MelanomaPhase 2NCT00001832
Lymphocyte Re-infusion During Immune Suppression to Treat Metastatic Melanoma
A Phase 2 study testing gp100:209-217 (210M), Montanide ISA-51 and IL-2 in people with Melanoma and Neoplasm Metastasis, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
This experiment will test the safety and effectiveness of a treatment for melanoma in which certain lymphocytes (a type of white blood cell) are taken from the patient, grown in the laboratory, and returned after the patient's immune system has been weakened with immune-suppressing drugs. Read more about this study
- Who is it for?
- Ages 7 years and olderHealthy volunteers can take part
- Conditions the study is for
- Melanoma, Neoplasm Metastasis
- What is being tested?
- gp100:209-217 (210M), Montanide ISA-51 and IL-2
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 170 participants
- Where
- 1 siteUnited States
- Study dates
- Aug 1999to May 2010
- 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 7 years and older
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- Patients must have evaluable metastatic melanoma that is refractory to standard therapy.
- Age greater than or equal to 16 years.
- Patients of both genders must be willing to practice birth control for four months after receiving the preparative regimen.
- Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0, 1 at entry to the trial and at the time of chemotherapy induction.
- Absolute neutrophil count greater than 1000/mm^3.
- Platelet count greater than 100,000/mm^3.
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- Hemoglobin greater than 8.0 g/dl.
- Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than two times the upper limit of normal.
- Serum creatinine less than or equal to 1.6 mg/dl.
- Total bilirubin less than or equal to 1.6 mg/dl, except for 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 therapy at the time the patient receives the preparative regimen.
- Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus.
- Life expectancy of greater than three months.
- No steroid therapy required.
- 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.
- Patients to receive high dose interleukin 2 (IL-2) must have no active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system.
- Patients who will receive high dose IL-2 as part of the phase I portion of this study or who will be randomized must be eligible to receive high dose IL-2.
- Any patient receiving IL-2 must sign a durable power of attorney.
Who cannot join
None listed.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Cancer Institute (NCI)
Bethesda, Maryland, 20892
About this study
Official title: Treatment of Patients With Metastatic Melanoma Using Cloned Lymphocytes Following the Administration of a Non-Myeloablative But Lymphocyte Depleting Regimen
This experiment will test the safety and effectiveness of a treatment for melanoma in which certain lymphocytes (a type of white blood cell) are taken from the patient, grown in the laboratory, and returned after the patient's immune system has been weakened with immune-suppressing drugs. Some patients will also receive interleukin-2 (IL-2), a drug that may enhance the activity of the re-infused lymphocytes.
Patients with metastatic melanoma (melanoma whose tumor has spread) who have been treated unsuccessfully with gp100 vaccination may participate in this study. They will undergo apheresis or a tumor biopsy, or both, to collect lymphocytes. In apheresis, whole blood is drawn through a needle in the arm. A machine separates the blood components and removes the white cells. The rest of the blood is returned to the donor through a needle in the other arm. A biopsy is a surgical procedure to remove a small piece of tumor tissue.
Read more
Several weeks before the lymphocytes are collected, patients will receive injections of growth colony stimulating factor (G-CSF) every day for five days. This drug stimulates white cell production, permitting as many cells as possible to be obtained during collection. The lymphocytes will then be grown in larger numbers in the laboratory.
Seven days before the cells are re-infused, the patient is admitted to the hospital and a catheter (small tube) is placed in a large vein in the chest or neck. Two drugs, cyclophosphamide and fludarabine, are given through the tube. These drugs suppress the immune system so that it will not interfere with the work of the reinfused lymphocytes. The lymphocytes are then injected through the catheter over a 30-minute period. After the infusion, patients who receive IL-2 will be given the drug in a high dose over a 15-minute period every eight hours for up to five days. Patients whose condition does not permit high-dose IL-2, such as those with a heart condition or lung problem, may receive a low-dose regimen, with the drug given as a shot under the skin of the thigh or abdomen for five days followed by a 2-day break, continuing for a total of six weeks. These patients receive a higher dose the first week and then half that dose the next five weeks.
Blood and tissue samples will be taken before and during the study to evaluate the size of the tumor and assess treatment. If, 3-5 weeks after therapy is completed, the patient's tumor has stabilized or shrunk, the entire treatment, except for chemotherapy, may be repeated two more times.
Read the detailed description
Patients with metastatic melanoma who are human immunodeficiency virus (HIV) and Hepatitis B negative and who have previously progressed after receiving standard therapy will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine and then will be treated by the adoptive transfer of lymphocytes reactive with shared antigens on their tumors. This study will evaluate the toxicity, immunologic effects and potential therapeutic role of this treatment.
- Conditions
- Melanoma, Neoplasm Metastasis
- Being tested
- gp100:209-217 (210M), Montanide ISA-51, IL-2, MART-1:26-35(27L), Abl cells
- Keywords
- Immunotherapy, Adoptive Transfer, IL-2, Toxicity, Clinical Response, Breast Cancer
- Medical subject headings
- Melanoma, Neoplasm Metastasis, Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
gp100:209-217 (210M)Drug
gp100 = gp100:209-217(210M) peptide - 1 mg in IFA SQ (in the subcutaneous tissue of each thigh) on the morning of the cell infusion, plus gp100:209-217(210M) peptide, 1 mg, in IFA injected into the subcutaneous tissue in two equal volumes, 1.0 mL for each injection, within 2cm of each other, in the thigh daily for five days starting on the morning of the cell infusion and then weekly for 3 more injections.
MART-1 = MART-1:26-35(27L) peptide- 1 mg in IFA SQ (in the subcutaneous tissue of each thigh) on the morning of the cell infusion, plus MART-1:26-35(27L) peptide, 1 mg, in IFA injected into the subcutaneous tissue in two equal volumes, 1.0 mL for each injection, within 2cm of each other, in the thigh daily for five days starting on the morning of the cell infusion and then weekly for 3 more injections.
Montanide ISA-51Drug
Also called IFA
MART-1 = MART-1:26-35(27L) peptide- 1 mg in IFA SQ (in the subcutaneous tissue of each thigh) on the morning of the cell infusion, plus MART-1:26-35(27L) peptide, 1 mg, in IFA injected into the subcutaneous tissue in two equal volumes, 1.0 mL for each injection, within 2cm of each other, in the thigh daily for five days starting on the morning of the cell infusion and then weekly for 3 more injections.
IL-2Drug
Also called Interleukin-2
125,000 IU/kg dose intravenous for 5 days for 6 weeks with 2 days rest per week.
720,000 IU/kg intravenous every 8 hours for a maximum of 12 doses.
MART-1:26-35(27L)Drug
Also called melanoma-associated antigen recognized by T cells
MART-1 = MART-1:26-35(27L) peptide- 1 mg in IFA SQ (in the subcutaneous tissue of each thigh) on the morning of the cell infusion, plus MART-1:26-35(27L) peptide, 1 mg, in IFA injected into the subcutaneous tissue in two equal volumes, 1.0 mL for each injection, within 2cm of each other, in the thigh daily for five days starting on the morning of the cell infusion and then weekly for 3 more injections.
Abl cellsBiological
Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days Abl cells IA = Lymphocytes 10^9-10^11 IA over 30 minutes on day 0, repeated in 14 to 21 days
FludarabineDrug
Also called Fludara
5x25 mg/m^2 intravenous
CyclophosphamideDrug
Also called Cytoxan
2x30 mg/kg, 2x60 mg/kg intravenous
GCSF (Growth colony stimulating factor)Biological
Also called Filgrastim
Beginning on day 1 or 2, GCSF will be administered subcutaneously at a dose of 5mcg/kg/day (not to exceed 300 mcg/day. Filgrastim administration will continue daily until neutrophil count > 1.0 x10^9/L x 3 days or > 5.0 x10^9/L.
ApheresisProcedure or surgery
| Study group | Role | What they receive |
|---|---|---|
| Abl Cells in culture | Experimental | Peripheral blood mononuclear cells (PBMC) and/or tumor infiltrating lymphocytes (TIL) obtained by apheresis or lesion excision to be cloned and expanded in the lab.The patients underwent an apheresis and/or an excision of their tumor.
