A Phase 1b Study of Cytokine-Induced Memory like (CIML) Natural Killer (NK) Cell Therapy in Recurrent Ovarian Cancer

The goal of this research study is to evaluate the safety and effectiveness of the use of
cytokine-induced memory-like (CIML) natural killer (NK) cell therapy in recurrent, high
grade ovarian cancer (HGOC).

Names of the study therapies involved in this study are:

CIML NK (cellular therapy) Interleukin-2 (IL-2)

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed recurrent
epithelial ovarian cancer. Eligible histologies include high grade serous, high
grade endometrioid and clear cell ovarian carcinoma.

- Participants must have measurable cancer defined by RECIST 1.1 criteria.

- Patients must have received at least 1 lines of prior systemic therapy and be deemed
platinum resistant/intolerant by their treating oncologist. Patients with germline
or somatic BRCA1 or BRCA2 mutations must have received prior PARP inhibitor therapy
as maintenance or treatment. Prior receipt of immune checkpoint blockade is allowed
if grade 3 or higher toxicities were not experienced.

- Age ≥18 years and <85 years old.

- ECOG performance status of 0 or 1.

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

- Absolute neutrophil count ≥1,000/mcL

- Platelets ≥75,000/mcL

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

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

- Serum creatinine ≤ 2.0 mg/dL OR glomerular filtration rate (GFR) ≥40
mL/min/1.73 m2

- Oxygen saturation: ≥ 90% on room air

- Left ventricular ejection fraction (cardiac function) ≥ 40%

- No laboratory evidence of ongoing hemolysis in opinion of investigator

- 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.

- 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.

- Physician assessment indicating the patient would be able to tolerate undergoing a
brief procedure for placement of an intraperitoneal port for NK cell infusion.

- Ability to understand and the willingness to sign a written informed consent
document.

- The effects of CIML NK cells and IL-2 on the developing human fetus are unknown. For
this reason and because CIML NK cells and IL-2 may be teratogenic, 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.

Exclusion Criteria:

- Participants who have had anti-tumor chemotherapy or other investigational agents
within two weeks prior to NK cell infusion (6 weeks for nitrosoureas or mitomycin
C), or immunotherapy within 6 weeks prior, or those who have not recovered from
adverse events due to agents administered more than two weeks prior.

- Participants with a bowel obstruction within the last 3 months or high risk for
bowel obstruction (in the opinion of the investigator) or current need for
parenteral nutrition or dependence on intravenous fluids.

- Participants who are receiving any other investigational agents.

- Solid organ transplant (allograft) recipients.

- Participants with known additional malignancy that is progressing or requires active
treatment, or history of other malignancy within 2 years of the first dose of study
treatment with the exception of cured basal cell or squamous cell carcinoma of the
skin, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in
situ of the cervix, or other non-invasive or indolent malignancy, or cancers from
which the patient has been disease-free for > 1 year after treatment with curative
intent.

- History of severe or anaphylactic allergic reactions attributed to compounds of
similar chemical or biologic composition to CIML NK cells or IL-2 or any of the
other agents used in study.

- For patients with prior exposure to check point inhibitor therapy, those with a
prior history of immune-related toxicity during immune therapy that resulted in
permanent discontinuation of therapy (as recommended per product label or consensus
guidelines) OR any immune-related toxicity requiring intensive or prolonged
immunosuppression to manage (with the exception of endocrinopathy that is
well-controlled on replacement hormones) are excluded.

- 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 [Wegener's granulomatosis]) and motor neuropathy considered of autoimmune
origin (e.g., GuillainBarre syndrome and myasthenia gravis). Patients with Hashimoto
thyroiditis are eligible.

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

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

- 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 fludarabine/cyclophosphamide 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 in the setting of marrow
suppression. Known non-infectious pneumonitis or any history of interstitial lung
disease.

- Receipt of a live vaccine within 30 days of start of study treatment. During
eligibility confirmation the study team is requested to confirm that according to
the planned NK cell dosing schedule, the washout period should be completed.

- Anaphylactic reactions to murine-based antibody therapy or iron dextran as the CIML
NK cell product contains similar reagents at end of manufacturing/infusion.

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