QUILT-3.076: Study of Autologous M-CENK in Subjects With Locally Advanced or Metastatic Solid Tumors

Inclusion Criteria:

Cohorts 1 and 2, Part A:

• Age ≥ 18 years old.
• Able to understand and provide a signed informed consent that fulfills the relevant Institutional Review Board (IRB) or Independent Ethics Committee (IEC) guidelines.
• Have histologically confirmed locally advanced, unresectable, or metastatic solid tumor.
• For subjects with genetic mutations or alterations in solid tumors (e.g. NSCLC, pancreatic cancer, melanoma), the subjects must have received prior appropriate disease specific targeted therapy and have progressed.
• Have at least 1 measurable lesion and/or non-measurable disease evaluable in accordance with RECIST Version 1.1.
• For subjects with a history of human immunodeficiency virus (HIV)
• Subjects with CD4+ T-cell (CD4+) counts ≥ 350 cells/uL and without a history of AIDS defining opportunistic infections.
• For subjects with a history of hepatitis B virus (HBV)
• Subjects who are chronic carriers of HBV infection (HBsAg-positive, undetectable or low HBV DNA, and normal ALT) who are not on HBV therapy, or in individuals who have serologic evidence of a resolved prior HBV infection (i.e., HBsAg-negative and anti-HBc-positive), anti-HBV prophylaxis should be assessed prior to enrollment.
• Subjects with chronic HBV infection with active disease who meet the criteria for anti HBV therapy should be on a suppressive antiviral therapy prior to enrollment.
• For subjects with a history of hepatitis C virus (HCV)
• Subjects with a history of HCV infection should have completed curative antiviral treatment and have a HCV viral load below the limit of quantification are eligible.
• Subjects who are HCV Ab positive but HCV RNA negative due to prior treatment or natural resolution are eligible.
• Subjects on concurrent HCV treatment and have HCV below the limit of quantification are eligible.

Note: Subjects who have a history of HIV/HBV/HCV or are seropositive will require Infectious Disease Marker (IDM) testing prior to apheresis collection.

• Subjects who currently have non-progressive brain metastasis and were previously treated with surgical resection/debulking, radiation, and stereotactic radiosurgery.
• Able to undergo an Apheresis procedure:
• Have adequate venous access
• Able to sit or recline for 5-6 hours with limited movement
• Hemoglobin must be ≥ 9.0 g/dL
• Platelet count must be ≥ 100,000 cells/mm3
• Vital signs must be within normal range
• Negative serum pregnancy test for females of childbearing potential.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• Ability to attend required study visits and return for adequate follow-up, as required by this protocol.
• Agreement to practice effective contraception for female subjects of child-bearing potential and non-sterile males. Female subjects of child-bearing potential must agree to use effective contraception for up to 30 days after completion of therapy, and non- sterile male subjects must agree to use a condom for up to 30 days after treatment. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), 2 forms of barrier methods (eg, condom, diaphragm) used with spermicide, and intrauterine devices (IUDs).

Cohort 2, Part B subjects only:

• Have documented progressive disease after receiving treatment with at least 2 prior lines of therapy or not be a candidate for therapy of proven efficacy for their disease. Prior immune therapy and prior treatment with a checkpoint inhibitor as per FDA indication for current standard of care therapy is allowed.
• Subjects cannot receive M-CENK before a 14-day washout period following treatment with an approved chemotherapy and approved or investigational immunotherapy (eg PD-1/PD-L1 inhibitors, CAR NK cells [PD-L1 t-haNK], N-803). A repeat lab at least 14 days after completion of the washout period is required.
• Subjects cannot receive M-CENK before a 30-day washout period following treatment with investigational chemotherapy. A repeat lab at least 30 days after completion of the washout period is required.
• Ability to attend required study visits and return for adequate follow-up, as required by this protocol.
• Agreement to practice effective contraception for female subjects of child-bearing potential and nonsterile males. Female subjects of child-bearing potential must agree to use effective contraception for up to 30 days after completion of therapy, and non- sterile male subjects must agree to use a condom for up to 30 days after treatment. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), 2 forms of barrier methods (eg, condom, diaphragm) used with spermicide, and intrauterine devices (IUDs).

Exclusion Criteria (Cohorts 1 and 2, Part A):

There is no exclusion criteria for cohorts 1 and 2, part A.

Exclusion Criteria (Cohort 2, Part B only):

*Note: All subjects must meet eligibility criteria at the time of enrollment. Additionally, all subjects will be re-evaluated to confirm that they still meet the eligibility criteria specified with an asterisk below once the M-CENK cells are manufactured and prior to to the first administration of M-CENK. The Sponsor will approve the subject's continued eligibility prior to receiving the manufactured M-CENK cells.

• *Life expectancy < 16 weeks based on the best judgment of the Investigator.
• *Involuntary weight loss of > 10% usual body weight between the time of enrollment and at the time of administration of M-CENK cells
• *Calorie or protein restrictive dietary regimen.
• *Serious uncontrolled concomitant disease that would contraindicate the use of the investigational drug used in this study or that would put the subject at high risk for treatment- related complications.
• Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, Addison's disease, autoimmune disease associated with lymphoma) requiring medical treatment.
• *Currently receiving or has received antibiotics since enrolling in the study or documented infection.
• History of organ transplant requiring immunosuppression.
• History of or active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), unless the inflammation is well controlled.
• *Inadequate organ function, evidenced by the following laboratory results:
• Absolute neutrophil count (ANC) < 1000 cells/mm3.
• Platelet count < 100,000 cells/mm3.
• Hemoglobin < 9 g/dL.
• Total bilirubin > 1.5 x the upper limit of normal (ULN; unless the subject has documented Gilbert's syndrome).
• AST (SGOT) or ALT (SGPT) > 2.5 × ULN (> 5 × ULN in subjects with liver metastases).
• Alkaline phosphatase (ALP) levels > 2.5 × ULN (> 5 × ULN in subjects with liver metastases, or >10 × ULN in subjects with bone metastases).
• Serum creatinine > 2.0 mg/dL or 177 μmol/L.
• Albumin < 2.8 g/dL. Note: Each site should use its own institution's upper limit of normal (ULN) to determine eligibility.
• *Subjects with ascites requiring paracentesis or pleural effusion requiring thoracentesis.
• *Uncontrolled hypertension (systolic > 160 mm Hg and/or diastolic > 110 mm Hg) or clinically significant (ie, active) cardiovascular disease, cerebrovascular accident/stroke, or myocardial infarction within 6 months prior to first study medication; unstable angina; congestive heart failure of New York Heart Association grade 2 or higher; or serious cardiac arrhythmia requiring medication.
• *Dyspnea at rest due to complications of advanced malignancy or other disease requiring continuous oxygen therapy. Oxygen therapy on an as needed or intermittent basis is allowed.
• *Current chronic daily treatment (since enrolling in the study) with systemic corticosteroids (dose equivalent to or greater than 10 mg/day methylprednisolone), excluding inhaled steroids. Short-term steroid use to prevent IV contrast allergic reaction or anaphylaxis in subjects who have known contrast allergies is allowed.
• *Known hypersensitivity to any component of the study medication(s).
• *Participation in an investigational drug study or history of receiving any investigational treatment or cytotoxic chemotherapy within 14 days prior to dosing for this study, except for hormone-lowering therapy in subjects with hormone-sensitive cancer.
• *Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol.
• *Concurrent participation in any interventional clinical trial since enrolling.
• *Pregnant and nursing women. A negative serum pregnancy test during screening and a negative pregnancy test within 24 hours prior to the first dose must be documented before M-CENK is administered to a female subject of childbearing potential.