They didn't receive any drugs. Receives: Procedure: Apheresis |
| Abl Cells IV + Cyclophosphamide 30 mg/kg | Experimental | Phase 1 Cyclophosphamide Dose Escalation: Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x30mg/kg + Cells intravenous (IV) Abl cells intravenous (IV) = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days Receives: Biological: Abl cells; Drug: Fludarabine; Drug: Cyclophosphamide |
| Abl Cells IV + Cyclophosphamide 60 mg/kg | Experimental | Phase 1 Cyclophosphamide Dose Escalation: Fludarabine 5x25mg/m2 + Cyclophosphamide 2x60mg/kg + Cells intravenous (IV) Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days Receives: Biological: Abl cells; Drug: Fludarabine; Drug: Cyclophosphamide |
| Abl Cells IV+Low Dose IV IL-2 (Initial) | Experimental | Phase 1 interleukin-2 (IL-2) Dose Escalation: Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intravenous (IV) + IV IL-2 (72,000 IU/kg q8h for a maximum of 15 doses) Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days Receives: Drug: IL-2; Biological: Abl cells; Drug: Fludarabine; Drug: Cyclophosphamide |
| Abl Cells IV+High Dose IV IL-2 (Initial) | Experimental | Phase 1 interleukin-2 (IL-2) Dose Escalation: Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intravenous (IV) + IV IL-2 (720,000 IU/kg q8h for a maximum of 12 doses) Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days Receives: Drug: IL-2; Biological: Abl cells; Drug: Fludarabine; Drug: Cyclophosphamide |
| Abl Cells IV + MTD IL-2 | Experimental | Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intravenous (IV) + IV interleukin-2 (IL-2) (720,000 IU/kg q8h for a maximum of 12 doses) + growth colony stimulating factor (G-CSF) (to shorten time to neutrophil recovery) Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days Receives: Biological: Abl cells; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: GCSF (Growth colony stimulating factor) |
| Abl Cells IA + MTD (prior cells IV on 6) | Experimental | Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intra-arterial (IA) + intravenous (IV) interleukin-2 (IL-2) (720,000 IU/kg q8h for a maximum of 12 doses) Prior Cells IV + growth colony stimulating factor (G-CSF) Abl cells IA = Lymphocytes 10^9-10^11 IA over 30 minutes on day 0, repeated in 14 to 21 days Receives: Drug: IL-2; Biological: Abl cells; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: GCSF (Growth colony stimulating factor) |
| Abl Cells IA + MTD IL-2 | Experimental | Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intra-arterial (IA) + intravenous (IV) interleukin-2 (IL-2) (720,000 IU/kg q8h for a maximum of 12 doses) + growth colony stimulating factor (G-CSF) Abl cells IA = Lymphocytes 10^9-10^11 IA over 30 minutes on day 0, repeated in 14 to 21 days Receives: Drug: IL-2; Biological: Abl cells; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: GCSF (Growth colony stimulating factor) |
| Abl Cells IA+MTD IL-2 (MART-1 reactive) | Experimental | Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intra-arterial (IA) + intravenous (IV) interleukin-2 (IL-2) (720,000 IU/kg q8h for a maximum of 12 doses) + growth colony stimulating factor (G-CSF) + melanoma- associated antigen recognized by T cells (MART-1):26-35(27L) Peptide 1mg/day (5-8 days) in patients with MART-1 reactive cells Abl cells IA = Lymphocytes 10^9-10^11 IA over 30 minutes on day 0, repeated in 14 to 21 days gp100 = gp100:209-217(210M) peptide - 1 mg in IFA SQ (in the subcutaneous tissue of each thigh) on the morning of the cell infusion, plus gp100:209-217(210M) peptide, 1 mg, in IFA injected into the subcutaneous tissue in two equal volumes, 1.0 mL for each injection, within 2cm of each other, in the thigh daily for five days starting on the morning of the cell infusion and then weekly for 3 more injections. Receives: Drug: Montanide ISA-51; Drug: MART-1:26-35(27L); Biological: Abl cells; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: GCSF (Growth colony stimulating factor) |
| Abl Cells IV + MTD IL-2 no GCSF | Experimental | Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intravenous (IV) + IV interleukin-2 (IL-2) (720,000 IU/kg q8h for a maximum of 12 doses) without growth colony stimulating factor (G-CSF) (to determine if G-CSF has harmful effects when adoptively transferring lymphocytes following a nonmyeloablative chemotherapy regimen) Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days Receives: Drug: IL-2; Biological: Abl cells; Drug: Fludarabine; Drug: Cyclophosphamide |
| Abl Cells IV+MTD IL-2 no GCSF | Experimental | Abl Cells intravenous (IV) + maximum tolerated dose (MTD) interleukin-2 (IL-2) no growth colony stimulating factor (GCSF)(gp100 reactive).
Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells IV + IV IL-2 (720,000 IU/kg q8h for a maximum of 12 doses) without G-CSF + gp100:209-217(210M) 1mg/day (2-8 days) in patients with gp100 reactive cells Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days Receives: Drug: gp100:209-217 (210M); Drug: IL-2; Biological: Abl cells; Drug: Fludarabine; Drug: Cyclophosphamide |
| Abl Cells IV+MTD IL-2 | Experimental | Abl Cells intravenous (IV)+ maximum tolerated dose (MTD) interleukin-2 (IL-2) no growth colony stimulating factor (GCSF) (melanoma-associated antigen recognized by T cells (MART-1)reactive).
Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells IV + IV interleukin-2 (IL-2) (720,000 IU/kg q8h for a maximum of 12 doses) without G-CSF + MART-1:26-35(27L) Peptide 1mg/day (5-8 days) in patients with MART-1 reactive cells Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days Receives: Drug: IL-2; Drug: MART-1:26-35(27L); Biological: Abl cells; Drug: Fludarabine; Drug: Cyclophosphamide |
| Abl Cells IV + SQ IL-2 with GCSF | Experimental | Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intravenous (IV) + subcutaneous (SQ) interleukin-2 (IL-2) (125,000 IU/kg/dose for 5 days for six weeks with 2 days rest per week) + growth colony stimulating factor (G-CSF) (to shorten time to neutrophil recovery), reactivity not specified Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days Receives: Drug: IL-2; Biological: Abl cells; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: GCSF (Growth colony stimulating factor) |
| Abl Cells IV + SQ | Experimental | Abl Cells intravenous (IV) + subcutaneous (SQ) interleukin-2 (IL-2) with growth colony stimulating factor (GCSF) (melanoma-associated antigen recognized by T cells (MART-1) reactive) Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells IV + SQ IL-2 (125,000 IU/kg/dose for 5 days for six weeks with 2 days rest per week) + G-CSF + MART-1:26-35(27L) Peptide 1mg/day (5-8 days) in patients with MART-1 reactive cells Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days Receives: Drug: IL-2; Drug: MART-1:26-35(27L); Biological: Abl cells; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: GCSF (Growth colony stimulating factor) |
| Abl Cells IV + SQ IL-2 with GCSF (no reactivity) | Experimental | Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intravenous (IV) + subcutaneous (SQ) interleukin-2 ( IL-2) (125,000 IU/kg/dose for 5 days for six weeks with 2 days rest per week) + growth colony stimulating factor (G-CSF) in patients with no reactivity Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days Receives: Drug: IL-2; Biological: Abl cells; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: GCSF (Growth colony stimulating factor) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Clinical Response
Complete response (CR) is defined as the disappearance of all clinical evidence of disease. Partial response (PR) is a 50% or greater decrease in the sum of the products of perpendicular diameters of all measurable lesions for at least one month. No new lesions may appear, and none may increase. Minor response (MR) is a 25-49% decrease in the sum of the products of the perpendicular diameters of all measurable lesions. Appearance of new lesions following a PR or CR are considered relapses. Patients with progressive disease (PD) and no evidence of stable disease will be taken off study after receiving IL-2.
Measured: Every three to four weeks after the treatment, for up to 5 years.
Secondary outcomes (1)
Number of Participants With Adverse Events
Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.
Measured: 10.5 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Nov 1999 (estimated)
- Study startAug 1999
- Primary completionMay 2010
- Study completionMay 2010
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 (2)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
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 170 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Steven Rosenberg, 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
- NCT00001832
- Sponsor's protocol ID
- 990158
- Other IDs
- 99-C-0158
- Status last verified
- Dec 2012
- First submitted
- 3 Nov 1999
- Last updated
- 21 Dec 2012
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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. doi: 10.1073/pnas.91.9.3515.
PubMed 8170938Yao X, Ahmadzadeh M, Lu YC, Liewehr DJ, Dudley ME, Liu F, Schrump DS, Steinberg SM, Rosenberg SA, Robbins PF. Levels of peripheral CD4(+)FoxP3(+) regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood. 2012 Jun 14;119(24):5688-96. doi: 10.1182/blood-2011-10-386482. Epub 2012 May 3.
PubMed 22555974
Study at a glance
From the registry record, last updated by the sponsor on 21 Dec 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment of Patients With Metastatic Melanoma Using Cloned Lymphocytes Following the Administration of a Non-Myeloablative But Lymphocyte Depleting Regimen
- ClinicalTrials.gov ID
- NCT00001832
- Acronym / sponsor ID
- 990158
- Conditions
- Melanoma, Neoplasm Metastasis
- Keywords
- Immunotherapy, Adoptive Transfer, IL-2, Toxicity, Clinical Response, Breast Cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 170 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- Aug 1999
- Primary completion
- May 2010 (actual)
- Study completion
- May 2010 (actual)
- First posted
- 4 Nov 1999 (estimated)
- Results
- Posted 21 Dec 2012
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This experiment will test the safety and effectiveness of a treatment for melanoma in which certain lymphocytes (a type of white blood cell) are taken from the patient, grown in the laboratory, and returned after the patient's immune system has been weakened with immune-suppressing drugs. Some patients will also receive interleukin-2 (IL-2), a drug that may enhance the activity of the re-infused lymphocytes.
Patients with metastatic melanoma (melanoma whose tumor has spread) who have been treated unsuccessfully with gp100 vaccination may participate in this study. They will undergo apheresis or a tumor biopsy, or both, to collect lymphocytes. In apheresis, whole blood is drawn through a needle in the arm. A machine separates the blood components and removes the white cells. The rest of the blood is returned to the donor through a needle in the other arm. A biopsy is a surgical procedure to remove a small piece of tumor tissue.
