MelanomaPhase 2NCT00923195
Radiation, Chemotherapy, Vaccine and Anti-MART-1 and Anti-gp100 Cells for Patients With Metastatic Melanoma
A Phase 2 study testing MART-1: 26-35(27L) Peptide, Montanide ISA 51 VG and gp100:154-162 Peptide in people with Melanoma and Skin Cancer, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma, Skin Cancer
- What is being tested?
- MART-1: 26-35(27L) Peptide, Montanide ISA 51 VG and gp100:154-162 Peptide
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 4 participants
- Where
- 1 siteUnited States
- Study dates
- Dec 2008to Aug 2011
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Metastatic melanoma with measurable disease.
- Previously received aldesleukin (IL-2) and have been either non-responders (progressive disease) or have recurred.
- 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).
- Greater than or equal to 18 years of age.
- Willing to sign a durable power of attorney.
- Able to understand and sign the Informed Consent Document.
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- 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 receiving the preparative regimen.
- Must be human leukocyte antigens (HLA-A*0201) positive
- Serology:
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- 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 hepatitis C antibody unless antigen negative.
- Hematology:
- Absolute neutrophil count greater than 1000/m^3
- White blood cell (WBC) (greater than 3000/mm^3.
- Platelet count greater than 100,000/mm^3.
- Hemoglobin greater than 8.0 g/dl.
- Chemistry
- Serum alanine aminotransferase (ALT)/aspartate aminotransferase (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.
- Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus.
- 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 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.
Who cannot join
- 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).
- Systemic steroid therapy.
- History of severe immediate hypersensitivity reaction to any of the agents used in this study.
- History of coronary revascularization
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- Documented left ventricular ejection fraction (LVEF) of less than 45 percent in patients with:
- Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, 2 degree or 3 degree heart block
- Age greater than or equal to 60 years old
- Documented forced expiratory volume 1 (FEV1) less than or equal to 60 percent predicted for patients with:
- A prolonged history of cigarette smoking (greater than 20 pack/year within the past 2 years)
- Symptoms of respiratory distress
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
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
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.
Read more
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.
Read the detailed description
Background:
- We have engineered human peripheral blood lymphocyte (PBLs) to express a T-cell receptor (TCR) that recognizes human leukocyte antigens (HLAA*0201) restricted epitopes derived from the gp100 or the MART-1 melanoma antigen.
- We constructed single retroviral vectors that contain both Alpha and Beta T cell receptor (TCR) chains and can mediate genetic transfer of this TCR with high efficiency (greater than 30 percent) without the need to perform any selection.
- In co-cultures with HLA-A*0201 positive melanomas these TCR transduced T cells secreted significant amount of interferon-gamma (IFN-y) but no significant secretion was observed in control co-cultures.
- gp100:154-162 TCR or MART-1:27-35 TCR transduced T-cells could efficiently kill HLAA*0201 positive tumors. There was little or no recognition of normal fibroblasts.
- Adoptive transfer of either of these TCR transferred gene modified peripheral blood lymphocyte (PBL) following a nonmyeloablative lymphodepleting regimen could mediate tumor regression in from 13-30 percent of patients with metastatic melanoma though no complete responses were seen.
Objectives:
Primary objectives:
- In cohort 1 and 2, to determine if the administration of both the anti-gp100:154-162 TCR-engineered and anti- MART-1:27-35 TCR-engineered peripheral blood lymphocytes (PBL), aldesleukin and either the gp100:154-162 peptide or the MART-1:26-35(27L) peptide to patients following a chemoradiation lymphodepleting preparative regimen will result in complete tumor regression in patients with metastatic melanoma.
- In cohort 3 and 4, to determine if the administration of both the anti-gp100:154-162 TCR-engineered and anti-MART-1:27-35 TCR-engineered CD8+ peripheral blood lymphocytes (PBL), aldesleukin and either the gp100:154-162 peptide or the MART-1:26-35(27L) peptide to patients following a chemoradiation lymphodepleting preparative regimen will result in complete tumor regression in patients with metastatic melanoma.
- Determine whether the administration of the specific vaccine (the gp100:154-162 peptide or the MART-1:26-35(27L) peptide) can increase the persistence of the specific transferred cells (anti-gp100:154-162 TCR PBL, anti-gp100:154-162 TCR CD8+ PBL, the anti-MART- 1:27-35 TCR PBL, or the anti-MART-1:27-35 TCR CD8+ PBL), respectively.
Secondary objectives:
- Determine the toxicity profile of these treatment regimen.
Eligibility:
Patients who are HLA-A*0201 positive and 18 years of age or older must have:
- metastatic melanoma with measurable disease
- been previously treated with IL-2 for melanoma;
- normal values for basic laboratory values.
Patients may not have:
- concurrent major medical illnesses;
- any form of primary or secondary immunodeficiency;
- severe hypersensitivity to any of the agents used in this study;
- contraindications for high dose aldesleukin administration.
Design:
- In cohort 1 and 2:
- Peripheral blood mononuclear cells (PBMC) will be obtained by leukapheresis (approximately 5 times 10(9) cells) and cultured in the presence of anti-CD3 (OKT3) and aldesleukin and separate aliquots will be transduced with the anti-gp100:154-162 TCR and the anti-MART-1:27-35 TCR retroviral vector.
- Transduction is initiated by exposure of approximately 10(8) to 5 times 10(8) cells to supernatant containing the retroviral vectors. These gp100 and MART-1 TCR transduced cells will be separately expanded and tested for their anti-tumor activity.
- Once engineered lymphocytes are demonstrated to be biologically active according to the strict criteria outlined in the Certificate of Analysis, patients will receive a chemoradiation lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine and 600 cGy total body irradiation followed by intravenous infusion of ex vivo tumor reactive, gp100 and MART-1 TCR gene-transduced cells plus IV aldesleukin (720,000 IU/kg q8h for a maximum of 15 doses).
- Patients will be randomized to receive either the gp100:154-162 peptide or the MART-1:26-35(27L) peptide emulsified in incomplete Freund's adjuvant.
- Patients will undergo complete evaluation of tumor with physical examination, computed tomography (CT) of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment and then monthly for approximately 3 to 4 months or until off study criteria are met.
- The study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled into each of two cohorts. If none of the 21 patients per cohort experiences a complete clinical response, then no further patients will be enrolled but if 1 or more of the first 21 evaluable patients enrolled in that cohort have a complete clinical response, then accrual to that cohort will continue until a total of 41 evaluable patients have been enrolled in that cohort.
- Cohort 1 and 2 will be closed with the approval of amendment D.
- Cohort 3 and 4 will be initiated with approval of amendment D.
- Peripheral blood mononuclear cells (PBMC) will be obtained by leukapheresis (approximately 5 times 10(9) cells) and CD8+ cells will be selected from the cultures, using the Miltenyi CliniMACS apparatus, prior to being stimulated and transduced. Separate aliquots of CD8+ cells will be transduced with the anti-gp100:154-162 TCR and the anti-MART-1:27-35 TCR retroviral vectors.
- Transduction is initiated by exposure of approximately 10(8) to 5 times 10(8) CD8+ cells to supernatant containing the retroviral vectors. These gp100 and MART-1 TCR transduced cells will be separately expanded and tested for their anti-tumor activity.
- Once engineered lymphocytes are demonstrated to be biologically active according to the strict criteria outlined in the Certificate of Analysis, patients will receive a chemoradiation lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine and 600 cGy total body irradiation followed by intravenous infusion of ex vivo tumor reactive, gp100 and MART-1 TCR gene-transduced CD8+ cells plus IV aldesleukin (720,000 IU/kg q8h for a maximum of 15 doses).
- Patients will be randomized to receive either the gp100:154-162 peptide (cohort 3) or the MART-1:26-35(27L) peptide (cohort 4) emulsified in incomplete Freund's adjuvant.
- 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 and then monthly for approximately 3 to 4 months or until off study criteria are met.
- The study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled into each of cohort 3 and 4. If none of the 21 patients per cohort experiences a complete clinical response, then no further patients will be enrolled but if 1 or more of the first 21 evaluable patients enrolled in that cohort have a complete clinical response, then accrual to that cohort will continue until a total of 41 evaluable patients have been enrolled in that cohort.
