Back to resultsProspective Randomized Comparative Study of Cell Transfer Therapy Using CD8+-Enriched Short-Term Cultured Anti-Tumor Autologous Lymphocytes Following a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen Compared to High-Dose Aldesleukin in M...
Primary Purpose
Skin Cancer, Melanoma, Metastatic Melanoma
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Aldesleukin
CD8 enriched Young TIL
Sponsored by
About this trial
This is an interventional treatment trial for Skin Cancer focused on measuring Immunotherapy, Metastatic Melanoma, Randomized, Cell Therapy, Skin Cancer, Melanoma
Eligibility Criteria
INCLUSION CRITERIA:
- Measurable metastatic melanoma with at least one lesion that is resectable for tumor infiltrating lymphocytes (TIL) generation. The lesion must be of at least 2cm in diameter that can be surgically removed with minimal morbidity (defined as any operation for which expected hospitalization is less than or equal to 7 days).
- Patients with 3 or less brain metastases are eligible. Note: If lesions are symptomatic or greater than or equal to 1 cm each, these lesions must have been treated and stable for 3 months for the patient to be eligible.
- No prior high-dose aldesleukin therapy at a dose of greater than or equal to 600,000 IU/kg.
- Greater than or equal to 18 years of age.
- Willing to practice birth control during treatment and for four months after receiving all protocol related therapy.
- Life expectancy of greater than three months.
- Willing to sign a durable power of attorney.
- Able to understand and sign the Informed Consent Document.
- Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
- Hematology:
- Absolute neutrophil count greater than 1000/mm^3 without support of filgrastim
- Normal White blood cell (WBC) (> 3000/mm^3).
- Hemoglobin greater than 8.0 g/dl
Platelet count greater than 100,000/mm^3
k. Serology:
- 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, or hepatitis C antibody or antigen.
l. Chemistry:
- Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than three times the upper limit of normal.
- Calculated creatinine clearance estimated glomerular filtration rate(eGFR) > 50 ml/min.
Total bilirubin less than or equal to 2 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3 mg/dl.
m. More than four weeks must have elapsed since any prior systemic therapy at the time the time of randomization, and patients' toxicities must have recovered to a grade 1 or less (except for alopecia or vitiligo). Patients must have stable or progressing disease after prior treatment. Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less or as specified in the eligibility criteria.
n. Six weeks must have elapsed since any prior anti-CTLA4 antibody therapy to allow antibody levels to decline.
o. Patients who have previously received any cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) antibody and have documented gastrointestinal (GI) toxicity must have a normal colonoscopy with normal colonic biopsies.
EXCLUSION CRITERIA:
- Prior cell transfer therapy which included a non-myeloablative or myeloablative chemotherapy regimen.
- 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.
- Systemic steroid therapy requirement.
- Active systemic infections, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system, as evidenced by a positive stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
- Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and Acquired Immunodeficiency Syndrome (AIDS)).
- Opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
- History of severe immediate hypersensitivity reaction to any of the agents used in this study.
- History of coronary revascularization or ischemic symptoms.
- Any patient known to have an left ventricular ejection fraction (LVEF) less than or equal to 45%.
- In patients > 60 years old, documented LVEF of less than or equal to 45%.
Documented forced expiratory volume 1 (FEV1) less than or equal to 60% predicted tested in patients with:
- A prolonged history of cigarette smoking
- Symptoms of respiratory dysfunction
Sites / Locations
- National Institutes of Health Clinical Center, 9000 Rockville Pike
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Experimental
Arm Label
Arm 1-Aldesleukin
Arm 2 - Adoptive cell therapy
Arm Description
Aldesleukin 720,000 IU/kg IV over 15 minute every eight hours and continuing for up to 5 days (maximum of 15 doses). Patients will receive one additional cycle of aldesleukin approximately 10-14 days after completion of the first cycle of aldesleukin.
Adoptive Cell Therapy consisting of the lymphocyte depleting preparative regimen consisting of fludarabine and cyclophosphamide, followed by infusion of between 1x10^9 to 2x10^11 CD8+ enriched tumor infiltrating lymphocytes (minimum of 5 x10^8) and the administration of high-dose aldesleukin.
Outcomes
Primary Outcome Measures
Response Rate
Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response (CR) is the disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progressive disease (PD) is at least a 20% increase in the sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD.
Progression Free Survival
Measured from the time of randomization to time of progression (or death).
Secondary Outcome Measures
Toxicity
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
NCT01118091
First Posted
May 5, 2010
Last Updated
October 6, 2015
Sponsor
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT01118091
Brief Title
Prospective Randomized Comparative Study of Cell Transfer Therapy Using CD8+-Enriched Short-Term Cultured Anti-Tumor Autologous Lymphocytes Following a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen Compared to High-Dose Aldesleukin in M...
Official Title
Prospective Randomized Comparative Study of Cell Transfer Therapy Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes Following a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen Compared to High-dose Aldesleukin in Metastatic Melanoma
Study Type
Interventional
2. Study Status
Record Verification Date
September 2015
Overall Recruitment Status
Completed
Study Start Date
April 2010 (undefined)
Primary Completion Date
April 2012 (Actual)
Study Completion Date
April 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
National Cancer Institute (NCI)
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Background:
- Adoptive cell therapy involves taking white blood cells called lymphocytes from patients' tumors, growing them in the laboratory in large numbers, and then giving the cells back to the patient to allow the cells to attack the tumor. Because this process is lengthy and difficult to perform, researchers have been developing improved means of performing adoptive cell therapy. Researchers are now interested in comparing adoptive cell therapy with the standard treatment for metastatic melanoma (skin cancer).
Objectives:
- To compare the effectiveness of adoptive cell therapy with standard high-dose aldesleukin as a treatment for metastatic melanoma.
Eligibility:
Individuals 18 years of age or older who have been diagnosed with metastatic melanoma and have not previously received aldesleukin therapy or cell therapy for their disease.
Participants must have at least one tumor that can be easily removed as part of the treatment procedure.
Design:
Participants will be screened with a full medical history, physical examination, blood and urine tests, and imaging scans to evaluate tumor size and treatment options.
Participants will be separated into two groups, in which one group will have adoptive cell therapy and one will have aldesleukin treatment.
Adoptive Cell Therapy
Participants will have a tumor sample taken in order to collect white blood cells for treatment. Participants whose tumors do not provide sufficient white blood cells may be switched to the aldesleukin-only treatment group.
The white blood cells will be grown in the laboratory for several weeks.
Prior to receiving cell therapy, participants will receive chemotherapy for 7 days to improve the chances of successful treatment.
Participants will have cell therapy followed by high-dose aldesleukin treatment every 8 hours for up to 5 days. This treatment will be followed by 1 to 2 weeks of recovery time as an inpatient at the clinical center.
Participants will be evaluated at 12 weeks following the start of the study, every 2 to 3 months for the first year, every 6 months for the next 5years, and then yearly thereafter..
Standard Aldesleukin Treatment
Participants will have high-dose aldesleukin treatment every 8 hours for up to 5 days (one cycle of treatment), and will have a second cycle of treatment 7 to 10 days after the first cycle.
If tests show that the tumors have grown, participants will be offered the chance to have additional cycles of aldesleukin, or begin a cell therapy treatment.
Participants will be evaluated at 12 weeks following the start of the study, every 2 to 3 months for the first year, every 6 months for the next 5years, and then yearly thereafter.
Detailed Description
Background:
Tumor Infiltrating Lymphocytes (TIL) can mediate the regression of bulky metastatic melanoma when administered to the autologous patient along with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen.
Although this adoptive cell therapy (ACT) has been shown capable of mediating objective clinical responses in patients with metastatic melanoma, including patients who have previously been treated with aldesleukin or chemotherapy, the treatment is only available in the Surgery Branch, National Cancer Institute (NCI) and in just one or two other institutions in the United States.