Several weeks before the lymphocytes are collected, patients will receive injections of growth colony stimulating factor (G-CSF) every day for five days. This drug stimulates white cell production, permitting as many cells as possible to be obtained during collection. The lymphocytes will then be grown in larger numbers in the laboratory.
Seven days before the cells are re-infused, the patient is admitted to the hospital and a catheter (small tube) is placed in a large vein in the chest or neck. Two drugs, cyclophosphamide and fludarabine, are given through the tube. These drugs suppress the immune system so that it will not interfere with the work of the reinfused lymphocytes. The lymphocytes are then injected through the catheter over a 30-minute period. After the infusion, patients who receive IL-2 will be given the drug in a high dose over a 15-minute period every eight hours for up to five days. Patients whose condition does not permit high-dose IL-2, such as those with a heart condition or lung problem, may receive a low-dose regimen, with the drug given as a shot under the skin of the thigh or abdomen for five days followed by a 2-day break, continuing for a total of six weeks. These patients receive a higher dose the first week and then half that dose the next five weeks.
Blood and tissue samples will be taken before and during the study to evaluate the size of the tumor and assess treatment. If, 3-5 weeks after therapy is completed, the patient's tumor has stabilized or shrunk, the entire treatment, except for chemotherapy, may be repeated two more times.
Detailed description
Patients with metastatic melanoma who are human immunodeficiency virus (HIV) and Hepatitis B negative and who have previously progressed after receiving standard therapy will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine and then will be treated by the adoptive transfer of lymphocytes reactive with shared antigens on their tumors. This study will evaluate the toxicity, immunologic effects and potential therapeutic role of this treatment.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 15
| Arm | Type | Receives |
|---|---|---|
| Abl Cells in culture | Experimental | Procedure: ApheresisPeripheral blood mononuclear cells (PBMC) and/or tumor infiltrating lymphocytes (TIL) obtained by apheresis or lesion excision to be cloned and expanded in the lab.The patients underwent an apheresis and/or an excision of their tumor. They didn't receive any drugs. |
| Abl Cells IV + Cyclophosphamide 30 mg/kg | Experimental | Biological: Abl cells, Drug: Fludarabine, Drug: CyclophosphamidePhase 1 Cyclophosphamide Dose Escalation: Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x30mg/kg + Cells intravenous (IV) Abl cells intravenous (IV) = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days |
| Abl Cells IV + Cyclophosphamide 60 mg/kg | Experimental | Biological: Abl cells, Drug: Fludarabine, Drug: CyclophosphamidePhase 1 Cyclophosphamide Dose Escalation: Fludarabine 5x25mg/m2 + Cyclophosphamide 2x60mg/kg + Cells intravenous (IV) Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days |
| Abl Cells IV+Low Dose IV IL-2 (Initial) | Experimental | Drug: IL-2, Biological: Abl cells, Drug: Fludarabine, Drug: CyclophosphamidePhase 1 interleukin-2 (IL-2) Dose Escalation: Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intravenous (IV) + IV IL-2 (72,000 IU/kg q8h for a maximum of 15 doses) Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days |
| Abl Cells IV+High Dose IV IL-2 (Initial) | Experimental | Drug: IL-2, Biological: Abl cells, Drug: Fludarabine, Drug: CyclophosphamidePhase 1 interleukin-2 (IL-2) Dose Escalation: Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intravenous (IV) + IV IL-2 (720,000 IU/kg q8h for a maximum of 12 doses) Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days |
| Abl Cells IV + MTD IL-2 | Experimental | Biological: Abl cells, Drug: Fludarabine, Drug: Cyclophosphamide, Biological: GCSF (Growth colony stimulating factor)Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intravenous (IV) + IV interleukin-2 (IL-2) (720,000 IU/kg q8h for a maximum of 12 doses) + growth colony stimulating factor (G-CSF) (to shorten time to neutrophil recovery) Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days |
| Abl Cells IA + MTD (prior cells IV on 6) | Experimental | Drug: IL-2, Biological: Abl cells, Drug: Fludarabine, Drug: Cyclophosphamide, Biological: GCSF (Growth colony stimulating factor)Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intra-arterial (IA) + intravenous (IV) interleukin-2 (IL-2) (720,000 IU/kg q8h for a maximum of 12 doses) Prior Cells IV + growth colony stimulating factor (G-CSF) Abl cells IA = Lymphocytes 10^9-10^11 IA over 30 minutes on day 0, repeated in 14 to 21 days |
| Abl Cells IA + MTD IL-2 | Experimental | Drug: IL-2, Biological: Abl cells, Drug: Fludarabine, Drug: Cyclophosphamide, Biological: GCSF (Growth colony stimulating factor)Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intra-arterial (IA) + intravenous (IV) interleukin-2 (IL-2) (720,000 IU/kg q8h for a maximum of 12 doses) + growth colony stimulating factor (G-CSF) Abl cells IA = Lymphocytes 10^9-10^11 IA over 30 minutes on day 0, repeated in 14 to 21 days |
| Abl Cells IA+MTD IL-2 (MART-1 reactive) | Experimental | Drug: Montanide ISA-51, Drug: MART-1:26-35(27L), Biological: Abl cells, Drug: Fludarabine, Drug: Cyclophosphamide, Biological: GCSF (Growth colony stimulating factor)Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intra-arterial (IA) + intravenous (IV) interleukin-2 (IL-2) (720,000 IU/kg q8h for a maximum of 12 doses) + growth colony stimulating factor (G-CSF) + melanoma- associated antigen recognized by T cells (MART-1):26-35(27L) Peptide 1mg/day (5-8 days) in patients with MART-1 reactive cells Abl cells IA = Lymphocytes 10^9-10^11 IA over 30 minutes on day 0, repeated in 14 to 21 days gp100 = gp100:209-217(210M) peptide - 1 mg in IFA SQ (in the subcutaneous tissue of each thigh) on the morning of the cell infusion, plus gp100:209-217(210M) peptide, 1 mg, in IFA injected into the subcutaneous tissue in two equal volumes, 1.0 mL for each injection, within 2cm of each other, in the thigh daily for five days starting on the morning of the cell infusion and then weekly for 3 more injections. |
| Abl Cells IV + MTD IL-2 no GCSF | Experimental | Drug: IL-2, Biological: Abl cells, Drug: Fludarabine, Drug: CyclophosphamidePhase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intravenous (IV) + IV interleukin-2 (IL-2) (720,000 IU/kg q8h for a maximum of 12 doses) without growth colony stimulating factor (G-CSF) (to determine if G-CSF has harmful effects when adoptively transferring lymphocytes following a nonmyeloablative chemotherapy regimen) Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days |
| Abl Cells IV+MTD IL-2 no GCSF | Experimental | Drug: gp100:209-217 (210M), Drug: IL-2, Biological: Abl cells, Drug: Fludarabine, Drug: CyclophosphamideAbl Cells intravenous (IV) + maximum tolerated dose (MTD) interleukin-2 (IL-2) no growth colony stimulating factor (GCSF)(gp100 reactive). Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells IV + IV IL-2 (720,000 IU/kg q8h for a maximum of 12 doses) without G-CSF + gp100:209-217(210M) 1mg/day (2-8 days) in patients with gp100 reactive cells Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days |
| Abl Cells IV+MTD IL-2 | Experimental | Drug: IL-2, Drug: MART-1:26-35(27L), Biological: Abl cells, Drug: Fludarabine, Drug: CyclophosphamideAbl Cells intravenous (IV)+ maximum tolerated dose (MTD) interleukin-2 (IL-2) no growth colony stimulating factor (GCSF) (melanoma-associated antigen recognized by T cells (MART-1)reactive). Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells IV + IV interleukin-2 (IL-2) (720,000 IU/kg q8h for a maximum of 12 doses) without G-CSF + MART-1:26-35(27L) Peptide 1mg/day (5-8 days) in patients with MART-1 reactive cells Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days |
| Abl Cells IV + SQ IL-2 with GCSF | Experimental | Drug: IL-2, Biological: Abl cells, Drug: Fludarabine, Drug: Cyclophosphamide, Biological: GCSF (Growth colony stimulating factor)Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intravenous (IV) + subcutaneous (SQ) interleukin-2 (IL-2) (125,000 IU/kg/dose for 5 days for six weeks with 2 days rest per week) + growth colony stimulating factor (G-CSF) (to shorten time to neutrophil recovery), reactivity not specified Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days |
| Abl Cells IV + SQ | Experimental | Drug: IL-2, Drug: MART-1:26-35(27L), Biological: Abl cells, Drug: Fludarabine, Drug: Cyclophosphamide, Biological: GCSF (Growth colony stimulating factor)Abl Cells intravenous (IV) + subcutaneous (SQ) interleukin-2 (IL-2) with growth colony stimulating factor (GCSF) (melanoma-associated antigen recognized by T cells (MART-1) reactive) Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells IV + SQ IL-2 (125,000 IU/kg/dose for 5 days for six weeks with 2 days rest per week) + G-CSF + MART-1:26-35(27L) Peptide 1mg/day (5-8 days) in patients with MART-1 reactive cells Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days |
| Abl Cells IV + SQ IL-2 with GCSF (no reactivity) | Experimental | Drug: IL-2, Biological: Abl cells, Drug: Fludarabine, Drug: Cyclophosphamide, Biological: GCSF (Growth colony stimulating factor)Phase 2 Fludarabine 5x25mg/m^2 + Cyclophosphamide 2x60mg/kg + Cells intravenous (IV) + subcutaneous (SQ) interleukin-2 ( IL-2) (125,000 IU/kg/dose for 5 days for six weeks with 2 days rest per week) + growth colony stimulating factor (G-CSF) in patients with no reactivity Abl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days |
Who may qualify
- Ages
- 7 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (19 listed)
- Patients must have evaluable metastatic melanoma that is refractory to standard therapy.