- Conditions
- Melanoma, Skin Cancer
- Being tested
- MART-1: 26-35(27L) Peptide, Montanide ISA 51 VG, gp100:154-162 Peptide, Radiation, Aldesleukin
- Keywords
- Metastatic Melanoma, Tumor Regression, Safety, Immunotherapy
- Medical subject headings
- Melanoma, Skin Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MART-1: 26-35(27L) PeptideDrug
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.
Montanide ISA 51 VGDrug
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.
gp100:154-162 PeptideDrug
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.
RadiationProcedure or surgery
2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute
AldesleukinDrug
Also called IL-2, Interleukin-2
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).
FludarabineDrug
Also called Fludara
Day -6 to -2: Fludarabine 25 mg/m2/day IVPB daily over 15-30 minutes for 5 days
CyclophosphamideDrug
Also called Cytoxan
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.
Anti-gp 100:154 TCR PBLGenetic
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
Anti-MART-1 F5 TCR PBLGenetic
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
| Study group | Role | What they receive |
|---|---|---|
| TBI 600cGy + PBL + HD IL-2+gp100:154-162 | Experimental | 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. Receives: 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 |
| TBI 600cGy+PBL+HD IL-2+MART-1:26-35(27L) | Experimental | 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. Receives: Drug: MART-1: 26-35(27L) Peptide; Drug: Montanide ISA 51 VG; Procedure: Radiation; Drug: Aldesleukin; Drug: Fludarabine; Drug: Cyclophosphamide; Genetic: Anti-MART-1 F5 TCR PBL |
What is being measured
The primary outcome is the main question the study is designed to answer.
Complete Response Rates for Patients With Metastatic Melanoma
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.
Measured: 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.
Secondary outcomes (1)
Toxicity Profile
Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
Measured: 32 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jun 2009 (estimated)
- Study startDec 2008
- Primary completionAug 2011
- Study completionAug 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for MelanomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 4 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Steven Rosenberg, M.D., National Institutes of Health Clinical Center (CC)
- Investigators
- Steven Rosenberg, M.D., Principal investigator, National Cancer Institute, National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00923195
- Sponsor's protocol ID
- 090051
- Other IDs
- 09-C-0051
- Status last verified
- Oct 2015
- First submitted
- 17 Jun 2009
- Last updated
- 28 Oct 2015
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
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. doi: 10.1073/pnas.91.14.6458.
PubMed 8022805Kawakami 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. doi: 10.1073/pnas.91.9.3515.
PubMed 8170938Kawakami 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. doi: 10.1084/jem.180.1.347.
PubMed 7516411Abate-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.
PubMed 23861247
Study at a glance
From the registry record, last updated by the sponsor on 28 Oct 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00923195
- Acronym / sponsor ID
- 090051
- Conditions
- Melanoma, Skin Cancer
- Keywords
- Metastatic Melanoma, Tumor Regression, Safety, Immunotherapy
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 4 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- Dec 2008
- Primary completion
- Aug 2011 (actual)
- Study completion
- Aug 2011 (actual)
- First posted
- 18 Jun 2009 (estimated)
- Results
- Posted 5 Nov 2012
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Background:
- We have engineered human peripheral blood lymphocyte (PBLs) to express a T-cell receptor (TCR) that recognizes human leukocyte antigens (HLAA*0201) restricted epitopes derived from the gp100 or the MART-1 melanoma antigen.
- We constructed single retroviral vectors that contain both Alpha and Beta T cell receptor (TCR) chains and can mediate genetic transfer of this TCR with high efficiency (greater than 30 percent) without the need to perform any selection.
- In co-cultures with HLA-A*0201 positive melanomas these TCR transduced T cells secreted significant amount of interferon-gamma (IFN-y) but no significant secretion was observed in control co-cultures.
- gp100:154-162 TCR or MART-1:27-35 TCR transduced T-cells could efficiently kill HLAA*0201 positive tumors. There was little or no recognition of normal fibroblasts.
- Adoptive transfer of either of these TCR transferred gene modified peripheral blood lymphocyte (PBL) following a nonmyeloablative lymphodepleting regimen could mediate tumor regression in from 13-30 percent of patients with metastatic melanoma though no complete responses were seen.
Objectives:
Primary objectives:
- In cohort 1 and 2, to determine if the administration of both the anti-gp100:154-162 TCR-engineered and anti- MART-1:27-35 TCR-engineered peripheral blood lymphocytes (PBL), aldesleukin and either the gp100:154-162 peptide or the MART-1:26-35(27L) peptide to patients following a chemoradiation lymphodepleting preparative regimen will result in complete tumor regression in patients with metastatic melanoma.
- In cohort 3 and 4, to determine if the administration of both the anti-gp100:154-162 TCR-engineered and anti-MART-1:27-35 TCR-engineered CD8+ peripheral blood lymphocytes (PBL), aldesleukin and either the gp100:154-162 peptide or the MART-1:26-35(27L) peptide to patients following a chemoradiation lymphodepleting preparative regimen will result in complete tumor regression in patients with metastatic melanoma.
- Determine whether the administration of the specific vaccine (the gp100:154-162 peptide or the MART-1:26-35(27L) peptide) can increase the persistence of the specific transferred cells (anti-gp100:154-162 TCR PBL, anti-gp100:154-162 TCR CD8+ PBL, the anti-MART- 1:27-35 TCR PBL, or the anti-MART-1:27-35 TCR CD8+ PBL), respectively.
Secondary objectives:
- Determine the toxicity profile of these treatment regimen.
Eligibility:
Patients who are HLA-A*0201 positive and 18 years of age or older must have:
- metastatic melanoma with measurable disease
- been previously treated with IL-2 for melanoma;
- normal values for basic laboratory values.
Patients may not have:
- concurrent major medical illnesses;
- any form of primary or secondary immunodeficiency;
- severe hypersensitivity to any of the agents used in this study;
- contraindications for high dose aldesleukin administration.
Design:
- In cohort 1 and 2:
- Peripheral blood mononuclear cells (PBMC) will be obtained by leukapheresis (approximately 5 times 10(9) cells) and cultured in the presence of anti-CD3 (OKT3) and aldesleukin and separate aliquots will be transduced with the anti-gp100:154-162 TCR and the anti-MART-1:27-35 TCR retroviral vector.
- Transduction is initiated by exposure of approximately 10(8) to 5 times 10(8) cells to supernatant containing the retroviral vectors. These gp100 and MART-1 TCR transduced cells will be separately expanded and tested for their anti-tumor activity.
- Once engineered lymphocytes are demonstrated to be biologically active according to the strict criteria outlined in the Certificate of Analysis, patients will receive a chemoradiation lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine and 600 cGy total body irradiation followed by intravenous infusion of ex vivo tumor reactive, gp100 and MART-1 TCR gene-transduced cells plus IV aldesleukin (720,000 IU/kg q8h for a maximum of 15 doses).
- Patients will be randomized to receive either the gp100:154-162 peptide or the MART-1:26-35(27L) peptide emulsified in incomplete Freund's adjuvant.
- Patients will undergo complete evaluation of tumor with physical examination, computed tomography (CT) of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment and then monthly for approximately 3 to 4 months or until off study criteria are met.
- The study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled into each of two cohorts. If none of the 21 patients per cohort experiences a complete clinical response, then no further patients will be enrolled but if 1 or more of the first 21 evaluable patients enrolled in that cohort have a complete clinical response, then accrual to that cohort will continue until a total of 41 evaluable patients have been enrolled in that cohort.
- Cohort 1 and 2 will be closed with the approval of amendment D.
- Cohort 3 and 4 will be initiated with approval of amendment D.
- Peripheral blood mononuclear cells (PBMC) will be obtained by leukapheresis (approximately 5 times 10(9) cells) and CD8+ cells will be selected from the cultures, using the Miltenyi CliniMACS apparatus, prior to being stimulated and transduced. Separate aliquots of CD8+ cells will be transduced with the anti-gp100:154-162 TCR and the anti-MART-1:27-35 TCR retroviral vectors.
- Transduction is initiated by exposure of approximately 10(8) to 5 times 10(8) CD8+ cells to supernatant containing the retroviral vectors. These gp100 and MART-1 TCR transduced cells will be separately expanded and tested for their anti-tumor activity.
- Once engineered lymphocytes are demonstrated to be biologically active according to the strict criteria outlined in the Certificate of Analysis, patients will receive a chemoradiation lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine and 600 cGy total body irradiation followed by intravenous infusion of ex vivo tumor reactive, gp100 and MART-1 TCR gene-transduced CD8+ cells plus IV aldesleukin (720,000 IU/kg q8h for a maximum of 15 doses).
- Patients will be randomized to receive either the gp100:154-162 peptide (cohort 3) or the MART-1:26-35(27L) peptide (cohort 4) emulsified in incomplete Freund's adjuvant.
- 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 and then monthly for approximately 3 to 4 months or until off study criteria are met.
- The study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled into each of cohort 3 and 4. If none of the 21 patients per cohort experiences a complete clinical response, then no further patients will be enrolled but if 1 or more of the first 21 evaluable patients enrolled in that cohort have a complete clinical response, then accrual to that cohort will continue until a total of 41 evaluable patients have been enrolled in that cohort.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| TBI 600cGy + PBL + HD IL-2+gp100:154-162 | Experimental | Drug: Montanide ISA 51 VG, Drug: gp100:154-162 Peptide, Procedure: Radiation, Drug: Aldesleukin, Drug: Fludarabine, Drug: Cyclophosphamide, Genetic: Anti-gp 100:154 TCR PBLDay 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. |
| TBI 600cGy+PBL+HD IL-2+MART-1:26-35(27L) | Experimental | Drug: MART-1: 26-35(27L) Peptide, Drug: Montanide ISA 51 VG, Procedure: Radiation, Drug: Aldesleukin, Drug: Fludarabine, Drug: Cyclophosphamide, Genetic: Anti-MART-1 F5 TCR PBLDay 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (26 listed)
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Key exclusion criteria (12 listed)
- 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).
- Systemic steroid therapy.
- History of severe immediate hypersensitivity reaction to any of the agents used in this study.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MART-1: 26-35(27L) PeptideDay 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 | TBI 600cGy+PBL+HD IL-2+MART-1:26-35(27L) |
| Montanide ISA 51 VGDay 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 | TBI 600cGy + PBL + HD IL-2+gp100:154-162, TBI 600cGy+PBL+HD IL-2+MART-1:26-35(27L) |
| gp100:154-162 PeptideDay 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 | TBI 600cGy + PBL + HD IL-2+gp100:154-162 |
| Radiation2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute | Procedure or surgery | TBI 600cGy + PBL + HD IL-2+gp100:154-162, TBI 600cGy+PBL+HD IL-2+MART-1:26-35(27L) |
| AldesleukinAlso: IL-2, Interleukin-2Within 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). | Drug | TBI 600cGy + PBL + HD IL-2+gp100:154-162, TBI 600cGy+PBL+HD IL-2+MART-1:26-35(27L) |
| FludarabineAlso: FludaraDay -6 to -2: Fludarabine 25 mg/m2/day IVPB daily over 15-30 minutes for 5 days | Drug | TBI 600cGy + PBL + HD IL-2+gp100:154-162, TBI 600cGy+PBL+HD IL-2+MART-1:26-35(27L) |
| CyclophosphamideAlso: CytoxanDay -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. | Drug | TBI 600cGy + PBL + HD IL-2+gp100:154-162, TBI 600cGy+PBL+HD IL-2+MART-1:26-35(27L) |
| Anti-gp 100:154 TCR PBLDay 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 | Genetic | TBI 600cGy + PBL + HD IL-2+gp100:154-162 |
| Anti-MART-1 F5 TCR PBLDay 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 | Genetic | TBI 600cGy+PBL+HD IL-2+MART-1:26-35(27L) |
Primary outcome
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.
1 secondary outcome
Toxicity Profile
Time frame: 32 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Oct 2015.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 8022805Kawakami 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. doi: 10.1073/pnas.91.14.6458.
- Background: PubMed 8170938Kawakami 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. doi: 10.1073/pnas.91.9.3515.
- Background: PubMed 7516411Kawakami 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. doi: 10.1084/jem.180.1.347.
- Derived from this study: PubMed 23861247Abate-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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Steven Rosenberg, M.D. principal investigator
National Cancer Institute, National Institutes of Health
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing MART-1: 26-35(27L) Peptide, Montanide ISA 51 VG and gp100:154-162 Peptide in people with Melanoma and Skin Cancer, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 26 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Oct 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 5 Nov 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00923195, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Oct 2015.