Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Melanoma

NCT01993719 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 14002214-C-0022
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• The National Cancer Institute (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 400 patients with melanoma.
• In this trial, we are determining if there is a difference in the response between patients who have received prior anti-programmed cell death-1 (PD-1) treatment to those who have not received this prior ant-PD1 treatment. Objectives: \- To determine if there is a difference in the rate of response between patients who have received prior anti-PD1 and those who have not. Eligibility: \- Individuals at least 18 years and less than or equal to 70 years of age who have metastatic melanoma. Design:
• Work up stage: Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected.
• Surgery: Surgery or biopsy will be performed to obtain tumor from which to grow white blood cells. White blood cells will be grown from the tumor in the laboratory.
• Leukapheresis: Participants will have leukapheresis to collect additional white blood cells. (Leukapheresis is a common procedure which removes only the white blood cells from the patient.)
• Treatment: Participants will receive standard dose chemotherapy to prepare their immune system to accept the white blood cells. Participants will receive an infusion of their own white blood cells grown from tumor. They will also receive aldesleukin for up to five days to boost the immune system s response to the white blood cells. 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.

Conditions

Metastatic Melanoma

Keywords

Melanoma; Adoptive Cell Therapy

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Treatment-related Grade 3-5 Adverse Events in Arm 1N and Arm 1P

  Number of participants with Grades 3-5 treatment-related adverse events were compared in Arm 1N and Arm 1P; and adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 3 is severe. Grade 4 is life-threatening, and Grade 5 is death related to adverse event.

  30 days after end of treatment

• Number of Participants Who Have a Clinical Response to Treatment (Objective Tumor Regression)

  Clinical response to treatment was assessed by the Response Evaluation Criteria In Solid Tumors (RECIST v1.0). Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progressive Disease (PD) is at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD.

  4 weeks after cell infusion, then every 3 months x 3 and then every 6 months for 5 years, then per Principal Investigator (PI) discretion up to 5 years or disease progression

• Overall Response Rate (ORR)

  Overall response is the best response recorded from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.0). Progression is at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

  Date of cells until time of disease progression, up to approximately 67.2 months.

Secondary Outcomes (5)

• Number of Treatment-related Adverse Events for Participants Who Received Pembrolizumab

  Date treatment consent signed until approximately 4 weeks following last dose of Pembrolizumab, up to 4 weeks

• Progression-free Survival (PFS)

  Date of cells until time of disease progression up to approximately 67.2 months.

• Overall Survival

  Date of cells until time to death, up until 90.1 months.

• Overall Survival

  An average of 25.6 months.

• Overall Progression Free Survival (PFS)

  Time to progression and time to death, approximately up to 67.2 months.

Other Outcomes (1)

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

  Date treatment consent signed to date off study, approximately 102 months and 9 days, 92 months and 19 days, 86 months and 9 days, 99 months and 16 days, and 86 months and 26 days for each group respectively.

Study Arms (5)

Arm 1N -Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin

EXPERIMENTAL

Standard Chemo Prep Regimen. Young Tumor Infiltrating Lymphocytes (TIL) Plus High Dose Interleukin-2, Standard Chemo Preparative Regimen in participants without prior treatment pembrolizumab or nivolumab Standard preparative regimen + Young Tumor Infiltrating Lymphocytes (TIL) Cells Aldesleukin: 720,000 IU/kg intravenous (IV) every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses). Fludarabine: 25 mg/m\^2/day intravenous piggy-back (IVPB) daily for 5 days Cyclophosphamide: 60 mg/kg/day X 2 days intravenous (IV) Young TIL: Day 0: Cells will be infused intravenously (IV)

Drug: Aldesleukin; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Young TIL

Arm 1P - Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin

EXPERIMENTAL

Standard Chemo Prep Regimen Young Tumor Infiltrating Lymphocytes (TIL) Plus High Dose Interleukin-2, Standard Chemo Preparative Regimen in participants previously treated with pembrolizumab or nivolumab. Standard preparative regimen + Young Tumor Infiltrating Lymphocytes (TIL) Cells Aldesleukin: 720,000 IU/kg intravenous (IV) every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses). Fludarabine: 25 mg/m\^2/day intravenous piggy-back (IVPB) daily for 5 days Cyclophosphamide: 60 mg/kg/day X 2 days intravenous (IV) Young TIL: Day 0: Cells will be infused intravenously (IV)

