QUILT-3.028: Study of haNK™ for Infusion in Subjects With Metastatic or Locally Advanced Solid Tumors

This is a phase 1 trial in subjects with metastatic or locally advanced solid tumors. The study will be conducted in two parts: part 1 will involve dose escalation using a 3 + 3 design, and part 2 will involve the expansion of the MTD or HTD to further evaluate the safety of haNK. In part 1, 3 to 6 subjects will be sequentially enrolled starting at dose cohort 1, and subjects will be assessed for DLTs.

• Cohort 1: 2 x 10^9 cells per infusion.
• Cohort 2: 4 x 10^9 cells per infusion.
• If needed, subjects will be enrolled into a dose de-escalation cohort (cohort -1): 1 x 10^9 cells per infusion.

In part 2, dose expansion will occur when the MTD or HTD has been determined. An additional 4 subjects may be enrolled in part 2, for a total of up to 10 subjects at the MTD or HTD.

Inclusion criteria

• Age ≥ 18 years old.
• Able to understand and provide a signed informed consent that fulfills the relevant IRB or IEC guidelines.
• Histologically confirmed, unresectable, locally advanced or metastatic solid malignancy.
• ECOG performance status of 0 to 2.
• Have at least 1 measurable lesion and/or non-measurable disease evaluable according to RECIST Version 1.1.
• Must have a recent formalin-fixed, paraffin-embedded (FFPE) tumor biopsy specimen following the conclusion of the most recent anticancer treatment. If an historic specimen is not available, the subject must be willing to undergo a biopsy during the screening period, if considered safe by the Investigator. If safety concerns preclude collection of a biopsy during the screening period, a tumor biopsy specimen collected prior to the conclusion of the most recent anticancer treatment may be used.
• Must be willing to provide pre- and post-infusion blood samples.
• Have received treatment with at least 1 prior line of therapy in the metastatic setting or not be a candidate for therapy of proven efficacy for their disease. Prior immune therapy is allowed.
• Resolution of all toxic side effects of prior chemotherapy, radiotherapy, or surgical procedures to CTCAE grade ≤ 1, with the exception of alopecia.
• Life expectancy ≥ 12 weeks.
• 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 are considered all female subjects being physiologically capable of becoming pregnant. Female subjects of child-bearing potential are usually premenopausal women or women with less than 12 months of amenorrhea post-menopause and who have not undergone surgical sterilization. Female subjects of child-bearing potential and non-sterile male subjects must agree to use effective contraception for at least 60 days (female) and 120 days (male) after the last dose of haNK. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), two forms of barrier methods (eg, condom, diaphragm) used with spermicide, intrauterine devices (IUDs), and abstinence.

Exclusion criteria

• History of persistent grade 2 or higher (CTCAE Version 4.03) hematological toxicity resulting from previous therapy.
• 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).
• History of organ transplant requiring immunosuppression.
• History of or active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis).
• Inadequate organ function, evidenced by the following laboratory results:

• White blood cell (WBC) count < 2,500 cells/mm^3
• Absolute neutrophil count < 1,500 cells/mm^3.
• Platelet count < 100,000 cells/mm3.
• Hemoglobin < 9 g/dL.
• Total bilirubin greater than the upper limit of normal (ULN; unless the subject has documented Gilbert's syndrome).
• Aspartate aminotransferase (AST [SGOT]) or alanine aminotransferase (ALT [SGPT]) > 2.5 × ULN (> 5 × ULN in subjects with liver metastases).
• Alkaline phosphatase 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.
• Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 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.
• Positive results of screening test for human immunodeficiency virus (HIV). However, subjects with HIV are allowed on the study if they meet the following criteria:

• CD4+ T-cell count >200 cells/mm^3.
• Stable antiretrovital therapy for at least 12 weeks prior to entry.
• Plasma HIV RNA levels below lower limit of quantification at screening, and no quantifiable HIV RNA levels within the 12 weeks preceding screening.
• Current chronic daily treatment (continuous for > 3 months) 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 within 28 days prior to screening for this study, except for testosterone-lowering therapy in men with prostate 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.
• Pregnant and nursing women. A negative serum pregnancy test within 72 hours before administration of haNK must be documented before any haNK is administered to a female subject of child-bear potential.