- Age greater than or equal to 16 years.
- Patients of both genders must be willing to practice birth control for four months after receiving the preparative regimen.
- Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0, 1 at entry to the trial and at the time of chemotherapy induction.
- Absolute neutrophil count greater than 1000/mm^3.
Key exclusion criteria (0 listed)
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 |
|---|---|---|
| gp100:209-217 (210M)gp100 = gp100:209-217(210M) peptide - 1 mg in IFA SQ (in the subcutaneous tissue of each thigh) on the morning of the cell infusion, plus gp100:209-217(210M) peptide, 1 mg, in IFA injected into the subcutaneous tissue in two equal volumes, 1.0 mL for each injection, within 2cm of each other, in the thigh daily for five days starting on the morning of the cell infusion and then weekly for 3 more injections. MART-1 = MART-1:26-35(27L) peptide- 1 mg in IFA SQ (in the subcutaneous tissue of each thigh) on the morning of the cell infusion, plus MART-1:26-35(27L) peptide, 1 mg, in IFA injected into the subcutaneous tissue in two equal volumes, 1.0 mL for each injection, within 2cm of each other, in the thigh daily for five days starting on the morning of the cell infusion and then weekly for 3 more injections. | Drug | Abl Cells IV+MTD IL-2 no GCSF |
| Montanide ISA-51Also: IFAMART-1 = MART-1:26-35(27L) peptide- 1 mg in IFA SQ (in the subcutaneous tissue of each thigh) on the morning of the cell infusion, plus MART-1:26-35(27L) peptide, 1 mg, in IFA injected into the subcutaneous tissue in two equal volumes, 1.0 mL for each injection, within 2cm of each other, in the thigh daily for five days starting on the morning of the cell infusion and then weekly for 3 more injections. | Drug | Abl Cells IA+MTD IL-2 (MART-1 reactive) |
| IL-2Also: Interleukin-2125,000 IU/kg dose intravenous for 5 days for 6 weeks with 2 days rest per week. 720,000 IU/kg intravenous every 8 hours for a maximum of 12 doses. | Drug | Abl Cells IA + MTD (prior cells IV on 6), Abl Cells IA + MTD IL-2, Abl Cells IV + MTD IL-2 no GCSF, Abl Cells IV + SQ, Abl Cells IV + SQ IL-2 with GCSF, Abl Cells IV + SQ IL-2 with GCSF (no reactivity), Abl Cells IV+High Dose IV IL-2 (Initial), Abl Cells IV+Low Dose IV IL-2 (Initial), Abl Cells IV+MTD IL-2, Abl Cells IV+MTD IL-2 no GCSF |
| MART-1:26-35(27L)Also: melanoma-associated antigen recognized by T cellsMART-1 = MART-1:26-35(27L) peptide- 1 mg in IFA SQ (in the subcutaneous tissue of each thigh) on the morning of the cell infusion, plus MART-1:26-35(27L) peptide, 1 mg, in IFA injected into the subcutaneous tissue in two equal volumes, 1.0 mL for each injection, within 2cm of each other, in the thigh daily for five days starting on the morning of the cell infusion and then weekly for 3 more injections. | Drug | Abl Cells IA+MTD IL-2 (MART-1 reactive), Abl Cells IV + SQ, Abl Cells IV+MTD IL-2 |
| Abl cellsAbl cells IV = Lymphocytes 10^9-10^11 IV over 30 minutes on day 0, repeated in 14 to 21 days Abl cells IA = Lymphocytes 10^9-10^11 IA over 30 minutes on day 0, repeated in 14 to 21 days | Biological | Abl Cells IA + MTD (prior cells IV on 6), Abl Cells IA + MTD IL-2, Abl Cells IA+MTD IL-2 (MART-1 reactive), Abl Cells IV + Cyclophosphamide 30 mg/kg, Abl Cells IV + Cyclophosphamide 60 mg/kg, Abl Cells IV + MTD IL-2, Abl Cells IV + MTD IL-2 no GCSF, Abl Cells IV + SQ, Abl Cells IV + SQ IL-2 with GCSF, Abl Cells IV + SQ IL-2 with GCSF (no reactivity), Abl Cells IV+High Dose IV IL-2 (Initial), Abl Cells IV+Low Dose IV IL-2 (Initial), Abl Cells IV+MTD IL-2, Abl Cells IV+MTD IL-2 no GCSF |
