NCT01236573

Brief Summary

Background: \- One experimental treatment for certain types of cancer is cell therapy, which involves collecting lymphocytes (white blood cells) from a tumor, growing them in the laboratory in large numbers, and then modifying the cells with a gene (interleukin-12 (IL-12)) that stimulates the immune system to attack and destroy the cancer cells. Because this treatment is experimental, researchers are interested in determining the side effects and overall effectiveness of cell therapy using white blood cells modified with IL-12 as a treatment for aggressive cancer. Objectives: \- To determine the safety and effectiveness of cell therapy using IL-12 modified tumor white blood cells to treat metastatic melanoma. Eligibility: \- Individuals greater than or equal to 18 years of age and less than or equal to age 66 who have been diagnosed with metastatic melanoma. Design:

  • Participants will be screened with a medical history, physical examination, blood and urine tests, and imaging studies.
  • Cells for treatment will be collected during tumor biopsy or surgery.
  • Prior to the start of cell therapy, participants will have imaging procedures, heart and lung function tests, and blood and urine tests, as well as leukapheresis to collect additional white blood cells.
  • For 5 days before the cell infusion, participants will be admitted for inpatient chemotherapy with cyclophosphamide and fludarabine to suppress the immune system in preparation for the cell therapy.
  • Participants will receive the modified white blood cells as an infusion 1 to 4 days after the last dose of chemotherapy. The day after the infusion, participants will receive filgrastim to stimulate blood cell growth.
  • Participants will remain as inpatients for at least 5 to 10 days to recover from the treatment, and will be followed regularly after the treatment to study side effects and general effectiveness.
  • Participants who initially respond to treatment but have a relapse may have one additional treatment using the same procedure.

Trial Health

57
Monitor

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
34

participants targeted

Target at P50-P75 for phase_1

Timeline
Completed

Started Oct 2010

Longer than P75 for phase_1

Geographic Reach
1 country

1 active site

Status
terminated

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

October 1, 2010

Completed
1 month until next milestone

First Submitted

Initial submission to the registry

November 5, 2010

Completed
3 days until next milestone

First Posted

Study publicly available on registry

November 8, 2010

Completed
4.3 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

March 1, 2015

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

March 1, 2015

Completed
8 months until next milestone

Results Posted

Study results publicly available

October 26, 2015

Completed
Last Updated

November 26, 2015

Status Verified

October 1, 2015

Enrollment Period

4.4 years

First QC Date

November 5, 2010

Results QC Date

August 20, 2015

Last Update Submit

October 26, 2015

Conditions

Skin CancerMetastatic Melanoma

Keywords

Gene TherapyImmunotherapyAdoptive Cell TherapyMetastatic Melanoma

Outcome Measures

Primary Outcomes (2)

  • Maximum Tolerated Dose (MTD)

    The MTD was determined by evaluating dose limiting toxicities (DLT) of participants that received increasing doses of intravenous infusion of IL-12 gene transduced tumor infiltrating lymphocytes (TIL) (i.e., 1x10\^6, 3x10\^6, 3x10\^7, 1x10\^7, 3x10\^7, 1x10\^8, 3x10\^8, 1x10\^9, and 3x10\^9) in cohorts 1-10. Maximum tolerated cell dose is the highest dose at which \</= 1 of 6 patients experienced a DLT (i.e. grade 2 or greater allergic reaction)).

    4 years

  • Response (Complete Response (CR) + Partial Response (PR)) to Therapy

    Response was determined 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 um 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 lesions.

    4 years

Secondary Outcomes (1)

  • Number of Participants With Adverse Events

    49 months and 20 days

Study Arms (11)

Group 1 - CD8 + TIL expressing IL-12 1x10^6

EXPERIMENTAL

Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of interleukin-12 (IL-12) gene-transduced tumor infiltrating lymphocytes (TIL).

Drug: FludarabineDrug: CyclophosphamideBiological: IL-12 transduced TIL

Group 2 - CD8 + TIL expressing IL-12 3x10^6

EXPERIMENTAL

Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.

Drug: FludarabineDrug: CyclophosphamideBiological: IL-12 transduced TIL

Group 3 - CD8 + TIL expressing IL-12 1x10^7

EXPERIMENTAL

Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.

Drug: FludarabineDrug: CyclophosphamideBiological: IL-12 transduced TIL

Group 4- CD8+TIL expressing IL-12 3x10^7

EXPERIMENTAL

Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.

Drug: FludarabineDrug: CyclophosphamideBiological: IL-12 transduced TIL

Group 5 - Bulk TIL expressing IL-12 1x10^7

EXPERIMENTAL

Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.

Drug: FludarabineDrug: CyclophosphamideBiological: IL-12 transduced TIL

Group 6 - Bulk TIL expressing IL-12 3x10^7

EXPERIMENTAL

Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.

Drug: FludarabineDrug: CyclophosphamideBiological: IL-12 transduced TIL

Group 7- Bulk TIL expressing IL-12 1x10^8

EXPERIMENTAL

Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.

Drug: FludarabineDrug: CyclophosphamideBiological: IL-12 transduced TIL

Group 8 - Bulk TIL expressing IL-12 3x10^8

EXPERIMENTAL

Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.

Drug: FludarabineDrug: CyclophosphamideBiological: IL-12 transduced TIL

Group 9 - Bulk TIL expressing IL-12 1x10^9

EXPERIMENTAL

Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.

Drug: FludarabineDrug: CyclophosphamideBiological: IL-12 transduced TIL

Group 10- Bulk TIL expressing IL12 3x10^9

EXPERIMENTAL

Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.

Drug: FludarabineDrug: CyclophosphamideBiological: IL-12 transduced TIL

Group 11 - Bulk TIL expressing MTD 1x10^9 (Phase 2)

EXPERIMENTAL

Maximum tolerated dose (MTD). Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.

Drug: FludarabineDrug: CyclophosphamideBiological: IL-12 transduced TIL

Interventions

FludarabineDRUG

Fludarabine 25 mg/m\^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.

Group 1 - CD8 + TIL expressing IL-12 1x10^6Group 10- Bulk TIL expressing IL12 3x10^9Group 11 - Bulk TIL expressing MTD 1x10^9 (Phase 2)Group 2 - CD8 + TIL expressing IL-12 3x10^6Group 3 - CD8 + TIL expressing IL-12 1x10^7Group 4- CD8+TIL expressing IL-12 3x10^7Group 5 - Bulk TIL expressing IL-12 1x10^7Group 6 - Bulk TIL expressing IL-12 3x10^7Group 7- Bulk TIL expressing IL-12 1x10^8Group 8 - Bulk TIL expressing IL-12 3x10^8Group 9 - Bulk TIL expressing IL-12 1x10^9
CyclophosphamideDRUG

Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) over 1 hr.

Group 1 - CD8 + TIL expressing IL-12 1x10^6Group 10- Bulk TIL expressing IL12 3x10^9Group 11 - Bulk TIL expressing MTD 1x10^9 (Phase 2)Group 2 - CD8 + TIL expressing IL-12 3x10^6Group 3 - CD8 + TIL expressing IL-12 1x10^7Group 4- CD8+TIL expressing IL-12 3x10^7Group 5 - Bulk TIL expressing IL-12 1x10^7Group 6 - Bulk TIL expressing IL-12 3x10^7Group 7- Bulk TIL expressing IL-12 1x10^8Group 8 - Bulk TIL expressing IL-12 3x10^8Group 9 - Bulk TIL expressing IL-12 1x10^9
IL-12 transduced TILBIOLOGICAL

On day 0 (one to four days after the last dose of fludarabine), cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes.

Group 1 - CD8 + TIL expressing IL-12 1x10^6Group 10- Bulk TIL expressing IL12 3x10^9Group 11 - Bulk TIL expressing MTD 1x10^9 (Phase 2)Group 2 - CD8 + TIL expressing IL-12 3x10^6Group 3 - CD8 + TIL expressing IL-12 1x10^7Group 4- CD8+TIL expressing IL-12 3x10^7Group 5 - Bulk TIL expressing IL-12 1x10^7Group 6 - Bulk TIL expressing IL-12 3x10^7Group 7- Bulk TIL expressing IL-12 1x10^8Group 8 - Bulk TIL expressing IL-12 3x10^8Group 9 - Bulk TIL expressing IL-12 1x10^9

Eligibility Criteria

Age18 Years - 66 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Metastatic melanoma with evaluable disease.
  • Greater than or equal to 18 years of age and less than or equal to age 66.
  • Willing to sign a durable power of attorney
  • Able to understand and sign the Informed Consent Document
  • Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1
  • Life expectancy of greater than three months
  • 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 the cells are no longer detected in the blood.
  • 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 be 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 ribonucleic acid (HCV RNA) negative.
  • Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus.
  • Hematology:
  • Absolute neutrophil count greater than 1000/mm\^3 without the support of filgrastim.
  • White blood cell (WBC) (\> 3000/mm\^3).
  • Platelet count greater than 100,000/mm\^3.
  • +6 more criteria

You may not qualify if:

  • Previous treatment with interleukin-12 (IL-12).
  • Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
  • Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
  • 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).
  • Concurrent systemic steroid therapy.
  • History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  • In patients \> 60 years old and/or history of coronary revasularization or ischemic symptoms, documented left ventricular ejection fraction (LVEF) of less than or equal to 45%.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

  • Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66. doi: 10.3322/canjclin.57.1.43.

    PMID: 17237035BACKGROUND

  • Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul;17(7):2105-16. doi: 10.1200/JCO.1999.17.7.2105.

    PMID: 10561265BACKGROUND

  • Gogas HJ, Kirkwood JM, Sondak VK. Chemotherapy for metastatic melanoma: time for a change? Cancer. 2007 Feb 1;109(3):455-64. doi: 10.1002/cncr.22427.

    PMID: 17200963BACKGROUND

  • Zhang L, Morgan RA, Beane JD, Zheng Z, Dudley ME, Kassim SH, Nahvi AV, Ngo LT, Sherry RM, Phan GQ, Hughes MS, Kammula US, Feldman SA, Toomey MA, Kerkar SP, Restifo NP, Yang JC, Rosenberg SA. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin Cancer Res. 2015 May 15;21(10):2278-88. doi: 10.1158/1078-0432.CCR-14-2085. Epub 2015 Feb 18.

    PMID: 25695689RESULT

  • Kerkar SP, Goldszmid RS, Muranski P, Chinnasamy D, Yu Z, Reger RN, Leonardi AJ, Morgan RA, Wang E, Marincola FM, Trinchieri G, Rosenberg SA, Restifo NP. IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. J Clin Invest. 2011 Dec;121(12):4746-57. doi: 10.1172/JCI58814. Epub 2011 Nov 7.

    PMID: 22056381DERIVED

MeSH Terms

Conditions

Skin NeoplasmsMelanoma

Interventions

fludarabineCyclophosphamide

Condition Hierarchy (Ancestors)

Neoplasms by SiteNeoplasmsSkin DiseasesSkin and Connective Tissue DiseasesNeuroendocrine TumorsNeuroectodermal TumorsNeoplasms, Germ Cell and EmbryonalNeoplasms by Histologic TypeNeoplasms, Nerve TissueNevi and Melanomas

Intervention Hierarchy (Ancestors)

Phosphoramide MustardsNitrogen Mustard CompoundsMustard CompoundsHydrocarbons, HalogenatedHydrocarbonsOrganic ChemicalsPhosphoramidesOrganophosphorus Compounds

Limitations and Caveats

Due to the unexpected toxicities, likely attributable to the tumor infiltrating lymphocytes (TIL) transduced with IL-12, and low percentage of durable responses, we decided to close this study.

Results Point of Contact

Title
Dr. Steven Rosenberg
Organization
National Cancer Institute
sar@mail.nih.gov
301-496-4164

Study Officials

  • Steven A Rosenberg, 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 1
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 5, 2010

First Posted

November 8, 2010

Study Start

October 1, 2010

Primary Completion

March 1, 2015

Study Completion

March 1, 2015

Last Updated

November 26, 2015

Results First Posted

October 26, 2015

Record last verified: 2015-10

Locations

US(1)