A Pilot Study of the Administration of Young Tumor Infiltrating Lymphocytes Following a Non-Myeloablative Lymphocyte Depleting Chemotrheraphy Regimen in Metastatic Melanoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01468818
First received: October 6, 2011
Last updated: July 31, 2014
Last verified: March 2014
  Purpose

BACKGROUND:

- Tumor Infiltrating Lymphocytes (TIL) can mediate the regression of bulky metastatic melanoma when administered to the autologous patient along with high-dose aldesleukin

(IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen.

  • IL-2 administration has been shown to increase the number of T regulatory cells and in our trials we have found a direct relationship between the number of IL-2 doses and the reconstitution of patients at one week with CD4+ Foxp3+ T regulatory cells.
  • In our analysis of factors that relate to the ability of this treatment to mediate objective responses, we have found a highly significant inverse correlation between reconstitution of CD4+ Foxp3+ T regulatory cells and the likelihood of achieving an objective response.
  • In our prior clinical trials of cell transfer using TIL after lymphodepletion with or without

    2Gy total body irradiation, patients who experienced an objective response received fewer doses of IL-2 compared to non-responders (p=0.007 and 0.03 respectively).

  • High levels of the homeostatic T cell growth factor, IL-15, are present in patient serum after the lymphodepleting regimen at the time of cell transfer.
  • These factors raise the possibility that IL-2 administration is not required after cell transfer.

OBJECTIVES:

  • The primary objective of this trial is to determine whether objective responses can be mediated in patients with metastatic melanoma who have received a lymphodepleting chemotherapy regimen and adoptive transfer of young tumor infiltrating lymphocytes and no IL-2 administration.
  • The secondary objective involves the determination of the level of transferred cells in the blood that persist at about 1 week and 1 month after transfer.

ELIGIBILITY:

  • Patients greater than or equal to 18 years old with pathologically confirmed diagnosis of metastatic melanoma.
  • Patients with measurable disease, absolute neutrophil count greater than 1000/mm3 and platelet count greater than 100,000/mm3.
  • Patients not eligible to receive IL-2 because of cardiovascular or respiratory problems or who refuse IL-2.

DESIGN:

  • Patients with metastatic melanoma will undergo resection to obtain tumor for generation of autologous TIL cultures.
  • Patients will receive a non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of young

autologous TIL.

- Patients will be evaluated for objective clinical response and for persistence of the transferred cells.


Condition Intervention Phase
Metastatic Melanoma
Skin Cancer
Drug: Cyclophosphamide
Drug: Fludarabine
Biological: Young TIL
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study of the Administration of Young Tumor Infiltrating Lymphocytes Following a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen in Metastatic Melanoma

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Determine whether objective responses can be mediated in patients with metastitic melanoma [ Time Frame: 2 Years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 35
Study Start Date: September 2011
Estimated Study Completion Date: August 2016
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single Arm
Patients will receive non-myeloablative lymphodepleting preparative regimen cons
Drug: Cyclophosphamide
Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15 mg/kg/day X 2 days over 1 hr.
Drug: Fludarabine
Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
Biological: Young TIL
Patients will receive non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of young TIL. On day 0, cells (1x10e9 to 2x10e11) will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (between one and four days after the last dose of fludarabine).

Detailed Description:

BACKGROUND:

- Tumor Infiltrating Lymphocytes (TIL) can mediate the regression of bulky metastatic melanoma when administered to the autologous patient along with high-dose aldesleukin

(IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen.

  • IL-2 administration has been shown to increase the number of T regulatory cells and in our trials we have found a direct relationship between the number of IL-2 doses and the reconstitution of patients at one week with CD4+ Foxp3+ T regulatory cells.
  • In our analysis of factors that relate to the ability of this treatment to mediate objective responses, we have found a highly significant inverse correlation between reconstitution of CD4+ Foxp3+ T regulatory cells and the likelihood of achieving an objective response.
  • In our prior clinical trials of cell transfer using TIL after lymphodepletion with or without

    2Gy total body irradiation, patients who experienced an objective response received fewer doses of IL-2 compared to non-responders (p=0.007 and 0.03 respectively).

  • High levels of the homeostatic T cell growth factor, IL-15, are present in patient serum after the lymphodepleting regimen at the time of cell transfer.
  • These factors raise the possibility that IL-2 administration is not required after cell transfer.

OBJECTIVES:

  • The primary objective of this trial is to determine whether objective responses can be mediated in patients with metastatic melanoma who have received a lymphodepleting chemotherapy regimen and adoptive transfer of young tumor infiltrating lymphocytes and no IL-2 administration.
  • The secondary objective involves the determination of the level of transferred cells in the blood that persist at about 1 week and 1 month after transfer.

ELIGIBILITY:

  • Patients greater than or equal to 18 years old with pathologically confirmed diagnosis of metastatic melanoma.
  • Patients with measurable disease, absolute neutrophil count greater than 1000/mm(3) and platelet count greater than 100,000/mm(3).
  • Patients not eligible to receive IL-2.

DESIGN:

  • Patients with metastatic melanoma will undergo resection to obtain tumor for generation of autologous TIL cultures.
  • Patients will receive a non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of young

autologous TIL.

- Patients will be evaluated for objective clinical response and for persistence of the transferred cells.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Measurable metastatic melanoma with available autologous TIL.
  • 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.
  • Able to understand and sign the Informed Consent Document
  • Clinical performance status of 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 receiving the treatment.
  • 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 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 RT-PCR and be HCV 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
  • WBC greater than or equal to 3000/mm(3)
  • Platelet count greater than or equal to 100,000/mm(3)
  • Hemoglobin > 8.0 g/dl
  • Chemistry:
  • Serum ALT/AST less than or equal to to 2.5 times the upper limit of normal
  • Serum Creatinine less than or equal to to 1.6 mg/dl
  • Total bilirubin less than or equal to to 1.5 mg/dl, except in patients with Gilbert s Syndrome who must have a total bilirubin less than 3.0 mg/dl.
  • 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 (except for toxicities such as alopecia or vitiligo).

Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less or as specified in the eligibility criteria.

  • Six weeks must have elapsed since any prior anti-CTLA4 antibody therapy to allow antibody levels to decline.
  • Patients must be ineligible to receive IL-2 based on evidence that may include ischemic heart disease, or arrhythmias, or poor ventricular ejection fraction (< 50%), or respiratory compromise (FEV1 < 60%), or clinically significant patient history which in the judgment of the investigator would compromise the patient s ability to tolerate aldesleukin.

EXCLUSION CRITERIA:

  • 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).
  • Concurrent systemic steroid therapy.
  • History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  • Patients with a ventricular ejection fraction (less than or equal to 30%), or respiratory compromise (FEV1 less than or equal to 40%).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01468818

Contacts
Contact: Linda Williams, R.N. (866) 820-4505 linda_williams@nih.gov
Contact: Steven A Rosenberg, M.D. (301) 496-4164 sar@mail.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    ncisbirc@mail.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01468818     History of Changes
Other Study ID Numbers: 110260, 11-C-0260
Study First Received: October 6, 2011
Last Updated: July 31, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Metastatic Melanoma
Adoptive Cell Therapy
Skin Cancer

Additional relevant MeSH terms:
Skin Neoplasms
Melanoma
Neoplasms by Site
Neoplasms
Skin Diseases
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites

ClinicalTrials.gov processed this record on August 01, 2014