Lung Cancer
Conditions
Keywords
adenocarcinoma of the lung, stage IV non-small cell lung cancer
Brief summary
The purpose of this study is to find out what effects (good and/or bad) a tumor vaccine used in combination with two drugs (ATRA and cytoxan) have on the patient and their cancer. We also want to find out if the vaccine and the drugs can boost the patient's immune system and how their immune system reacts, both before and after the vaccine treatment.
Detailed description
This protocol describes a phase II study involving patients with stage IV adenocarcinoma of the lung. Treatment will consist of Cyclophosphamide (300 mg/m²) to be given IV on day 1 and day 57. On day 4 immunization with intradermal vaccine injections at 4 separate sites (bilateral upper arms and bilateral upper thighs will be repeated every 14 days times 2 followed by every 28 days times 3 (day 4, 18, 32, 60, 88, and 116). Decavac (tetanus shot) 0.5 cc intramuscular (IM) will be given after the first vaccine. ATRA (150 mg/m2/day) oral three times daily (TID) dosing administered after the first and fourth vaccines (day 5-7 & day 61-63). Those patients achieving stable disease (SD), partial response (PR), or complete response (CR) at restaging after the initial 6 vaccines will receive additional vaccines every 3 months until disease progression. The vaccine will consist of GM.CD40L bystander cells admixed with an equivalent number of the 2 allogeneic tumor cell lines. There will be a +/- 7 day window for all study related exams, tests, and procedures.
Interventions
BIOLOGICALVaccine Treatment
We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Intradermal vaccine was given every 14 days x3, followed by monthly x3.
DRUGCyclophosphamide
Cyclophosphamide (300 mg/m\^2 IV) was administered before 1st and 4th vaccines to deplete regulatory T-cells.
All-trans retinoic acid was given (150/mg/m\^2/day) after 1st and 4th vaccines to enhance dendritic differentiation.
Sponsors
National Cancer Institute (NCI)
National Institutes of Health (NIH)
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed metastatic adenocarcinoma of the lung * Eastern Cooperative Oncology Group (ECOG) performance status of 0, or 1 * No radiation therapy within 2 weeks of first vaccine administration * No chemotherapy within 4 weeks of first vaccine administration * No steroid therapy within 4 weeks of first vaccine administration * Patient's written informed consent * Adequate organ function (measured within a week of beginning treatment) * Patients will be tested for human leukocyte antigen A0201 (HLA-A0201) as determined by flow cytometry followed by molecular analysis of a peripheral blood specimen, however this result will not be an inclusion criterion. * Measurable metastatic tumor as defined by standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Lesions must be accurately measured in at least one dimension with the longest diameter greater than or equal 20mm. With spiral computer tomography (CT) scan, lesion must be greater than or equal to 10 mm at least one dimension. * Patient's must have received, and completed first line chemotherapy.
Exclusion criteria
* Symptomatic brain metastasis * Any acute medical problems requiring active intervention * Current corticosteroid (other than replacement doses in patients who are hypoadrenal) or other immunosuppressive therapy * Any other pre-existing immunodeficiency condition (including known HIV infection) * Pregnant or lactating women -- Patients in reproductive age must agree to use contraceptive methods for the duration of the study (\*A pregnancy test will be obtained before treatment). * Eastern Cooperative Oncology Group (ECOG) performance status of 2, 3 or 4
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Evaluable Participants With Tumor Response | 3 years | Number of participants with evaluable peripheral blood mononuclear cells (PBMCs) who demonstrated sustained tumor peptide-specific T-cell activation after vaccination. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and after each vaccination. T-cell activation profiles were analyzed by ELISpot assay and tested by generalized Wilcoxon for correlation to survival. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to Progression (TTP) | 3 years | Analysis of Time to Progression and Survival Endpoints. All patients will be considered in the analysis of progression free survival time (time from start of treatment to progression or death) and survival time (time from initiation of treatment to death). Progression is defined using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as at least a 20% increase in the sum of the longest diameter (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. Follow-up for this analysis will continue for all patients for their lifetimes. Time to progression and survival probabilities over time will be calculated by the method of Kaplan-Meier. |
| Median Overall Survival (OS) | 3 years | Analysis of Time to Progression and Survival Endpoints. All patients will be considered in the analysis of progression free survival time (time from start of treatment to progression or death) and survival time (time from initiation of treatment to death). Follow-up for this analysis will continue for all patients for their lifetimes. Time to progression and survival probabilities over time will be calculated by the method of Kaplan-Meier. |
| Number of Participants With Serious Adverse Events (SAEs) | 3 years | Toxicity will be assessed using the NCI Common Terminology Criteria for Adverse Criteria (CTAE-3),Version 3.0 (www.ctep.cancer.gov). Particular attention will assess the presence of symptomatic lymphadenopathy or any local skin / soft tissue reaction at the vaccine site. Blood tests for ANA and rheumatoid factor will be performed on any patient who develops evidence of autoimmune phenomena. |
Countries
United States
Participant flow
Recruitment details
24 participants were accrued at a single center from 10/2006 to 6/2008.
Participants by arm
| Arm | Count |
|---|---|
| Combination Immunotherapy Vaccine + Cytoxan + ATRA as outlined in Detailed Description
Vaccine Treatment : We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Intradermal vaccine was given every 14 days x3, followed by monthly x3.
All-trans retinoic acid (ATRA) : All-trans retinoic acid was given (150/mg/m\^2/day) after 1st and 4th vaccines to enhance dendritic differentiation.
Cyclophosphamide : Cyclophosphamide (300 mg/m\^2 IV) was administered before 1st and 4th vaccines to deplete regulatory T-cells. | 24 |
| Total | 24 |
Baseline characteristics
| Characteristic | Combination Immunotherapy |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 12 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age Continuous | 64 years |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 24 / 24 |
| serious Total, serious adverse events | 11 / 24 |
Outcome results
Primary
Number of Evaluable Participants With Tumor Response
Number of participants with evaluable peripheral blood mononuclear cells (PBMCs) who demonstrated sustained tumor peptide-specific T-cell activation after vaccination. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and after each vaccination. T-cell activation profiles were analyzed by ELISpot assay and tested by generalized Wilcoxon for correlation to survival.
Time frame: 3 years
Population: 14 participants with evaluable PBMCs
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Immunotherapy | Number of Evaluable Participants With Tumor Response | 5 participants |
Secondary
Median Overall Survival (OS)
Analysis of Time to Progression and Survival Endpoints. All patients will be considered in the analysis of progression free survival time (time from start of treatment to progression or death) and survival time (time from initiation of treatment to death). Follow-up for this analysis will continue for all patients for their lifetimes. Time to progression and survival probabilities over time will be calculated by the method of Kaplan-Meier.
Time frame: 3 years
Population: All participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Immunotherapy | Median Overall Survival (OS) | 8 months |
Secondary
Median Time to Progression (TTP)
Analysis of Time to Progression and Survival Endpoints. All patients will be considered in the analysis of progression free survival time (time from start of treatment to progression or death) and survival time (time from initiation of treatment to death). Progression is defined using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as at least a 20% increase in the sum of the longest diameter (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. Follow-up for this analysis will continue for all patients for their lifetimes. Time to progression and survival probabilities over time will be calculated by the method of Kaplan-Meier.
Time frame: 3 years
Population: All participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Immunotherapy | Median Time to Progression (TTP) | 2.4 months |
Secondary
Number of Participants With Serious Adverse Events (SAEs)
Toxicity will be assessed using the NCI Common Terminology Criteria for Adverse Criteria (CTAE-3),Version 3.0 (www.ctep.cancer.gov). Particular attention will assess the presence of symptomatic lymphadenopathy or any local skin / soft tissue reaction at the vaccine site. Blood tests for ANA and rheumatoid factor will be performed on any patient who develops evidence of autoimmune phenomena.
Time frame: 3 years
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Immunotherapy | Number of Participants With Serious Adverse Events (SAEs) | 11 participants |