| FludarabineAlso: Fludara5x25 mg/m^2 intravenous | Drug | Abl Cells IA + MTD (prior cells IV on 6), Abl Cells IA + MTD IL-2, Abl Cells IA+MTD IL-2 (MART-1 reactive), Abl Cells IV + Cyclophosphamide 30 mg/kg, Abl Cells IV + Cyclophosphamide 60 mg/kg, Abl Cells IV + MTD IL-2, Abl Cells IV + MTD IL-2 no GCSF, Abl Cells IV + SQ, Abl Cells IV + SQ IL-2 with GCSF, Abl Cells IV + SQ IL-2 with GCSF (no reactivity), Abl Cells IV+High Dose IV IL-2 (Initial), Abl Cells IV+Low Dose IV IL-2 (Initial), Abl Cells IV+MTD IL-2, Abl Cells IV+MTD IL-2 no GCSF |
| CyclophosphamideAlso: Cytoxan2x30 mg/kg, 2x60 mg/kg intravenous | Drug | Abl Cells IA + MTD (prior cells IV on 6), Abl Cells IA + MTD IL-2, Abl Cells IA+MTD IL-2 (MART-1 reactive), Abl Cells IV + Cyclophosphamide 30 mg/kg, Abl Cells IV + Cyclophosphamide 60 mg/kg, Abl Cells IV + MTD IL-2, Abl Cells IV + MTD IL-2 no GCSF, Abl Cells IV + SQ, Abl Cells IV + SQ IL-2 with GCSF, Abl Cells IV + SQ IL-2 with GCSF (no reactivity), Abl Cells IV+High Dose IV IL-2 (Initial), Abl Cells IV+Low Dose IV IL-2 (Initial), Abl Cells IV+MTD IL-2, Abl Cells IV+MTD IL-2 no GCSF |
| GCSF (Growth colony stimulating factor)Also: FilgrastimBeginning on day 1 or 2, GCSF will be administered subcutaneously at a dose of 5mcg/kg/day (not to exceed 300 mcg/day. Filgrastim administration will continue daily until neutrophil count > 1.0 x10^9/L x 3 days or > 5.0 x10^9/L. | Biological | Abl Cells IA + MTD (prior cells IV on 6), Abl Cells IA + MTD IL-2, Abl Cells IA+MTD IL-2 (MART-1 reactive), Abl Cells IV + MTD IL-2, Abl Cells IV + SQ, Abl Cells IV + SQ IL-2 with GCSF, Abl Cells IV + SQ IL-2 with GCSF (no reactivity) |
| Apheresis | Procedure or surgery | Abl Cells in culture |
Primary outcome
Clinical Response
Time frame: Every three to four weeks after the treatment, for up to 5 years.
Complete response (CR) is defined as the disappearance of all clinical evidence of disease. Partial response (PR) is a 50% or greater decrease in the sum of the products of perpendicular diameters of all measurable lesions for at least one month. No new lesions may appear, and none may increase. Minor response (MR) is a 25-49% decrease in the sum of the products of the perpendicular diameters of all measurable lesions. Appearance of new lesions following a PR or CR are considered relapses. Patients with progressive disease (PD) and no evidence of stable disease will be taken off study after receiving IL-2.
1 secondary outcome
Number of Participants With Adverse Events
Time frame: 10.5 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Dec 2012.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- 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.
- Derived from this study: PubMed 22555974Yao X, Ahmadzadeh M, Lu YC, Liewehr DJ, Dudley ME, Liu F, Schrump DS, Steinberg SM, Rosenberg SA, Robbins PF. Levels of peripheral CD4(+)FoxP3(+) regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood. 2012 Jun 14;119(24):5688-96. doi: 10.1182/blood-2011-10-386482. Epub 2012 May 3.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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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 gp100:209-217 (210M), Montanide ISA-51 and IL-2 in people with Melanoma and Neoplasm Metastasis, 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 19 inclusion and 0 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 21 Dec 2012. 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 21 Dec 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?
Clinical Response (time frame: Every three to four weeks after the treatment, for up to 5 years.). 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 NCT00001832, which also lists 2 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 21 Dec 2012.