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Non-Small Cell Lung CancerPhase 1NCT03215810

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

A Phase 1 study testing Tumor-infiltrating Lymphocytes (TIL), Nivolumab and Cyclophosphamide in people with Non-Small Cell Lung Cancer and Metastatic Non-small Cell Lung Cancer, run by H. Lee Moffitt Cancer Center and Research Institute at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Tumor-infiltrating Lymphocytes (TIL), Nivolumab and Cyclophosphamide
Could I receive a placebo?
No, everyone receives an active treatment
How many people
20 participants
Where
2 sitesUnited States
Study dates
11 Oct 2017to 9 Jun 2023
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • University of Florida Health Cancer Center.

    Gainesville, Florida, 32608

  • H. Lee Moffitt Cancer Center and Research Institute

    Tampa, Florida, 33612

Other trials in United States

About this study

Official title: A Phase I Clinical Trial Combining Nivolumab and Tumor Infiltrating Lymphocytes (TIL) for Patients With 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.

Read the 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.
Being tested
Tumor-infiltrating Lymphocytes (TIL), Nivolumab, Cyclophosphamide, Fludarabine, Tumor-infiltrating Lymphocyte Therapy
Keywords
Stage IV, NSCLC, Recurrent, TIL, Tumor-infiltrating Lymphocyte Therapy (TIL)
Medical subject headings
Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Carcinoma, Adenosquamous, Adenocarcinoma, Recurrence

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Tumor-infiltrating Lymphocytes (TIL)Procedure or surgery

    Also called TIL

    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.

  • NivolumabDrug

    Also called Opdivo

    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.

  • CyclophosphamideDrug

    Also called Cytoxan

    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.

  • FludarabineDrug

    Also called Fludara

    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.

  • Tumor-infiltrating Lymphocyte TherapyOther

    Also called TIL

    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 (IL2)Drug

    Also called IL2, Proleukin®

    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.

Study groups in NCT03215810
Study groupRoleWhat they receive
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.
Receives: Procedure: Tumor-infiltrating Lymphocytes (TIL); Drug: Nivolumab; Drug: Cyclophosphamide; Drug: Fludarabine; Other: Tumor-infiltrating Lymphocyte Therapy; Drug: Interleukin-2 (IL2)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Rate of Dose Limiting Toxicity (DLT)

    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.

    Measured: Up to 40 months

Secondary outcomes (1)

  1. Number of Participants With Objective Response

    Participants displaying objective response associated with the treatment regimen per Response Evaluation Criteria in Solid Tumors (RECIST v.1.1). 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.

    Measured: Up to 40 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Jul 2017
  2. Study start11 Oct 2017
  3. Primary completion13 Feb 2021
  4. Study completion9 Jun 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
20 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03215810
Sponsor's protocol ID
MCC-19122
Other IDs
CA209-9JA
Status last verified
Jul 2023
First submitted
11 Jul 2017
Last updated
24 Jul 2023
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Creelan BC, Wang C, Teer JK, Toloza EM, Yao J, Kim S, Landin AM, Mullinax JE, Saller JJ, Saltos AN, Noyes DR, Montoya LB, Curry W, Pilon-Thomas SA, Chiappori AA, Tanvetyanon T, Kaye FJ, Thompson ZJ, Yoder SJ, Fang B, Koomen JM, Sarnaik AA, Chen DT, Conejo-Garcia JR, Haura EB, Antonia SJ. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nat Med. 2021 Aug;27(8):1410-1418. doi: 10.1038/s41591-021-01462-y. Epub 2021 Aug 12.

    PubMed 34385708

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Tumor-infiltrating Lymphocytes (TIL), Nivolumab and Cyclophosphamide in people with Non-Small Cell Lung Cancer and Metastatic Non-small Cell Lung Cancer, run by H. Lee Moffitt Cancer Center and Research Institute at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 Apr 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Rate of Dose Limiting Toxicity (DLT) (time frame: Up to 40 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03215810, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jul 2023; AzTrials last refreshed its copy on 7 Nov 2026.

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