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Lymphocyte Re-infusion During Immune Suppression to Treat Metastatic Melanoma

Primary Purpose

Melanoma, Neoplasm Metastasis

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

gp100:209-217 (210M)

Montanide ISA-51

IL-2

MART-1:26-35(27L)

Abl cells

Fludarabine

Cyclophosphamide

GCSF (Growth colony stimulating factor)

Apheresis

About this trial

This is an interventional treatment trial for Melanoma focused on measuring Immunotherapy, Adoptive Transfer, IL-2, Toxicity, Clinical Response, Breast Cancer

Eligibility Criteria

7 Years - undefined (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

INCLUSION CRITERIA 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. 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.

Sites / Locations

National Cancer Institute (NCI)

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm 11

Arm 12

Arm 13

Arm 14

Arm 15

Arm Type

Experimental

Arm Label

Abl Cells in culture

Abl Cells IV + Cyclophosphamide 30 mg/kg

Abl Cells IV + Cyclophosphamide 60 mg/kg

Abl Cells IV+Low Dose IV IL-2 (Initial)

Abl Cells IV+High Dose IV IL-2 (Initial)

Abl Cells IV + MTD IL-2

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 no GCSF

Abl Cells IV+MTD IL-2 no GCSF

Abl Cells IV+MTD IL-2

Abl Cells IV + SQ IL-2 with GCSF

Abl Cells IV + SQ

Abl Cells IV + SQ IL-2 with GCSF (no reactivity)

Arm Description

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.

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

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

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

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

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

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

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.

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

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

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

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 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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Full Information

NCT ID

NCT00001832

First Posted

November 3, 1999

Last Updated

December 19, 2012

Sponsor

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT00001832

Brief Title

Lymphocyte Re-infusion During Immune Suppression to Treat Metastatic Melanoma

Official Title

Treatment of Patients With Metastatic Melanoma Using Cloned Lymphocytes Following the Administration of a Non-Myeloablative But Lymphocyte Depleting Regimen

Study Type

Interventional

2. Study Status

Record Verification Date

December 2012

Overall Recruitment Status

Completed

Study Start Date

August 1999 (undefined)

Primary Completion Date

May 2010 (Actual)

Study Completion Date

May 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Melanoma, Neoplasm Metastasis

Keywords

Immunotherapy, Adoptive Transfer, IL-2, Toxicity, Clinical Response, Breast Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

170 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Abl Cells in culture

Arm Type

Experimental

Arm Description

Arm Title

Abl Cells IV + Cyclophosphamide 30 mg/kg

Arm Type

Experimental

Arm Description

Arm Title

Abl Cells IV + Cyclophosphamide 60 mg/kg

Arm Type

Experimental

Arm Description

Arm Title

Abl Cells IV+Low Dose IV IL-2 (Initial)

Arm Type

Experimental

Arm Description

Arm Title

Abl Cells IV+High Dose IV IL-2 (Initial)

Arm Type

Experimental

Arm Description

Arm Title

Abl Cells IV + MTD IL-2

Arm Type

Experimental

Arm Description

Arm Title

Abl Cells IA + MTD (prior cells IV on 6)

Arm Type

Experimental

Arm Description

Arm Title

Abl Cells IA + MTD IL-2

Arm Type

Experimental

Arm Description

Arm Title

Abl Cells IA+MTD IL-2 (MART-1 reactive)

Arm Type

Experimental

Arm Description

Arm Title

Abl Cells IV + MTD IL-2 no GCSF

Arm Type

Experimental

Arm Description

Arm Title

Abl Cells IV+MTD IL-2 no GCSF

Arm Type

Experimental

Arm Description

Arm Title

Abl Cells IV+MTD IL-2

Arm Type

Experimental

Arm Description

Arm Title

Abl Cells IV + SQ IL-2 with GCSF

Arm Type

Experimental

Arm Description

Arm Title

Abl Cells IV + SQ

Arm Type

Experimental

Arm Description

Arm Title

Abl Cells IV + SQ IL-2 with GCSF (no reactivity)

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

gp100:209-217 (210M)

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Montanide ISA-51

Other Intervention Name(s)

IFA

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

IL-2

Other Intervention Name(s)

Interleukin-2

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

MART-1:26-35(27L)

Other Intervention Name(s)

melanoma-associated antigen recognized by T cells

Intervention Description

Intervention Type

Biological

Intervention Name(s)

Abl cells

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Other Intervention Name(s)

Fludara

Intervention Description

5x25 mg/m^2 intravenous

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

Cytoxan

Intervention Description

2x30 mg/kg, 2x60 mg/kg intravenous

Intervention Type

Biological

Intervention Name(s)

GCSF (Growth colony stimulating factor)

Other Intervention Name(s)

Filgrastim

Intervention Description

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.

Intervention Type

Procedure

Intervention Name(s)

Apheresis

Primary Outcome Measure Information:

Title

Clinical Response

Description

Time Frame

Every three to four weeks after the treatment, for up to 5 years.

Secondary Outcome Measure Information:

Title

Number of Participants With Adverse Events

Description

Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.

Time Frame

10.5 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

7 Years

Accepts Healthy Volunteers

Eligibility Criteria

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Steven Rosenberg, M.D.

Organizational Affiliation

National Cancer Institute, National Institutes of Health

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Cancer Institute (NCI)

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

8170938

Citation

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.

Results Reference

background

PubMed Identifier

22555974

Citation

Yao 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.

Results Reference

derived

Links:

URL

http://clinicalstudies.info.nih.gov/detail/A_1999-C-0158.html

Description

NIH Clinical Center Detailed Web Page

Learn more about this trial

Lymphocyte Re-infusion During Immune Suppression to Treat Metastatic Melanoma

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