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A Phase II Prospective Randomized Study of Cell Transfer Therapy for Metastatic Melanoma Using Tumor Infiltrating Lymphocytes Plus IL-2 Comparing Two Different Chemotherapy Preparative Regimens

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 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:
NCT01993719
First received: November 22, 2013
Last updated: August 30, 2014
Last verified: August 2014
  Purpose

Background:

  • Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes can mediate the regression of bulky metastatic melanoma when administered along with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen consisting of cyclophosphamide and fludarabine.
  • In a series of consecutive trials using this chemotherapy preparative regimen alone or with 2 Gy or 12 Gy total body irradiation (TBI) objective response rates using RECIST criteria were 49%, 52%, and 72%, respectively. Of the 20 complete regressions seen in this trial, 19 are on-going at 70 to 114 months.
  • The chemotherapy alone preparative regimen required in-patient treatment and was associated with significant neutropenia and thrombocytopenia requiring multiple transfusions and treatment for febrile neutropenia.
  • We would thus now like to evaluate ACT with TIL comparing the standard cyclophosphamide and fludarabine regimen with a reduced preparative regimen (300 mg/m(2) cyclophosphamide qd times 3 and fludarabine (30 mg/m2 qd times 3) that is associated with less neutropenia and thrombocytopenia and can be administered as an outpatient.

Objectives:

  • To determine, in a prospective randomized trial, whether patients receiving TIL plus a lower dose chemotherapy preparative regimen followed by aldesleukin are able to attain a response rate equivalent to TIL plus our standard chemotherapy regimen followed by aldesleukin.
  • To assess bone marrow toxicity of the two regimens to determine the duration and severity of anemia, neutropenia and/or thrombocytopenia.
  • Platelet and red cell transfusion requirement and progression free survival and overall survival will be evaluated as secondary endpoints.

Eligibility:

  • Age greater than or equal to 18 and less than or equal to 66 years
  • Evaluable metastatic melanoma
  • Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL
  • No contraindications to high-dose aldesleukin administration
  • No concurrent major medical illnesses or any form of immunodeficiency

Design:

  • Patients with metastatic melanoma will have lesions resected and after TIL growth is established, patients will be prospectively randomized to receive ACT with TIL plus aldesleukin comparing two different chemotherapy preparative regimens.
  • Up to 120 patients may be enrolled over 4-5 years.

Condition Intervention Phase
Metastatic Melanoma
Drug: Aldesleukin
Drug: Fludarabine
Drug: Cyclophosphamide
Biological: Young Tumor Infiltrating Lymphocytes (young TIL)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Prospective Randomized Study of Cell Transfer Therapy for Metastatic Melanoma Using Tumor Infiltrating Lymphocytes Plus IL-2 Comparing Two Different Chemotherapy Preparative Regimens

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Determine whether patients receiving TIL plus a lower dose chemotherapy preparative regimen followed by aldesleukin are able to attain a response rate equivalent to TIL plus our standard chemotherapy regimen followed by aldesleukin. [ Time Frame: 4-5 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To evaluate the relative platelet and red cell transfusion requirements on the two arms [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 120
Study Start Date: November 2013
Estimated Study Completion Date: September 2019
Estimated Primary Completion Date: September 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm 1
Standard dose chemotherapy + Young TIL + Aldesleukin
Drug: Aldesleukin
720,000 IU/kg IV over 15 minute every eight hours (+/- 1 hour) for up to 5 days.
Drug: Fludarabine
(standard dose) 25 mg/m(2)/day IVPB daily over 15-30 minutes for 5 days vs (low dose) 30mg/m2 IV over 30 minutes x 3 days
Drug: Cyclophosphamide
(standard dose) 60 mg/kg/day over 1 hour for 2 days IV vs (low dose) 300mg/m2 IV over 1 hour x 3 days.
Biological: Young Tumor Infiltrating Lymphocytes (young TIL)
Autologous young TIL infusion will be administered intravenously over 20 to 30 minutes (minimum 1 X 10(9) and up to a maximum of 2 X 10(11) lymphocytes).
Experimental: Arm 2
Low dose chemotherapy + Young TIL + Aldesleukin
Drug: Aldesleukin
720,000 IU/kg IV over 15 minute every eight hours (+/- 1 hour) for up to 5 days.
Drug: Fludarabine
(standard dose) 25 mg/m(2)/day IVPB daily over 15-30 minutes for 5 days vs (low dose) 30mg/m2 IV over 30 minutes x 3 days
Drug: Cyclophosphamide
(standard dose) 60 mg/kg/day over 1 hour for 2 days IV vs (low dose) 300mg/m2 IV over 1 hour x 3 days.
Biological: Young Tumor Infiltrating Lymphocytes (young TIL)
Autologous young TIL infusion will be administered intravenously over 20 to 30 minutes (minimum 1 X 10(9) and up to a maximum of 2 X 10(11) lymphocytes).

Detailed Description:

Background:

  • Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes can mediate the regression of bulky metastatic melanoma when administered along with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen consisting of cyclophosphamide and fludarabine.
  • In a series of consecutive trials using this chemotherapy preparative regimen alone or with 2 Gy or 12 Gy total body irradiation (TBI) objective response rates using RECIST criteria were 49%, 52%, and 72%, respectively. Of the 20 complete regressions seen in this trial, 19 are on-going at 70 to 114 months.
  • The chemotherapy alone preparative regimen required in-patient treatment and was associated with significant neutropenia and thrombocytopenia requiring multiple transfusions and treatment for febrile neutropenia.
  • We would thus now like to evaluate ACT with TIL comparing the standard cyclophosphamide and fludarabine regimen with a reduced preparative regimen (300 mg/m(2) cyclophosphamide qd times 3 and fludarabine (30 mg/m2 qd times 3) that is associated with less neutropenia and thrombocytopenia and can be administered as an outpatient.

Objectives:

  • To determine, in a prospective randomized trial, whether patients receiving TIL plus a lower dose chemotherapy preparative regimen followed by aldesleukin are able to attain a response rate equivalent to TIL plus our standard chemotherapy regimen followed by aldesleukin.
  • To assess bone marrow toxicity of the two regimens to determine the duration and severity of anemia, neutropenia and/or thrombocytopenia.
  • Platelet and red cell transfusion requirement and progression free survival and overall survival will be evaluated as secondary endpoints.

Eligibility:

  • Age greater than or equal to 18 and less than or equal to 66 years
  • Evaluable metastatic melanoma
  • Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL
  • No contraindications to high-dose aldesleukin administration
  • No concurrent major medical illnesses or any form of immunodeficiency

Design:

  • Patients with metastatic melanoma will have lesions resected and after TIL growth is established, patients will be prospectively randomized to receive ACT with TIL plus aldesleukin comparing two different chemotherapy preparative regimens.
  • Up to 120 patients may be enrolled over 4-5 years.
  Eligibility

Ages Eligible for Study:   18 Years to 66 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

-INCLUSION CRITERIA:

  1. Measurable metastatic melanoma with at least one lesion that is resectable for TIL generation.
  2. Confirmation of diagnosis of metastatic melanoma by the Laboratory of Pathology of NCI.
  3. 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.
  4. Greater than or equal to 18 years of age and less than or equal to 66 years of age.
  5. Able to understand and sign the Informed Consent Document
  6. Clinical performance status of ECOG 0 or 1.
  7. Life expectancy of greater than three months.
  8. 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.
  9. 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 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 RT-PCR and be HCV RNA negative.
  10. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
  11. 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
  12. Chemistry:

    • Serum ALT/AST less than or equal to 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 1.5 mg/dl, except in patients with Gilbert s Syndrome who must have a total bilirubin less than 3.0 mg/dl.
  13. 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). Patients must have progressive disease after prior treatment.

    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.

  14. Six weeks must have elapsed from the time of any antibody therapy that could affect an anti cancer immune response, including anti-CTLA4 antibody therapy, so at the time the patient receives the preparative regimen to allow antibody levels to decline. Note: Patients who have previously received ipilimumab and have documented GI toxicity must have a colonoscopy with normal colonic biopsies.

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. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  3. 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).
  4. Active systemic infections, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system, as evidenced by a positive stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
  5. Concurrent systemic steroid therapy.
  6. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  7. History of coronary revascularization or ischemic symptoms.
  8. Documented LVEF of less than or equal to 45%, testing is required in patients with:

    • Age greater than or equal to 60 years old
    • Clinically significant atrial and or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block.
  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: NCT01993719

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: NCT01993719     History of Changes
Other Study ID Numbers: 140022, 14-C-0022
Study First Received: November 22, 2013
Last Updated: August 30, 2014
Health Authority: United States: Federal Government

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

Additional relevant MeSH terms:
Melanoma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Neuroendocrine Tumors
Nevi and Melanomas
Aldesleukin
Cyclophosphamide
Alkylating Agents
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Antiviral Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014