated
with marrow suppressive therapy.

- Individuals with active uncontrolled hepatitis B or C are ineligible as they are at
high risk of lethal treatment-related hepatotoxicity after conditioning therapy.

- Individuals with a history of a different malignancy are ineligible except for the
following circumstances: 1. History of other malignancy and have had complete
remission of disease for at least 2 years; 2. Diagnosed and treated within the past
2 years for: nonmetastatic melanoma, surgically resected (not needing systemic
chemotherapy) squamous cell carcinoma of skin and nonmetastatic prostate cancer not
needing systemic chemotherapy.

- History of severe allergic reactions attributed to compounds of similar chemical or
biologic composition to IL-2 or other agents used in study.

- Participants who are receiving any other investigational agents for this condition

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris or cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance
with study requirements.

- Prior history of Grade 2 or higher hemolytic anemia (>/= 2g decrease in hemoglobin
plus laboratory evidence of hemolysis) from any cause

Inclusion Criteria to Start Investigational Treatment Plan (Screening visit #2)

- Patient was eligible for protocol per section 3.1.

- Bone marrow biopsy at screening visit #2 shows < 5% in the bone marrow aspirate (if
cellularity > 20% and not aspicular). If aspirate is hypocellular and/or aspicular,
bone marrow core biopsy is required to show < 5% blasts based on
immunohistochemistry.

- ECOG performance status ≤2 (see Appendix A)

- Participants must meet the following laboratory and organ function as defined below:

- Absolute neutrophil count > 500/microL

- Platelets > 50,000/microL

- Total bilirubin: ≤1.5 x institutional upper limit of normal (ULN) (except
Gilbert's or disease-related hemolysis, then < 3 x ULN)

- AST(SGOT)/ALT(SGPT): ≤3 x institutional ULN

- creatinine clearance ≥ 45 mL/min; calculated by the Cockcroft Gault formula

- oxygen saturation ≥ 90% on room air

- left ventricular ejection fraction (LVEF) > 40%

- No significant change in clinical status that would, in the opinion of the
investigator, increase the risk of adverse events associated with CIML NK infusion,
(e.g., symptomatic congestive heart failure, unstable angina, cardiac arrhythmia)

- Negative pregnancy test for women of childbearing potential only.

- Subjects must be able to swallow pills.

- No evidence of ongoing hemolysis in opinion of investigator

- No venetoclax or HMA for ≥ 7 days prior to screening visit #2

Exclusion Criteria to Start Investigational Treatment Plan (Screening visit #2)

- No live vaccines within the last 6 months.

- No ongoing or active infections.

- Moderate/strong inhibitors of CYP3A except of antifungal medications (such as
posaconazole, voriconazole) which the patient is on and the dose of venetoclax has
already been adjusted. These are excluded as moderate/strong inhibitors of CYP3A
induce higher drug levels of venetoclax which in turns carry the risk of CIML NK
cell elimination.

Criteria to Receive CIML NK Infusion

- Adequate organ function within 24 hours of NK cell infusion as defined below:

- Total bilirubin: ≤1.5 x institutional upper limit of normal (ULN) (except
Gilbert's or disease-related hemolysis, then < 3 x ULN)

- AST(SGOT)/ALT(SGPT): ≤3 x institutional ULN

- No Grade ≥3 non-hematologic toxicities of cyclophosphamide and fludarabine
conditioning (except for Grade 3 nausea, vomiting, diarrhea, or constipation).

- No significant change in clinical status that would, in the opinion of the
investigator, increase the risk of adverse events associated with CIML NK infusion,
(e.g., significant hypoxemia, symptomatic congestive heart failure, unstable angina,
cardiac arrhythmia)

- No evidence of active, uncontrolled infection. Patients receiving antibiotics for an
infection may be treated if they have clinically responded to antibiotics. These
cases should be reviewed with the study PI before proceeding.

- No live vaccines within the last 6 months

- Systemic steroid therapy (oral or IV) of > 10mg prednisone or equivalent dose of
other steroid agent on the day of NK cell infusion

If any of the above criteria are noted at these time points, please discuss with PI the
benefits/risks of proceeding with the CIML infusion and document rationale for course of
action taken in study regulatory binder. However, patient may still receive CIML NK
infusion if relevant parameters are reviewed and both PI and IND holder agree with
proceeding.

If inclusion/exclusion criteria are not met on planned day of CIML NK cell infusion, the
NK cell infusion may be delayed for up to 24 hours to enable inclusion criteria to be
met.

Criteria to Receive Venetoclax

- Adequate organ function within 24 hours of venetoclax initiation as defined below:

- Total bilirubin: ≤1.5 x institutional upper limit of normal (ULN) (except
Gilbert's or disease-related hemolysis, then < 3 x ULN)

- AST(SGOT)/ALT(SGPT): ≤3 x institutional ULN

- No Grade ≥3 non-hematologic toxicities of cyclophosphamide and fludarabine
conditioning (except for Grade 3 nausea, vomiting, diarrhea, or constipation).

- No significant change in clinical status that would, in the opinion of the
investigator, increase the risk of adverse events associated with venetoclax
administration, (e.g., significant hypoxemia, symptomatic congestive heart failure,
unstable angina, cardiac arrhythmia, severe ongoing tumor lysis syndrome)

- No evidence of active, uncontrolled infection. Patients receiving antibiotics for an
infection may be treated if they have clinically responded to antibiotics. These
cases should be reviewed with the study PI before proceeding.

- No live vaccines within the last 6 months