Drug: Aldesleukin; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Young TIL

Arm 2/Foll By Arm 1P-Low dose Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin

EXPERIMENTAL

Decreased Chemo Prep Regimen+Retreat. Young TIL+High Dose Interleukin-2, Decreased Chemo Preparative Regimen. Young TIL+High Dose Interleukin-2, Standard Chemo (Retreat). Lower dose preparative regimen + Young TIL Cells. Aldesleukin: 720,000 IU/kg IV every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses). Fludarabine: 30 mg/kg/day intravenous piggy-back (IVPB) daily for 3 days. Cyclophosphamide: Days -5 to -3 (low-dose arm): Cyclophosphamide 300 mg/m\^2 IV over 60 minutes. Young TIL: Day 0: Cells will be infused IV. Retreatment: Standard Chemo Prep Regimen. Aldesleukin: 720,000 IU/kg IV every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses). Fludarabine: 25 mg/m\^2/day intravenous piggy-back (IVPB) daily for 5 days. Cyclophosphamide: 60 mg/kg/day X 2 days IV. Young TIL: Day 0: Cells will be infused IV.

Drug: Aldesleukin; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Young TIL

Arm 2- Low Dose Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin

EXPERIMENTAL

Decreased Chemo Prep Regimen. Young Tumor Infiltrating Lymphocytes (TIL) Plus High Dose Interleukin-2 Lower Dose preparative regimen + Young Tumor Infiltrating Lymphocytes (TIL) Cells Aldesleukin: 720,000 IU/kg intravenous (IV) every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses). Fludarabine: 30 mg/kg/day intravenous piggy-back (IVPB) daily for 3 days Cyclophosphamide: Days -5 to -3 (low-dose arm): Cyclophosphamide 30 mg/kg IV over 60 minutes for 2 days. Young TIL: Day 0: Cells will be infused intravenously (IV)

Drug: Aldesleukin; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Young TIL

Arm 1P/Foll By Arm-1P/R-Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin

EXPERIMENTAL

Standard Chemo Prep Regimen(SCPR)+Retreat. Young TIL+High Dose(HD) Interleukin-2, SCPR. Young TIL+HD Interleukin-2, SC(Retreat). SCPR+Young TIL Cells retreatment with SCPR+Young TIL Cells+pembrolizumab. Aldesleukin:720,000 IU/kgIV every eight hours (+/-1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses). Fludarabine:25 mg/m\^2/day intravenous piggy-back(IVPB) daily for 5 days. Cyclophosphamide:60 mg/kg/day X 2 days IV. Young TIL:Day 0: Cells will be infused IV. Retreatment with standard preparative regimen+Young TIL Cells+pembrolizumab. Aldesleukin:720,000 IU/kg IV every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses). Fludarabine:25 mg/m\^2/day intravenous piggy-back (IVPB) daily for 5 days. Cyclophosphamide:60 mg/kg/day X 2 days IV. Young TIL: Day 0:Cells will be infused IV. Pembrolizumab:2 mg/kg IV on Days -2, 21 (+/- 2 days), 42 (+/- 2 days), and 63 (+/- 2 days).

Drug: Aldesleukin; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Young TIL; Drug: Pembrolizumab

Interventions

Aldesleukin DRUG

720,000 IU/kg intravenous (IV) every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses).

Also known as: Proleukin

Arm 1N -Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin; Arm 1P - Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin; Arm 1P/Foll By Arm-1P/R-Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin; Arm 2- Low Dose Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin; Arm 2/Foll By Arm 1P-Low dose Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin

Fludarabine DRUG

25 mg/m\^2/day intravenous piggy-back (IVPB) daily for 5 days

Also known as: Fludara

Arm 1N -Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin; Arm 1P - Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin; Arm 1P/Foll By Arm-1P/R-Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin; Arm 2/Foll By Arm 1P-Low dose Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin

Cyclophosphamide DRUG

60 mg/kg/day X 2 days intravenous (IV)

Also known as: Cytoxan

Arm 1N -Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin; Arm 1P - Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin; Arm 1P/Foll By Arm-1P/R-Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin; Arm 2/Foll By Arm 1P-Low dose Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin

Young TIL BIOLOGICAL

Day 0: Cells will be infused intravenously (IV)

Also known as: Young Tumor Infiltrating Lymphocytes

Arm 1N -Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin; Arm 1P - Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin; Arm 1P/Foll By Arm-1P/R-Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin; Arm 2- Low Dose Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin; Arm 2/Foll By Arm 1P-Low dose Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin

Pembrolizumab DRUG

2 mg/kg intravenous (IV) on Days -2, 21 (+/- 2 days), 42 (+/- 2 days), and 63 (+/- 2 days).

Also known as: Keytruda

Arm 1P/Foll By Arm-1P/R-Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Measurable metastatic melanoma with at least one lesion that is resectable for tumor infiltrating lymphocytes (TIL) generation and at least one other lesion that can be measured by Response Evaluation Criteria In Solid Tumors (RECIST) criteria.
• Confirmation of diagnosis of metastatic melanoma by the Laboratory of Pathology of National Cancer Institute (NCI).
• 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.
• Greater than or equal to 18 years of age and less than or equal to 70 years of age.
• Ability of subject to understand and the willingness to sign the Informed Consent Document
• Willing to sign a durable power of attorney.
• Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2.
• Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after treatment.
• Serology:
• Seronegative for human immunodeficiency virus (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 are less responsive to the experimental treatment and more susceptible to its toxicities.)
• Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by reverse transcription polymerase chain reaction (RT-PCR) and be hepatitis C virus (HCV) ribonucleic acid (RNA) negative.
• Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
• Hematology:
• Absolute neutrophil count greater than 1000/mm(3) without the support of filgrastim
• White blood cell (WBC) greater than or equal to 3000/mm(3)

You may not qualify if:

• Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
• Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
• 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).
• Active systemic infections, (e.g.: requiring anti-infective treatment), coagulation disorders or any other active major medical illnesses.
• Concurrent systemic steroid therapy.
• History of severe immediate hypersensitivity reaction to any of the agents used in this study.
• History of coronary revascularization or ischemic symptoms.
• Any patient known to have an left ventricular ejection fraction (LVEF) less than or equal to 45%
• Documented LVEF of less than or equal to 45%, note: testing is required in patients with:
• Age greater than or equal to 65 years old
• Clinically significant atrial and or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or history of ischemic heart disease or chest pain.
• Patients who are receiving other investigational agents
• Documented forced expiratory volume (FEV1) less than or equal to 60% predicted tested in patients with:
• A prolonged history of cigarette smoking (20 pack (pk)/year of smoking within the past 2 years).
• Symptoms of respiratory dysfunction

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (2)

• Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008 Nov 10;26(32):5233-9. doi: 10.1200/JCO.2008.16.5449. Epub 2008 Sep 22.

  PMID: 18809613 BACKGROUND

• O'Brien SM, Kantarjian HM, Cortes J, Beran M, Koller CA, Giles FJ, Lerner S, Keating M. Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol. 2001 Mar 1;19(5):1414-20. doi: 10.1200/JCO.2001.19.5.1414.

  PMID: 11230486 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Melanoma

Interventions

aldesleukin; fludarabine; fludarabine phosphate; Cyclophosphamide; pembrolizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: Dr. Stephanie L. Goff
• Organization: National Cancer Institute

stephanie.goff@nih.gov

240-760-6214

Study Officials

• Stephanie L Goff, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 22, 2013
• First Posted: November 25, 2013
• Study Start: December 12, 2013
• Primary Completion: October 14, 2021
• Study Completion: July 6, 2022
• Last Updated: January 18, 2023
• Results First Posted: January 18, 2023

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data will be available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the Study Principal Investigator (PI).

Locations

US (1)