Despite our reports of the objective regressions in patients receiving adoptive cell therapy (ACT), doubts have been raised concerning the possible influence of patient selection bias that may have accounted for the increase in survival using ACT compared to historical controls.
ACT is a cumbersome and labor intensive procedure which has discouraged many from applying it. We have recently developed simplifications in the technique for generating TIL that are also capable of mediating objective responses.
To evaluate the efficacy of ACT we are now proposing a prospective randomized trial to compare this form of therapy with standard available treatment for patients with metastatic melanoma.
Objectives:
To determine, in a prospective randomized trial, the response rate and progression free survival of patients with metastatic melanoma receiving either ACT or standard high-dose aldesleukin treatment.
Survival rate will be evaluated as a secondary endpoint.
To determine the toxicity of these two treatment regimens.
Eligibility:
Patients who are 18 years of age or older must have:
Evaluable metastatic melanoma;
No prior treatment with high-dose aldesleukin (greater than or equal to 600,000 IU IL-2 q8h or the equivalent)
No contraindications to high-dose aldesleukin administration;
No concurrent major medical illnesses or any form of immunodeficiency;
Lesions of at least 2cm in diameter that can be surgically removed with minimal morbidity.
Design:
Prior to amendment D, patients with metastatic melanoma lesions that can be resected with minimal morbidity will be prospectively randomized to receive either ACT using CD8+ young TIL (arm 2) and aldesleukin (arm 1) following a non-myeloablative chemotherapy preparative regimen, or will receive standard high-dose aldesleukin therapy.
With the approval of amendment D, arm 1 and 2 will be closed, and two new arms will be opened. Patients with metastatic melanoma lesions that can be resected with minimal morbidity will be prospectively randomized to receive either ACT using young TIL (arm 4) and aldesleukin (arm 3) following a non-myeloablative chemotherapy preparative regimen, or will receive standard high-dose aldesleukin therapy.
Response rate and time to progression will be evaluated for all patients on an intent-to-treat basis.
Patients may crossover to the other treatment arm after progressive disease is documented by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, if still eligible.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Skin Cancer, Melanoma, Metastatic Melanoma
Keywords
Immunotherapy, Metastatic Melanoma, Randomized, Cell Therapy, Skin Cancer, Melanoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
12 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Arm 1-Aldesleukin
Arm Type
Active Comparator
Arm Description
Aldesleukin 720,000 IU/kg IV over 15 minute every eight hours and continuing for up to 5 days (maximum of 15 doses). Patients will receive one additional cycle of aldesleukin approximately 10-14 days after completion of the first cycle of aldesleukin.
Arm Title
Arm 2 - Adoptive cell therapy
Arm Type
Experimental
Arm Description
Adoptive Cell Therapy consisting of the lymphocyte depleting preparative regimen consisting of fludarabine and cyclophosphamide, followed by infusion of between 1x10^9 to 2x10^11 CD8+ enriched tumor infiltrating lymphocytes (minimum of 5 x10^8) and the administration of high-dose aldesleukin.
Intervention Type
Biological
Intervention Name(s)
Aldesleukin
Intervention Description
Aldesleukin 720,000 IU/kg IV over 15 minute every eight hours and continuing for up to 5 days (maximum of 15 doses). Patients will receive one additional cycle of aldesleukin approximately 10-14 days after completion of the first cycle of aldesleukin.
Intervention Type
Biological
Intervention Name(s)
CD8 enriched Young TIL
Intervention Description
Adoptive Cell Therapy consisting of the lymphocyte depleting preparative regimen consisting of fludarabine and cyclophosphamide, followed by infusion of between 1x10^9 to 2x10^11 CD8+ enriched tumor infiltrating lymphocytes (minimum of 5 x 10^8) and the administration of high-dose aldesleukin.
Primary Outcome Measure Information:
Title
Response Rate
Description
Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response (CR) is the disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progressive disease (PD) is at least a 20% increase in the sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD.
Time Frame
3 years
Title
Progression Free Survival
Description
Measured from the time of randomization to time of progression (or death).
Time Frame
3 years
Secondary Outcome Measure Information:
Title
Toxicity
Description
Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.
Time Frame
3 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA:
Measurable metastatic melanoma with at least one lesion that is resectable for tumor infiltrating lymphocytes (TIL) generation. The lesion must be of at least 2cm in diameter that can be surgically removed with minimal morbidity (defined as any operation for which expected hospitalization is less than or equal to 7 days).
Patients with 3 or less brain metastases are eligible. Note: If lesions are symptomatic or greater than or equal to 1 cm each, these lesions must have been treated and stable for 3 months for the patient to be eligible.
No prior high-dose aldesleukin therapy at a dose of greater than or equal to 600,000 IU/kg.
Greater than or equal to 18 years of age.
Willing to practice birth control during treatment and for four months after receiving all protocol related therapy.
Life expectancy of greater than three months.
Willing to sign a durable power of attorney.
Able to understand and sign the Informed Consent Document.
Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
Hematology:
Absolute neutrophil count greater than 1000/mm^3 without support of filgrastim
Normal White blood cell (WBC) (> 3000/mm^3).
Hemoglobin greater than 8.0 g/dl
Platelet count greater than 100,000/mm^3
k. Serology:
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, or hepatitis C antibody or antigen.
l. Chemistry:
Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than three times the upper limit of normal.
Calculated creatinine clearance estimated glomerular filtration rate(eGFR) > 50 ml/min.
Total bilirubin less than or equal to 2 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3 mg/dl.
m. More than four weeks must have elapsed since any prior systemic therapy at the time the time of randomization, and patients' toxicities must have recovered to a grade 1 or less (except for alopecia or vitiligo). Patients must have stable or progressing disease after prior treatment. Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less or as specified in the eligibility criteria.
n. Six weeks must have elapsed since any prior anti-CTLA4 antibody therapy to allow antibody levels to decline.
o. Patients who have previously received any cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) antibody and have documented gastrointestinal (GI) toxicity must have a normal colonoscopy with normal colonic biopsies.
EXCLUSION CRITERIA:
Prior cell transfer therapy which included a non-myeloablative or myeloablative chemotherapy regimen.
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.
Systemic steroid therapy requirement.
Active systemic infections, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system, as evidenced by a positive stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and Acquired Immunodeficiency Syndrome (AIDS)).
Opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
History of severe immediate hypersensitivity reaction to any of the agents used in this study.
History of coronary revascularization or ischemic symptoms.
Any patient known to have an left ventricular ejection fraction (LVEF) less than or equal to 45%.
In patients > 60 years old, documented LVEF of less than or equal to 45%.
Documented forced expiratory volume 1 (FEV1) less than or equal to 60% predicted tested in patients with:
A prolonged history of cigarette smoking
Symptoms of respiratory dysfunction
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ramaprasad Srinivasan, M.D.
Organizational Affiliation
National Cancer Institute (NCI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
17237035
Citation
Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66. doi: 10.3322/canjclin.57.1.43.
Results Reference
background
PubMed Identifier
10685652
Citation
Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000 Feb;6 Suppl 1:S11-4.
Results Reference
background
PubMed Identifier
17896204
Citation
Kirkwood MW, Yeates KO, Taylor HG, Randolph C, McCrea M, Anderson VA. Management of pediatric mild traumatic brain injury: a neuropsychological review from injury through recovery. Clin Neuropsychol. 2008 Sep;22(5):769-800. doi: 10.1080/13854040701543700. Epub 2007 Sep 1.
Results Reference
background
Learn more about this trial
Prospective Randomized Comparative Study of Cell Transfer Therapy Using CD8+-Enriched Short-Term Cultured Anti-Tumor Autologous Lymphocytes Following a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen Compared to High-Dose Aldesleukin in M...
We'll reach out to this number within 24 hrs