Nivolumab, Tumor Infiltrating Lymphocytes, Chemotherapy, and Aldesleukin in Treating Patients with Recurrent or Stage IV Non-small Lung Cancer

Status: Active

Description

This pilot phase I trial studies the side effects of nivolumab, tumor infiltrating lymphocytes, chemotherapy, and aldesleukin in treating patients with non-small lung cancer that is stage IV or has come back after period of improvement. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Tumor infiltrating lymphocytes involve the use of special immune cells called T-cells. A T-cell is a type of lymphocyte, or white blood cell. Lymphocytes protect the body from viral infections, help other cells fight bacterial and fungal infections, produce antibodies, fight cancers, and coordinate the activities of other cells in the immune system. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine phosphate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Aldesleukin may help the body respond to treatment on the immune system. Giving nivolumab, tumor infiltrating lymphocytes, chemotherapy, and aldesleukin may work better in treating patients with non-small lung cancer.

Eligibility Criteria

Inclusion Criteria

  • SCREENING INCLUSION CRITERIA
  • 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 computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers on clinical exam
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Expected survival > 6 months
  • Patients with activating EGFR mutation or 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
  • Within 7 days (+ 3 day window) of enrollment: Hemoglobin >= 9.0 g/dL
  • Within 7 days (+ 3 day window) of enrollment: Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (> 1000 per mm^3)
  • Within 7 days (+ 3 day window) of enrollment: Platelet count >= 100 x 10^9/L (> 100,000 per mm^3)
  • Within 7 days (+ 3 day window) of enrollment: Prothrombin time (PT) and partial thromboplastin time (PTT) =< 1.5 x the institutional upper limit of normal (ULN), (this will not apply to subjects with confirmed Factor XII deficiency)
  • Within 7 days (+ 3 day window) of enrollment: Serum bilirubin =< 1.5 x the institutional ULN, or =< 3 x ULN if confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology)
  • Within 7 days (+ 3 day window) of enrollment: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN unless liver metastases are present, in which case it must be =< 5 x ULN
  • Within 7 days (+ 3 day window) of enrollment: Serum creatinine of =< 1.5 x institutional ULN
  • Within 7 days (+ 3 day window) of enrollment: Albumin >= 2.5 g/dl
  • Positive screening 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 (MUGA) within past 6 months with demonstrated left ventricular ejection fraction (LVEF) > 50%
  • Pulmonary function tests within past 6 months showing diffusion capacity of the lung for carbon monoxide (DLCO) > 50% of predicted; adjusted DLCO based on hemoglobin concentration should be used, if available
  • RAPID EXPANSION PROTOCOL (REP) ELIGIBILITY: Clinical performance status equivalent to ECOG 0-1 at the last calendar clinical visit
  • REP ELIGIBILITY: Has not had a partial or complete response to nivolumab treatment
  • REP ELIGIBILITY: Absolute neutrophil count greater than or equal to 1000/mcL
  • REP ELIGIBILITY: Platelet count greater than or equal to 100,000/mcL
  • REP ELIGIBILITY: Hemoglobin greater than or equal to 8.0 g/dL (Note that this threshold is slightly lower than the initial trial screening parameter since most subjects will require blood transfusion at some point during the protocol treatment, and the established threshold for transfusion is 8 gm/dL)
  • REP ELIGIBILITY: Serum ALT and AST less than three times the institutional upper limit of normal
  • REP ELIGIBILITY: Serum creatinine of =< 1.5 x institutional ULN
  • REP ELIGIBILITY: Total bilirubin less than or equal to 2.0 mg/dL, except in patients with Gilbert’s syndrome who must have a total bilirubin less than 3.0 mg/dL
  • REP ELIGIBILITY: Patient has central IV access or request for central IV access submitted
  • CHEMOTHERAPY/CELL INFUSION ELIGIBILITY: Patients must have adequate TIL available as per Moffitt Cell Therapies current standard operating procedures (SOP)
  • CHEMOTHERAPY/CELL INFUSION ELIGIBILITY: Male patients with female partners of childbearing potential and female patients of childbearing potential must agree to use contraception for six months after receiving the preparative regimen
  • CHEMOTHERAPY/CELL INFUSION ELIGIBILITY: For women of child-bearing potential, a negative serum pregnancy testing will be verified within 7 days prior to treatment
  • CHEMOTHERAPY/CELL INFUSION ELIGIBILITY: Clinical performance status equivalent to ECOG 0-1 at the clinical visit prior to lymphodepletion
  • CHEMOTHERAPY/CELL INFUSION ELIGIBILITY: Absolute neutrophil count greater than or equal to 1000/mcL
  • CHEMOTHERAPY/CELL INFUSION ELIGIBILITY: Platelet count greater than or equal to 100,000/mcL
  • CHEMOTHERAPY/CELL INFUSION ELIGIBILITY: Hemoglobin greater than or equal to 8.0 g/dL (Note that this threshold is slightly lower than the initial trial screening parameter since most subjects will require blood transfusion at some point during the protocol treatment, and the established threshold for transfusion is 8 gm/dL)
  • CHEMOTHERAPY/CELL INFUSION ELIGIBILITY: Serum ALT and AST less than three times the institutional upper limit of normal
  • CHEMOTHERAPY/CELL INFUSION ELIGIBILITY: Serum creatinine less than or equal to 1.7 mg/dL
  • CHEMOTHERAPY/CELL INFUSION ELIGIBILITY: Total bilirubin less than or equal to 2.0 mg/dL, except in patients with Gilbert’s syndrome who must have a total bilirubin less than 3.0 mg/dL
  • CHEMOTHERAPY/CELL INFUSION ELIGIBILITY: Patients with electrocardiogram (EKG) within 14 days of initiation of chemotherapy demonstrating no new significant rhythm, axis or ST segment changes will be included; if clinically significant, new EKG changes are present, patients may be included if cardiac stress test indicates no reversible cardiac ischemia
  • CHEMOTHERAPY/CELL INFUSION ELIGIBILITY: Urinalysis within 14 days demonstrating that no urinary tract infection is present
  • CHEMOTHERAPY/CELL INFUSION ELIGIBILITY: Compete history and physical examination will be required within 2 weeks prior to initiation of chemotherapy

Exclusion Criteria

  • SCREENING EXCLUSION CRITERIA
  • More than 5 lines of prior systemic therapy in the preceding three 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 * Oral hydrocortisone, only for the purposes of a documented and confirmed adrenal insufficiency diagnosis, is permitted if =< 25 mg daily total dose * 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: * Chemotherapy within the past 4 weeks * Tyrosine kinase inhibitor (TKI) within the past 1 week * 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
  • Patients known to be human immunodeficiency virus (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 version [v]4 grade 2) from previous anti-cancer therapy; subjects 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
  • Patients who have a significant history of pulmonary disease that necessitates the use of supplemental oxygen, and patients with resting pulse oximetry < 92% on room air
  • Active or prior documented autoimmune disease within the past 2 years; NOTE: Subjects 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

Locations & Contacts

Florida

Gainesville
University of Florida Health Science Center - Gainesville
Status: In review
Contact: Frederic Joseph Kaye
Email: Fkaye@ufl.edu
Tampa
Moffitt Cancer Center
Status: Active
Contact: Benjamin C. Creelan
Phone: 813-745-7640

Trial Objectives and Outline

PRIMARY OBJECTIVE:

I. To demonstrate that treatment with nivolumab in patients undergoing tumor infiltrating lymphocyte (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.

SECONDARY OBJECTIVES:

I. To determine the objective response rate associated with the treatment regimen.

II. To determine the progression-free survival associated with the treatment regimen.

OUTLINE:

NIVOLUMAB PRE-TREATMENT: After tumor harvest, patients receive nivolumab intravenously (IV) over 30-60 minutes on days -63, -49, -35, and -21. Treatment repeats every 2 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity.

LYMPHODEPLETING CHEMOTHERAPY: Patients then receive cyclophosphamide IV over 2 hours on days -7 to -6 and fludarabine phosphate intravenous piggyback (IVPB) over approximately 30 minutes on days -7 to -3.

TIL INFUSION AND ALDESLEUKIN: Patients then receive TIL infusion IV on day 0. Beginning 8-12 hours after infusion, patients receive aldesleukin IV for approximately 7-10 days.

NIVOLUMAB POST-TREATMENT: Beginning approximately 2 weeks after aldesleukin, patients receive nivolumab IV over 30-60 minutes every 4 weeks for 12 months in the absence of disease progression or unacceptable toxicity. Patients who achieve a partial response (PR)/complete response (CR) after the first 4 doses continue to receive nivolumab every 4 weeks until disease progression.

After completion of study treatment, patients are followed up every 4 weeks for 1 year, every 12 weeks for 1 year, every 6 months for 2 years, and then yearly thereafter.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Moffitt Cancer Center

Principal Investigator
Benjamin C. Creelan

Trial IDs

Primary ID MCC-19122
Secondary IDs NCI-2017-01966, Bristol-Myers Squibb CA209-9JA
Clinicaltrials.gov ID NCT03215810