The purpose of this study is to determine the safety and efficacy of MILs™ - NSCLC alone and
in combination with nivolumab with or without tadalafil in subjects with locally advanced and
unresectable or metastatic NSCLC who are refractory or relapsing to a PD-1 containing
This study will examine the safety and efficacy of Marrow Infiltrating Lymphocytes-Non-Small
Cell Lung Cancer (MILs™ - NSCLC) combined with nivolumab with or without tadalafil in
subjects with locally advanced and unresectable and metastatic NSCLC who were refractory to,
or have relapsed on, an anti-PD-1 containing regimen. MILs™ - NSCLC are an adoptive cell
therapy product derived via the activation and expansion of bone marrow T cells. Subjects
will have bone marrow harvested during the Screening Period which will be used to manufacture
the MILs™ - NSCLC. The MILs™ - NSCLC will then be administered on Day 0. Nivolumab will be
administered on Day 1 and will continue every four weeks until treatment discontinuation.
Tadalafil will be administered on Day 1 and will continue daily until treatment
1. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
2. Locally advanced and unresectable, or metastatic NSCLC.
3. Histologically or cytologically confirmed, either squamous or non-squamous NSCLC.
4. Measurable disease as per RECIST 1.1
5. Willingness to undergo bone marrow aspiration (BMA).
6. No more than one treatment regimen following an anti-PD-1 antibody containing
treatment regimen prior to BMA collection.
a. Subjects may have BMA collected while on an anti-PD-1 antibody containing treatment
regimen or while on a treatment regimen immediately following an anti-PD-1 antibody
containing treatment regimen.
7. BMA may be collected while on an anti-PD-1 antibody containing treatment regimen or
while on a treatment regimen immediately following an anti-PD-1 antibody containing
treatment regimen. However, the subjects must have radiographic evidence of disease
progression prior to lymphodepletion.
8. ≥ 21 days have lapsed since last cytotoxic chemotherapy treatment prior to collection
of the BMA.
9. Previous treatment with the appropriate targeted therapy if the subject has known
10. Willingness to provide a fresh tumor biopsy during Screening Period or formalin-fixed,
paraffin-embedded tissue collected at the time of most recent relapse. Note: Archival
tissue regardless of biopsy date may be considered.
11. Adequate renal, hepatic and bone marrow function defined as total bilirubin </= 1.5 x
ULN (except for subjects with Gilbert's disease ≤ 3.0 x ULN with direct bilirubin </=
1.5 x ULN ). Aminotransferase (AST) / Alanine Aminotransferase (ALT) </= 3.0 X ULN
(subjects with liver involvement will be allowed </= 5.0 X ULN). Serum creatinine </=
1.5 x ULN; if serum creatinine is 1.5 to 2.0 × ULN, then the creatinine clearance
(calculated using the Cockcroft-Gault formula or measured) must be ≥ 40 mL/min.
Lymphocyte >/= 0.7 x 10^9/L. ANC >/= 1.5 x 10^9/L. Platelets >/= 100 × 10^9/L. WBC >/=
2.0 ×10^9/L. Hemoglobin > 9.0 g/dL.
12. Women of childbearing potential and male subjects (even if they are surgically
sterilized or had a vasectomy) and their partners must agree to abstain or to use an
effective form of birth control during the study for at least 6 months following
administration of the last dose of lymphodepletion or for at least 5 months following
the last dose of nivolumab for females and 7 months for males, whichever is longer. In
addition, male subjects must not donate sperm during this period.
13. Capable of giving and has provided a signed ICF, which includes compliance with the
requirements and restrictions listed in the ICF and in this protocol.
1. Insufficient activation/expansion of T cells or other problems with the subject's
MILs™ - NSCLC product which would prohibit administration.
2. Major surgical procedure within 7 days of the first dose of lymphodepletion treatment.
3. Prior malignancy active within the previous 3 years from date of BMA collection except
for locally curable cancers that have been apparently cured, such as basal or squamous
cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate,
cervix, or breast.
4. Subjects with symptomatic uncontrolled brain metastases requiring treatment with
steroids or anti-seizure medications within 28 days prior to the BMA are excluded.
However, participants with brain metastases that have been previously treated and are
stable on subsequent scan(s) are allowed and subjects with untreated possible brain
metastases that are new at the time of screening and are < 1 cm and asymptomatic are
allowed. Subjects with asymptomatic untreated CNS disease may undergo BMA prior to
treatment of such disease.
5. Infection requiring treatment with intravenous antibiotics, antifungal, or antiviral
agents within 7 days prior to the BMA.
6. Presence of an autoimmune disease requiring active systemic treatment.
7. Clinically significant, uncontrolled cardiovascular disease, including congestive
heart failure Grade III or IV according to the New York Heart Association
classification, myocardial infarction or unstable angina within the previous 6 months
prior to BMA collection.
8. Known diagnosis of human immunodeficiency virus (HIV) or active viral hepatitis.
9. Administration of neutrophil growth factor support within 14 days prior to the BMA.
10. Use of systemic corticosteroids (glucocorticoids) for greater than one day within 28
days prior to the BMA.
11. Planned use of systemic corticosteroids (glucocorticoids) for greater than one day
within 28 days prior to MILs™ - NSCLC administration.
12. Prior radiation to both sides of the pelvis. Prior radiation to one side of the pelvis
is permitted as long as the other side of the pelvis.
13. Subjects with history of life-threatening toxicity related to prior immune therapy
except those that are unlikely to re-occur with standard countermeasures.
14. Receipt of live attenuated vaccine within 30 days of planned Day 0.
15. History of allergy or hypersensitivity to MILs™-NSCLC, cyclophosphamide, fludarabine,
nivolumab, tadalafil or their components.
16. Pregnant or lactating females.
17. Prior or ongoing clinically significant illness, medical condition, surgical history,
physical finding, or laboratory abnormality that, in the Investigator's opinion, could
affect the safety of the subject or impair the assessment of study results.
18. Unwilling or unable to comply with the protocol.