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Chemotherapy Followed by ESO-1 Lymphocytes and Aldesleukin to Treat Metastatic Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT00670748
First received: May 1, 2008
Last updated: September 9, 2014
Last verified: August 2014

May 1, 2008
September 9, 2014
April 2008
June 2015   (final data collection date for primary outcome measure)
  • In cohorts 1 and 2, determine if the administration of anti-ESO TCR engineered PBL and aldesleukin following preparative chemotherapy regimen results in objective tumor regression [ Time Frame: Approximately 3 years ] [ Designated as safety issue: Yes ]
  • In cohorts 3 and 4, determine if the administration of anti-ESO TCR-engineered PBL,aldesleukin and ALVAC ESO-1 vaccine following preparative chemotherapy regimen results in objective tumor regression [ Time Frame: Approximately 3 years ] [ Designated as safety issue: Yes ]
Clinical tumor regression [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00670748 on ClinicalTrials.gov Archive Site
Not Provided
  • In vivo survival of TCR gene-engineered cells [ Designated as safety issue: No ]
  • Toxicity [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Chemotherapy Followed by ESO-1 Lymphocytes and Aldesleukin to Treat Metastatic Cancer
Phase II Study of Metastatic Cancer That Expresses NY-ESO-1 Using Lymphodepleting Conditioning Followed by Infusion of Anti-NY ESO-1 TCR-Gene Engineered Lymphocytes

Background:

-This study uses an experimental cancer treatment that uses the patient s own lymphocytes (type of white blood cell), which are specially selected and genetically modified to target and destroy their tumor.

Objectives:

-To test the safety of the treatment and determine if it can cause the patient s tumor to shrink.

Eligibility:

  • Patients greater than 18 years and less than or equal to 66 years of age whose cancer has spread beyond the original site and does not respond to standard treatment.
  • Patients have tissue type HLA-A*0201.
  • Patients cancer cells have the ESO-1 gene.

Design:

  • Workup: Patients have scans, x-rays, laboratory tests, and other tests as needed.
  • Patients have leukapheresis to collect cells for laboratory treatment and later reinfusion. For this procedure, whole blood is collected thorough a tube in a vein, the desired cells are extracted from the blood, and the rest of the blood is returned to the patient.
  • Chemotherapy: Patients have low-dose chemotherapy for 1 week to prepare the immune system to receive the treated lymphocytes.
  • Cell infusion and aldesleukin (IL-2) treatment: Patients receive the lymphocytes by a 30-minute infusion through a vein. Starting within 24 hours of the infusion, they receive high-dose aldesleukin infusions every 8 hours for up to 5 days (maximum15 doses).
  • Recovery: Patients rest for 1 to 2 weeks to recover from the effects of chemotherapy and aldesleukin.
  • Tumor biopsy: Patients may be asked to undergo a biopsy (surgical removal of a small piece of tumor) after treatment to look at the effects of treatment on the immune cells in the tumor.
  • Follow-up: After treatment is completed, patients return to the clinic once a month for several months for physical examinations, a review of side effects, laboratory tests and scans. They may undergo leukapheresis at some visits to look at the effect of treatment on the immune system and check the viability of the infused cells. Patients then return to the NIH clinic once a year for 5 years and then complete a follow-up questionnaire for another 10 years.
  • Retreatment: Patients whose tumor shrinks or disappears following treatment and then recurs may receive one additional treatment, using the same regimen of chemotherapy, lymphocyte infusion and IL-2 treatment.

Background:

  • We have constructed a single retroviral vector that contains both alpha and beta chains of a T cell receptor (TCR) that recognizes the NY-ESO-1 (ESO) tumor antigen, which can be used to mediate genetic transfer of this TCR with high efficiency (> 30%) without the need to perform any selection.
  • In co-cultures with HLA-A2 and ESO double positive tumors, anti-ESO TCR transduced T cells secreted significant amount of IFN-gamma and additional secretion of cytokines with high specificity.
  • Poxviruses encoding tumor antigens, similar to the ALVAC ESO-1 vaccine have been shown to successfully immunize patients against these antigens.

Objectives:

Primary objectives:

  • Determine if the administration of anti-ESO TCR engineered peripheral blood lymphocytes (PBL) and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic cancer that expresses the ESO antigen.
  • Determine if the administration of anti-ESO TCR engineered PBL, aldesleukin, and ALVAC ESO-1 vaccine to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic cancer that expresses the ESO antigen.

Secondary objectives:

  • Determine the in vivo survival of TCR gene-engineered cells.
  • Determine the toxicity profile of this treatment regimen.

Eligibility:

  • Patients who are HLA-A*0201 positive and 18 years of age or older must have:

    • metastatic cancer whose tumors express the ESO antigen;
    • previously received and have been a non-responder to or recurred to standard care for metastatic disease, except for melanoma patients;
  • Patients may not have:

    • contraindications for high dose aldesleukin administration.

Design:

  • PBMC obtained by leukapheresis (approximately 5 X 10(9) cells) will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth.
  • Transduction is initiated by exposure of approximately 10(8) to 5 X 10(8) cells to retroviral vector supernatant containing the anti-ESO TCR genes.
  • Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo tumor reactive, TCR genetransduced PBMC plus IV aldesleukin (720,000 IU/kg q8h for a maximum of 15 doses) with or without ALVAC ESO-1 vaccine. Subcutaneous injection of ALVAC ESO-1 vaccine will be administered on day 0 approximately 2 hours prior to intravenous infusion of cells and a second dose of ALVAC ESO-1 vaccine is given on day 14 (+/- 2 days).
  • Patients will undergo complete evaluation of tumor with physical examination, CT of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment. If the patient has SD or tumor shrinkage, repeat complete evaluations will be performed every 1-3 months. After the first year, patients continuing to respond will continue to be followed with this evaluation every 3-4 months until off study criteria are met.

Cohorts 1 and 2:

  • Patients will be entered into two cohorts based on histology: cohort 1 will include patients with metastatic melanoma or renal cell cancer; cohort 2 will include patients with other types of metastatic cancer.
  • For each of the 2 strata evaluated, the study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled. For each of these two arms of the trial, if 0 or 1 of the 21 patients experiences a clinical response, then no further patients will be enrolled but if 2 or more of the first 21 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled in that stratum.
  • For both strata, the objective will be to determine if the combination of high dose aldesleukin, lymphocyte depleting chemotherapy, and anti-ESO TCR-gene engineered lymphocytes is able to be associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of a modest 20% PR + CR rate (p1=0.20).

Cohorts 3 and 4:

  • For patients receiving ALVAC ESO-1 vaccine, patients will also be entered into two cohorts based on histology: cohort 3 for patients with metastatic melanoma or renal cell cancer and cohort 4 for patients with other histologies and all patients will receive the treatment regimen including the ALVAC ESO-1 vaccine.
  • For each of these 2 new strata, the study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled. For each of these two new cohorts of the trial, if 0 or 1 of the 21 patients experiences a clinical response, then no further patients will be enrolled but if 2 or more of the first 21 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled in that stratum.
  • For both strata, the objective will be to determine if the combination of high dose aldesleukin, lymphocyte depleting chemotherapy, anti-ESO TCR-gene engineered lymphocytes, and ALVAC ESO-1 vaccine is able to be associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of a modest 20% PR + CR rate (p1=0.20).
Interventional
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Metastatic Melanoma
  • Metastatic Renal Cell Cancer
  • Metastatic Cancer
  • Biological: Anti-NY ESO-1 TCR PBL
    Patients will receive non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of anti-NY ESO-1 TCR PBL and high dose aldesleukin. On day 0,cells (1x10e8 to 1x10e11)will be infused intravenously on the Patient Care Unit over 20-30 minutes.
  • Drug: aldesleukin
    Aldeskeukin 720,000 IU/kg IV (based on total body weight)over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days(maximum of 15 doses)
  • Drug: cyclophosphaide
    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 phosphate
    Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
  • Biological: ALVAC NY ESO-1 vaccine
    Approximately two hours prior to cell infusion, patients will receive 0.5 mL containing a target dose of 10e7 CCID50 (with a range of approximately 10e6.4 to 10e7.9 / mL) of the ESO-1 ALVAC virus S.C. in each extremity (total of 4 x 10e7 CCID50/2 mL.
  • Experimental: Cohort 1
    Patients with melanoma or renal cell cancer (RCC) will receive non-myeloablative lymphodepleting regimen of cyclophosphamide and fludarabine followed by anti-NY ESO-1 TCR PBL and high dose aldesleukin
    Interventions:
    • Biological: Anti-NY ESO-1 TCR PBL
    • Drug: aldesleukin
    • Drug: cyclophosphaide
    • Drug: fludarabine phosphate
  • Experimental: Cohort 2
    Patients with cancers other than melanoma or RCC will receive non-myeloablative lymphodepleting regimen of cyclophosphamide and fludarabine followed by anti-NY ESO-1 TCR PBL and high dose aldesleukin
    Interventions:
    • Biological: Anti-NY ESO-1 TCR PBL
    • Drug: aldesleukin
    • Drug: cyclophosphaide
    • Drug: fludarabine phosphate
  • Experimental: Cohort 3
    Patients with melanoma or RCC will receive non-myeloablative lymphodepleting regimen ofcyclophosphamide and fludarabine followed by ALVAC NY-ESO-1 vaccine, anti-NY ESO-1 TCR PBL and high dose aldesleukin
    Interventions:
    • Biological: Anti-NY ESO-1 TCR PBL
    • Drug: aldesleukin
    • Drug: cyclophosphaide
    • Drug: fludarabine phosphate
    • Biological: ALVAC NY ESO-1 vaccine
  • Experimental: Cohort 4
    Patients with cancers other than melanoma or RCC will receive non-myeloablative lymphodepleting regimen of cyclophosphamide and fludarabine followed by ALVAC NY-ESO-1 vaccine, anti-NY ESO-1 TCR PBL and high dose aldesleukin
    Interventions:
    • Biological: Anti-NY ESO-1 TCR PBL
    • Drug: aldesleukin
    • Drug: cyclophosphaide
    • Drug: fludarabine phosphate
    • Biological: ALVAC NY ESO-1 vaccine

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
45
September 2015
June 2015   (final data collection date for primary outcome measure)
  • INCLUSION CRITERIA:
  • Metastatic cancer that expresses ESO as assessed by one of the following methods: RT-PCR on tumor tissue, or by immunohistochemistry of resected tissue, or serum antibody reactive with ESO. Metastatic cancer diagnosis will be confirmed by the Laboratory of Pathology at the NCI.
  • Patients with histologies other than metastatic melanoma, must have previously received systemic standard care (or effective salvage chemotherapy regimens) for metastatic disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurred.
  • Greater than or equal to 18 years of age. and less than or equal to 66 years of age.
  • Willing to sign a durable power of attorney.
  • 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 for four months after receiving the preparative regimen.
  • Patients must be HLA-A*0201 positive
  • 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 hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive, then patients must be tested for the presense of antigen by RT-PCR and be HCV RNA negative.
  • Hematology:

    • Absolute neutrophil count greater than 1000/mm(3) without the support of filgrastim.
    • WBC (greater than 3000/mm(3)).
    • Platelet count greater than 100,000/mm(3).
    • Hemoglobin greater than 8.0 g/dl.
  • Chemistry:

    • Serum ALT/AST less 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.
  • 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).
  • Six weeks must have elapsed since prior ipilimumabtherapy to allow antibody levels to decline.
  • Patients who have previously received ipilimumab or ticilimumab anti-PD1 or anti-PD-L1 antibodies, and have documented GI toxicity must have a normal colonoscopy with normal colonic biopsies.

EXCLUSION CRITERIA:

  • Prior vaccination with an ALVAC containing vaccine for patients who will receive the ALVAC ESO-1 vaccine (cohorts 3 or 4).
  • 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.
  • Known systemic hypersensitivity to any of the vaccine components, including egg products or Neomycin for patients who will receive the ALVAC ESO-1 vaccine (cohorts 3 or 4).
  • 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 LVEF less than or equal to 45 percent.
  • Documented LVEF of less than or equal to 45 percent tested in patients with:

    • History of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block.
    • Age greater than or equal to 60 years old.
  • Documented FEV1 less than or equal to 60 percent predicted tested in patients with:

    • A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2 years).
    • Symptoms of respiratory dysfunction
Both
18 Years to 66 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00670748
080121, 08-C-0121
Not Provided
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
August 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP