Nivolumab and Tumor Infiltrating Lymphocytes (TIL) in Advanced Non-Small Cell Lung Cancer
Condition: Non-Small Cell Lung Cancer; Metastatic Non-small Cell Lung Cancer; Squamous Cell Carcinoma; Advanced NSCLC; Adenosquamous Carcinoma; Adenocarcinomas
MeSH terms: Carcinoma; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Adenosquamous
Intervention: Tumor-infiltrating Lymphocytes (TIL); Nivolumab; Cyclophosphamide; Fludarabine; Tumor-infiltrating Lymphocyte Therapy; Interleukin-2 (IL2)
Intervention description: Tumor harvest for TIL growth in the lab: A sample of the participant's tumor will be collected and sent to the lab for TIL growth. TIL will be prepared and cryopreserved.; Nivolumab will be administered intravenously at a fixed dose of 240 mg for 4 doses every 2 weeks prior to TIL. Nivolumab dose will be fixed at 480 mg every 4 weeks up to 12 months after TIL.; Cyclophosphamide will be administered at 60 mg/kg/day IV in 250 mL normal saline (NS) over approximately 2 hours. Cyclophosphamide will be initiated seven days prior to the anticipated TIL transfer, and the precise timing will depend on the rate of in vitro TIL growth. The dose will be based on the patient's body weight, but to prevent undue toxicity, it will not exceed a dose greater than 140% of the maximum ideal body weight per Metropolitan Life Insurance Company, Height and Weight Table.; After administration of Cyclophosphamide, Fludarabine will then be infused at 25 mg/m^2 intravenous piggyback (IVPB) daily over approximately 30 minutes starting 5 days prior to TIL transfer. To prevent undue toxicity with fludarabine, the dose will be based on body surface area (BSA), but will not exceed a dose calculated on surface areas based on body weights greater than 140% of the maximum ideal body weight per Metropolitan Life Insurance Company Height and Weight Tables.; On day 0, all patients will receive TIL administered according to the current Moffitt Cell Therapy TIL Standard Operating Procedure (SOP). Eight (8) to twelve (12) hours after completing the TIL infusion, all participants will begin intermediate-dose decrescendo interleukin-2 (IL-2).; Interleukin-2 (IL-2) - a drug used to help the body's response to treatment on the immune system. A high dose regimen of IL-2 will be given after the infusion of the T-cells.
Intervention MeSH terms: Cyclophosphamide; Nivolumab; Fludarabine; Interleukin-2
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Stage IV; NSCLC; Recurrent; TIL; Tumor-infiltrating Lymphocyte Therapy (TIL)

Summary:

      Investigators plan to study the safety, side effects, and benefits of tumor-infiltrating
      lymphocytes (TILs) when they are given with the drug nivolumab. Nivolumab is a type of
      immunotherapy - a drug that is used to boost the ability of the immune system to fight
      cancer, infection, and other diseases.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age >18 years

          -  Able to understand and give written informed consent

          -  Confirmed or suspected diagnosis of stage IV or recurrent non-small cell lung cancer
             (NSCLC). For suspected NSCLC, diagnosis must be histologically or cytologically
             confirmed prior to start of nivolumab treatment. Neuroendocrine cancers, or mixed
             neuroendocrine features in >10% of tumor cells, are excluded.

          -  Tumor deemed accessible by metastasectomy (TIL harvest) which expects to yield >1.5
             cm^3 of resectable tumor amount.

          -  Measurable disease, even after resection of applicable lesion for TIL harvest. Defined
             as ≥1 lesion that is ≥10 mm in one dimension by CT scan, MRI, or calipers on clinical
             exam.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Expected survival > 6 months

          -  Patients with activating Epidermal Growth Factor Receptor (EGFR) mutation or
             Anaplastic Lymphoma Kinase (ALK) rearrangement which is expected to be responsive to
             available tyrosine kinase inhibitor therapy, must have been previously treated with an
             applicable tyrosine kinase inhibitor.

          -  Adequate normal organ and marrow function in an assessment performed within 7 days (+
             3 day window) of enrollment, defined as: Hemoglobin ≥ 9.0 g/dL; Absolute neutrophil
             count (ANC) ≥ 1.0 x 10^9/L (> 1000 per mm^3); Platelet count ≥ 100 x 10^9/L (>100,000
             per mm^3); Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) ≤ 1.5x the
             institutional upper limit of normal (ULN), (This will not apply to patients with
             confirmed Factor XII deficiency.); Serum bilirubin ≤ 1.5x the institutional ULN, or ≤
             3x ULN if confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia
             that is predominantly unconjugated in the absence of hemolysis or hepatic pathology);
             Aspartate Aminotransferase (AST) (SGOT)/Alanine Aminotransferase (ALT) (SGPT) ≤ 2.5x
             institutional ULN unless liver metastases are present, in which case it must be ≤ 5x
             ULN; Serum creatinine of ≤ 1.5x institutional ULN; Albumin ≥ 2.5 g/dl.

          -  Positive screening Epstein Barr Virus (EBV) antibody titer on screening test.

          -  Cardiac stress test within past 6 months without evidence of reversible ischemia.

          -  Cardiac echocardiogram, stress test, or Multigated Acquisition Scan (MUGA) within past
             6 months with demonstrated left ventricular ejection fraction (LVEF) > 50%

          -  Pulmonary function tests within past 6 months showing Diffusion Lung Capacity for
             Carbon Monoxide (DLCO) >50% of predicted. Adjusted DLCO based on hemoglobin
             concentration should be used, if available.

        Exclusion Criteria:

          -  More than 5 lines of prior systemic therapy in the preceding 3 years.

          -  Any previous treatment with a PD-1 or PD-L1 inhibitor, including but not limited to:
             nivolumab, atezolizumab, pembrolizumab, or durvalumab.

          -  Current or prior use of any immunosuppressive medications, such as corticosteroids,
             within 14 days before enrollment. a.) Oral hydrocortisone, only for the purposes of a
             documented and confirmed adrenal insufficiency diagnosis, is permitted if ≤ 25 mg
             daily total dose. b.) Inhaled, intranasal, or topical corticosteroids are permitted.

          -  Patients with untreated brain metastases. Treated brain metastases with radiation or
             surgery are allowed if: ≤ 3 cm in size AND ≤ 4 in number AND there is no evidence of
             progressive disease, on brain imaging ≥ 28 days after last day of central nervous
             system (CNS) treatment.

          -  History of leptomeningeal metastases.

          -  Current or prior use of anticancer therapy before TIL collection: a.) Chemotherapy
             within the past 4 weeks; b.) Tyrosine kinase inhibitor (TKI) within the past 1 week;
             c.) Investigational therapy within the past 4 weeks or 4 half-lives, whichever is
             shorter.

          -  Uncontrolled intercurrent illness including, but not limited to, symptomatic
             congestive heart failure, unstable angina pectoris, cardiac arrhythmia (other than
             stable atrial fibrillation) and significant carotid artery stenosis.

          -  Known to be HIV positive, hepatitis B or C positive, or both Rapid Plasma Reagin (RPR)
             and Fluorescent Treponemal Antibody (FTA positive). (Hepatitis B surface or core
             antibody alone is not indicative of Hepatitis B Virus (HBV) infection).

          -  Patients with rapidly progressing tumors, as judged by the investigator.

          -  Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from
             electrocardiograms (ECGs) using Bazett's Correction

          -  Known history of previous tuberculosis

          -  Receipt of live attenuated vaccination within 30 days prior to first anticipated dose
             of nivolumab.

          -  History of allogeneic organ transplant

          -  History of primary immunodeficiency

          -  History of severe hypersensitivity to nivolumab, cyclophosphamide, fludarabine,
             interleukin-2, or any excipient

          -  Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results

          -  Patients with active systemic infections requiring intravenous antibiotics within 1
             week prior to enrollment.

          -  Any unresolved toxicity (>CTCAE v4 grade 2) from previous anti-cancer therapy.
             Patients with irreversible toxicity that is not reasonably expected to be exacerbated
             by the investigational product may be included (e.g., hearing loss, peripheral
             neuropathy).

          -  History of pneumonitis or drug-related inflammatory lung disease

          -  Have a significant history of pulmonary disease that necessitates the use of
             supplemental oxygen, and patients with resting pulse oximetry less than 92% on room
             air.

          -  Active or prior documented autoimmune disease within the past 2 years. NOTE: Patients
             with vitiligo, Grave's disease, limited site eczema, or limited site plaque psoriasis
             not requiring systemic treatment (within the past 2 years), or other autoimmune
             conditions which are not expected to recur, are allowed after approval from the
             medical monitor or Principal Investigator (PI).

          -  Patients with other prior malignancies must have had a ≥ 2-year disease-free interval,
             except for: in situ carcinoma of the cervix, in situ ductal carcinoma of the breast,
             in situ prostate cancer, in situ bladder cancer. These must have been deemed stable
             and not expected to relapse. In addition, early stage skin cancers, including basal,
             squamous cell cutaneous carcinoma, and melanoma, are permitted if previously treated
             with curative intent and not expected to relapse.

          -  Women who are pregnant or lactating.

          -  Women of childbearing potential and fertile men unwilling to use effective
             contraception during study until 4 months after conclusion of the treatment period.