T Cell Receptor Immunotherapy for Patients With Metastatic Non-Small Cell Lung Cancer

Study Description

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Brief Summary:

Background:

The NCI Surgery Branch has developed an experimental therapy that involves taking white blood cells from patients' tumors, growing them in the laboratory in large numbers, and then giving the cells back to the patient. These cells are called Tumor Infiltrating Lymphocytes, or TIL and we have given this type of treatment to over 100 patients. In this study, we are selecting a specific subset of white blood cells from the tumor that we think are the most effective in fighting tumors and will use only these cells in making the tumor fighting cells.

Objective:

The purpose of this study is to see if these specifically selected tumor fighting cells can cause non-small cell lung cancer (NSCLC) tumors to shrink and to see if this treatment is safe.

Eligibility:

- Adults age 18-70 with NSCLC who have a tumor that can be safely removed.

Design:

• Work up stage: Patients will be seen as an outpatient at the NIH clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed
• Surgery: If the patients meet all of the requirements for the study they will undergo surgery to remove a tumor that can be used to grow the TIL product.
• Leukapheresis: Patients may undergo leukapheresis to obtain additional white blood cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.}
• Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the TIL cells and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment.

Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits take up to 2 days.

Condition or disease	Intervention/treatment	Phase
Advanced Non-Small Cell Lung Cancer; Squamous Cell Carcinoma; Advanced NSCLC; Adenosquamous Carcinoma; Adenocarcinomas	Drug: Aldesleukin; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Young TIL	Phase 2

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Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	85 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase II Study Using Autologous Young Tumor-Infiltrating Lymphocytes (TIL) Derived From Patients With Non-Small Cell Lung Cancer Following Non-Myeloablative Lymphocyte Depleting Preparative Regimen
Study Start Date :	April 17, 2014
Estimated Primary Completion Date :	October 23, 2024
Estimated Study Completion Date :	October 23, 2025

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Arm 1/High-Dose Aldesleukin; Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine plus young TIL plus high-dose Aldesleukin	Drug: Aldesleukin; Aldesleukin at 720,000 (Arm 1) or 72,000 (Arm 2) IU/kg IV based on total body weight) over 15 minutes approximately every eight hours (+/- 1hr) beginning within 24 hours of cell infusion and continuing for up to a maximum of 9 doses in Arm 1 and 12 doses in Arm 2.; Drug: Fludarabine; Days -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.; Drug: Cyclophosphamide; Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15 mg/kg/day X 2 days over 1 hour.; Biological: Young TIL; On day 0, TIL will be infused intravenously (IV) on the Patient Care Unit over 20 to 30 minutes.
Experimental: Arm 2/Low-Dose Aldesleukin; Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine plus young TIL plus low-dose Aldesleukin	Drug: Aldesleukin; Aldesleukin at 720,000 (Arm 1) or 72,000 (Arm 2) IU/kg IV based on total body weight) over 15 minutes approximately every eight hours (+/- 1hr) beginning within 24 hours of cell infusion and continuing for up to a maximum of 9 doses in Arm 1 and 12 doses in Arm 2.; Drug: Fludarabine; Days -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.; Drug: Cyclophosphamide; Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15 mg/kg/day X 2 days over 1 hour.; Biological: Young TIL; On day 0, TIL will be infused intravenously (IV) on the Patient Care Unit over 20 to 30 minutes.

Outcome Measures

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Primary Outcome Measures :

1. Rate of tumor regression [ Time Frame: 6 and 12 weeks after cell infusion, then every 3 months x3, every 6 months x2 years, then PI discretion ]
   Percentage of patients who have a clinical response to treatment (objective tumor regression)

Secondary Outcome Measures :

1. Phenotypic and functional characteristics of TIL. [ Time Frame: 2-4 years post cell infusion ]
   Find in vitro characteristics of the infused cells which correlate with in vivo antitumor activity. Evaluation of the activity, specificity, and telomere length of infused TIL.
2. Frequency of treatment related adverse events. [ Time Frame: 30 days after end of treatment ]
   Aggregate of all adverse events and their frequency
3. Feasibility of generating TIL from patients with NSCLC [ Time Frame: 3-6 months post cell harvest ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 70 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

• INCLUSION CRITERIA:

  1. Measurable metastatic (stage IV) or unresectable non-small cell lung cancer (including but not limited to squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinomas) with at least one lesion that is resectable for TIL generation. (Note: neuroendocrine tumors are not eligible.)
  2. Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.
  3. All patients must have had at least one appropriate first line systemic therapy and progressed.
  4. Clinical performance status of ECOG 0 or 1.
  5. Greater than or equal to 18 years of age and less than or equal to 70 years of age.
  6. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after treatment.
  7. Willing to sign a durable power of attorney
  8. Able to understand and sign the Informed Consent Document

I. Hematology:

• Absolute neutrophil count greater than 1000/mm3 without support of filgrastim
• Normal WBC (> 3000/mm3).
• Hemoglobin greater than 8.0 g/dl. Subjects may be transfused to reach this cut-off.

• Platelet count greater than 100,000/mm3

  j. Serology:

• Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune competence and thus may be less responsive to the experimental treatment and more susceptible to its toxicities.)

• Seronegative for active hepatitis B, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RTPCR and be HCV RNA negative.

  k. Chemistry:

• Serum ALT/AST less than 2.5 times the upper limit of normal.
• Serum creatinine less than or equal to 1.6 mg/dl.

• Total bilirubin less than or equal to 2 mg/dl, except in patients with Gilbert s Syndrome, who must have a total bilirubin less than or equal to 3 mg/dl.

  l.Women of child-bearing potential must have a negative pregnancy test because of the

potentially dangerous effects of the treatment on the fetus.

m. More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients toxicities must have recovered to a grade 1 or less. Patients may have undergone minor surgical procedures or local radiotherapy within the past 4 weeks.

n. More than two weeks must have elapsed since any prior palliation for major bronchial occlusion or bleeding at the time the patient receives the preparative regimen, and patient s toxicities must have recovered to a grade 1 or less.

o. Subjects must be co-enrolled in protocol 03-C-0277

EXCLUSION CRITERIA:

1. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
2. Ongoing need for pharmacological immunosuppression, including steroids
3. Active systemic infections (e.g.: requiring anti-infective treatment), coagulation disorders or any other active or uncompensated major medical illnesses.
4. Major bronchial occlusion or bleeding not amenable to palliation.

5. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency

   Disease and AIDS).

6. Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
7. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
8. Any patient known to have an LVEF less than or equal to 45%.

9. Documented LVEF of less than or equal to 45% tested in patients with:

   -Clinically significant atrial and/or ventricular arrhythmias including but not limited to:

   atrial fibrillation, ventricular tachycardia, second or third degree heart block or have a history of ischemic heart disease, chest pain

   -Age greater than or equal to 65 years old

10. Documented FEV1 of less than or equal to 50% predicted in patients with clinical

    symptomatology.

11. Any of the following will exclude patients from the high-dose aldesleukin arm, but may be eligible for the low-dose aldesleukin arm:

    • Greater than 2 invasive thoracic procedures
    • Poor exercise tolerance
    • Greater than 66 years of age
12. Clinically significant patient history which in the judgment of the Principal Investigator would compromise the patient s ability to tolerate high-dose.
13. Patients who are receiving any other investigational agents.

Contacts and Locations

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Contacts

Contact: Mary E. Link, R.N.	(866) 820-4505	IRC@nih.gov

Locations

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike	Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center 866-820-4505 irc@nih.gov

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator:	James C Yang, M.D.	National Cancer Institute (NCI)

More Information

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Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Delbaldo C, Michiels S, Rolland E, Syz N, Soria JC, Le Chevalier T, Pignon JP. Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD004569. Review. Update in: Cochrane Database Syst Rev. 2012;4:CD004569.

Boni C, Tiseo M, Boni L, Baldini E, Recchia F, Barone C, Grossi F, Germano D, Matano E, Marini G, Labianca R, Di Costanzo F, Bagnulo A, Pennucci C, Caroti C, Mencoboni M, Zanelli F, Prochilo T, Cafferata MA, Ardizzoni A; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). Triplets versus doublets, with or without cisplatin, in the first-line treatment of stage IIIB-IV non-small cell lung cancer (NSCLC) patients: a multicenter randomised factorial trial (FAST). Br J Cancer. 2012 Feb 14;106(4):658-65. doi: 10.1038/bjc.2011.606. Epub 2012 Jan 12.

Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M; West Japan Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010 Feb;11(2):121-8. doi: 10.1016/S1470-2045(09)70364-X. Epub 2009 Dec 18.

Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT02133196 History of Changes
Other Study ID Numbers:	140104; 14-C-0104
First Posted:	May 7, 2014
Last Update Posted:	August 3, 2018
Last Verified:	August 1, 2018

Studies a U.S. FDA-regulated Drug Product:		Yes

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

Metastatic; Non-Small Cell Lung Cancer; NSCLC; Lung Cancer

Additional relevant MeSH terms:

Carcinoma; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Adenocarcinoma; Carcinoma, Adenosquamous; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic	Bronchial Neoplasms; Neoplasms, Squamous Cell; Neoplasms, Complex and Mixed; Cyclophosphamide; Fludarabine phosphate; Fludarabine; Aldesleukin; Interleukin-2; Vidarabine; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents