Radiation, Chemotherapy, Vaccine and Anti-MART-1 and Anti-gp100 Cells for Patients With Metastatic Melanoma

Study Description

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Brief Summary:

Background:

• Melanoma antigen recognized by T-cells (MART-1) and gp100 are two genes found in melanoma cells. An experimental procedure developed for treating patients with advanced melanoma uses these genes and a type of virus to make special cells called anti-MART-1 and anti-gp100 cells, which are designed to destroy the patient's tumor. The cells are created in the laboratory using the patient's own tumor cells or blood cells.
• The procedure also uses one of two vaccines-the anti-MART-1 peptide or the anti-gp100 peptide-to stimulate cells in the immune system that may increase the effectiveness of the anti-MART-1 and anti-gp100 cells. Both vaccines are made from a virus that is modified to carry a copy of the MART-1 gene or gp100 gene. The virus cannot cause disease in humans.

Objectives:

- To evaluate the safety and effectiveness of anti-MART-1 and anti-gp100 cells and peptide vaccines for treating patients with advanced melanoma.

Eligibility:

- Patients 18 years of age with metastatic melanoma for whom standard treatments, including aldesleukin (IL-2) therapy to boost immune response, have not been effective.

Design:

• Participants have an initial evaluation with complete medical history, as well as scans, x-rays, and other tests as directed by researchers. Most of the treatments for this study will be given on an inpatient basis.
• Before the treatment begins, participants will undergo leukapheresis (removal of selected blood cells) to obtain cells for preparing the anti-MART-1 and anti-gp100 cells, and for later stem cell transplantation.
• Preinfusion treatment: 5 days of chemotherapy and 2 days of total-body irradiation to prepare the immune system for receiving the anti-MART-1 and anti-gp100 cells.
• Infusion of cells, followed by IL-2 treatment to improve immune response. IL-2 is given as a 15-minute infusion through a vein every 8 hours for a maximum of 15 doses (over 5 days).
• After the cell infusion, participants will be divided into two groups and will receive either the gp100 peptide or MART-1 vaccine, given once a week for 3 weeks. Participants will also have stem cell transplantation (from previously collected stem cells) to promote cell survival.
• Periodic follow-up clinic visits after hospital discharge for physical examination, review of treatment side effects, laboratory tests and scans every 1 to 6 months.

Condition or disease	Intervention/treatment	Phase
Melanoma; Skin Cancer	Drug: MART-1: 26-35(27L) Peptide; Drug: Montanide ISA 51 VG; Drug: gp100:154-162 Peptide; Procedure: Radiation; Drug: Aldesleukin; Drug: Fludarabine; Drug: Cyclophosphamide; Genetic: Anti-gp 100:154 TCR PBL; Genetic: Anti-MART-1 F5 TCR PBL	Phase 2

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Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	4 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase II Study of Metastatic Melanoma Using a Chemoradiation Lymphodepleting Conditioning Regimen Followed by Infusion of Anti-Mart-1 and Anti-gp100 TCR-Gene Engineered Lymphocytes and Peptide Vaccines
Study Start Date :	December 2008
Actual Primary Completion Date :	August 2011
Actual Study Completion Date :	August 2011

Arms and Interventions

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Arm	Intervention/treatment
Experimental: TBI 600cGy + PBL + HD IL-2+gp100:154-162; Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Within 24 hours of cell infusion administration of aldesleukin will be initiated as 720,000 IU/kg/dose IV over 15 minutes every 8 hours for up to 5 days (maximum 15 doses).Radiation: 2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute.	Drug: Montanide ISA 51 VG; Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Drug: gp100:154-162 Peptide; Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Procedure: Radiation; 2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute Drug: Aldesleukin; Within 24 hours of cell infusion administration of aldesleukin will be initiated as 720,000 IU/kg/dose IV over 15 minutes every 8 hours for up to 5 days (maximum 15 doses).; Other Names: IL-2; Interleukin-2 Drug: Fludarabine; Day -6 to -2: Fludarabine 25 mg/m2/day IVPB daily over 15-30 minutes for 5 days; Other Name: Fludara Drug: Cyclophosphamide; Day -6 to -5: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with mesna15 mg/kg/day over 1 hr X 2 days.; Other Name: Cytoxan Genetic: Anti-gp 100:154 TCR PBL; Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or theMART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14
Experimental: TBI 600cGy+PBL+HD IL-2+MART-1:26-35(27L); Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Within 24 hours of cell infusion administration of aldesleukin will be initiated as 720,000 IU/kg/dose IV over 15 minutes every 8 hours for up to 5 days (maximum 15 doses).Radiation: 2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute.	Drug: MART-1: 26-35(27L) Peptide; Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Drug: Montanide ISA 51 VG; Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Procedure: Radiation; 2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute Drug: Aldesleukin; Within 24 hours of cell infusion administration of aldesleukin will be initiated as 720,000 IU/kg/dose IV over 15 minutes every 8 hours for up to 5 days (maximum 15 doses).; Other Names: IL-2; Interleukin-2 Drug: Fludarabine; Day -6 to -2: Fludarabine 25 mg/m2/day IVPB daily over 15-30 minutes for 5 days; Other Name: Fludara Drug: Cyclophosphamide; Day -6 to -5: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with mesna15 mg/kg/day over 1 hr X 2 days.; Other Name: Cytoxan Genetic: Anti-MART-1 F5 TCR PBL; Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or theMART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14

Outcome Measures

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Primary Outcome Measures :

1. Complete Response Rates for Patients With Metastatic Melanoma [ Time Frame: Every 4-6 weeks after initial treatment regimen. If the patient has stable disease or tumor shrinkage, complete evaluations will be repeated every 1-3 months. ]
   Complete response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response is a disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progression is at least a 20% increase in the sum of the 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 is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum LD.

Secondary Outcome Measures :

1. Toxicity Profile [ Time Frame: 32 months ]
   Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

• INCLUSION CRITERIA:

  1. Metastatic melanoma with measurable disease.
  2. Previously received aldesleukin (IL-2) and have been either non-responders (progressive disease) or have recurred.
  3. Positive for gp100 and melanoma antigen recognized by T-cells (MART-1) (at least 1 plus and greater than 5 percent) as assessed by immunohistochemistry (IHC) in the Clinical Laboratory Improvement Amendments (CLIA) approved test in the Laboratory of Pathology, Center for cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH).
  4. Greater than or equal to 18 years of age.
  5. Willing to sign a durable power of attorney.
  6. Able to understand and sign the Informed Consent Document.
  7. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
  8. Life expectancy of greater than three months.
  9. 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 preparative regimen.
  10. Must be human leukocyte antigens (HLA-A*0201) positive
  11. Serology:
  1. 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.)
  2. Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen negative.

  l. Hematology:

  1. Absolute neutrophil count greater than 1000/m^3
  2. White blood cell (WBC) (greater than 3000/mm^3.
  3. Platelet count greater than 100,000/mm^3.
  4. Hemoglobin greater than 8.0 g/dl.

  m. Chemistry

  1. Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than or equal to 2.5 times the upper limit of normal.
  2. Serum creatinine less than or equal to 1.6 mg/dl.
  3. 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.

  n. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus.

  o. 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).

  p. Six weeks must have elapsed since prior anti-CTLA4 (cytotoxic T-lymphocyte antigen 4) antibody therapy to allow antibody levels to decline, and patients who have previously received anti-CTLA4 antibody must have a normal 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 preparative chemotherapy on the fetus or infant.
2. 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.
3. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
4. Systemic steroid therapy.
5. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
6. History of coronary revascularization
7. Documented left ventricular ejection fraction (LVEF) of less than 45 percent in patients with:

a) Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, 2 degree or 3 degree heart block

b) Age greater than or equal to 60 years old

h. Documented forced expiratory volume 1 (FEV1) less than or equal to 60 percent predicted for patients with:

1. A prolonged history of cigarette smoking (greater than 20 pack/year within the past 2 years)
2. Symptoms of respiratory distress

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Steven Rosenberg, M.D.	National Cancer Institute, National Institutes of Health

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications:

Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Sakaguchi K, Appella E, Yannelli JR, Adema GJ, Miki T, Rosenberg SA. Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6458-62.

Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Rivoltini L, Topalian SL, Miki T, Rosenberg SA. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3515-9.

Kawakami Y, Eliyahu S, Sakaguchi K, Robbins PF, Rivoltini L, Yannelli JR, Appella E, Rosenberg SA. Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J Exp Med. 1994 Jul 1;180(1):347-52.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Abate-Daga D, Hanada K, Davis JL, Yang JC, Rosenberg SA, Morgan RA. Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes. Blood. 2013 Aug 22;122(8):1399-410. doi: 10.1182/blood-2013-04-495531. Epub 2013 Jul 16.

Responsible Party:	Steven Rosenberg, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:	NCT00923195 History of Changes
Obsolete Identifiers:	NCT00814684
Other Study ID Numbers:	090051; 09-C-0051
First Posted:	June 18, 2009
Results First Posted:	November 5, 2012
Last Update Posted:	October 28, 2015
Last Verified:	October 2015

Keywords provided by Steven Rosenberg, M.D., National Institutes of Health Clinical Center (CC):

Metastatic Melanoma; Tumor Regression; Safety; Immunotherapy

Additional relevant MeSH terms:

Melanoma; Skin Neoplasms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Neoplasms by Site; Skin Diseases; Cyclophosphamide; Fludarabine phosphate; Fludarabine; Aldesleukin	Interleukin-2; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Antimetabolites, Antineoplastic; Antimetabolites; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents