Clinical Trials /

Nivolumab and Tumor Infiltrating Lymphocytes (TIL) in Advanced Non-Small Cell Lung Cancer



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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting


Phase 1

Trial Eligibility



  • Brief Title: Nivolumab and Tumor Infiltrating Lymphocytes (TIL) in Advanced Non-Small Cell Lung Cancer
  • Official Title: A Phase I Clinical Trial Combining Nivolumab and Tumor Infiltrating Lymphocytes (TIL) for Patients With Advanced Non-Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: MCC-19122
  • NCT ID: NCT03215810


  • Non-Small Cell Lung Cancer
  • Metastatic Non-small Cell Lung Cancer
  • Squamous Cell Carcinoma
  • Advanced NSCLC
  • Adenosquamous Carcinoma
  • Adenocarcinomas


NivolumabOpdivoTIL+ Nivolumab
CyclophosphamideCytoxanTIL+ Nivolumab
FludarabineFludaraTIL+ Nivolumab
Interleukin-2 (IL2)IL2, Proleukin®TIL+ Nivolumab


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.

Detailed Description

      In this study, these special immune T-cells will be taken from a sample of the participant's
      tumor tissue that will be surgically removed. Certain parts of these cells will be
      multiplied, or grown, in the laboratory, using the drug interleukin-2 (IL-2) during part of
      the process. They will then be given back to the participant by an infusion in their veins.
      These cells are called tumor- infiltrating lymphocytes (TILs). The use of TILs involves a
      combination of drugs, including the following:

        -  Fludarabine and cyclophosphamide - two types of chemotherapy drugs. These drugs will be
           used for what is called lymphodepletion. The purpose of lymphodepletion in this study is
           to temporarily reduce the number of normal lymphocytes circulating in the participant's
           body before they are given the TILs that were grown in the lab. This is so that there
           will be more "space" for the lymphocytes (TILs) that will be infused in their veins.

        -  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 participant receives
           the infusion of the T-cells.

Trial Arms

TIL+ NivolumabExperimentalTumor-infiltrating Lymphocyte Therapy (TIL) + Nivolumab Treatment Plan: Tumor harvest, Tumor-infiltrating Lymphocytes growth, 4 cycles of nivolumab, cytoreductive chemotherapy with cyclophosphamide and fludarabine, TIL infusion, Interleukin-2 treatment.
  • Nivolumab
  • Cyclophosphamide
  • Fludarabine
  • Interleukin-2 (IL2)

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

          -  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

          -  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

          -  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

          -  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.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of Dose Limiting Toxicity (DLT)
Time Frame:Up to 40 months
Safety Issue:
Description:Investigators plan to demonstrate that treatment with nivolumab in patients undergoing TIL therapy is safe with a continuous Pocock-type stopping boundary for serious toxicity of < 17%, with safety reported based upon Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria. DLT defined as: any grade ≥3 immune-related adverse event definitely attributable to nivolumab. DLT related to adoptive cell therapy will be defined as a non-hematologic grade 4 or higher adverse event that is immediately life-threatening occurring upon or after the start of therapy that is immediately life-threatening and not related to non-small cell lung cancer or other pre-existing condition. Safety: Toxicity will be assessed within 4 weeks of the adoptive TIL transfer. The accrual will be halted if excessive numbers of participants with toxicity are seen. For example, if there are 5 or more out of 10 participants (full follow-up) with toxicity, the trial will be stopped.

Secondary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:Up to 40 months
Safety Issue:
Description:Objective response rate associated with the treatment regimen. The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. Investigators plan to see if the treatment produces a best overall radiologic response rate in patients who progress on nivolumab monotherapy in unselected NSCLC of 20% or more. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD) taking as references the smallest sum LD.


Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:H. Lee Moffitt Cancer Center and Research Institute

Trial Keywords

  • Stage IV
  • Recurrent
  • TIL
  • Tumor-infiltrating Lymphocyte Therapy (TIL)

Last Updated

August 16, 2021