Adenocarcinoma, Lung Cancer
Conditions
Keywords
stage IV, adenocarcinoma, vaccine therapy, immunology, tumor vaccine, colony stimulating factor(CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), CC chemokine ligand 21 (CCL21), Chemokine [C-C motif] ligand 21 (CCL21), human leukocyte antigen serotype (HLA)
Brief summary
The purpose of this study is to find out what effects (good and bad) a tumor vaccine used in combination with GM.CD40L and CCL21 have on the patient and their cancer. We also want to find out if the vaccine and the drugs can boost the immune system of these patients and how their immune system reacts, both before and after the vaccine treatment.
Detailed description
The vaccine will be made by mixing two kinds of cells: 1) some lung cancer cells, which have been grown in the lab, and 2) experimental bystander (present but not taking part in the immune response) cells. All the cells in the vaccine will be treated with high-dose X-rays to make sure that none of them grow and cause more cancer. The bystander cells are human cells that have been genetically changed to express GM-CSF and CD40L. These are called GM.CD40L. (That is the original cells, called K562, with the genes for human GM-CSF and CD40L inserted into them). These changes are designed to help boost the participants' immune system to better fight the cancer in their body. GM-CSF is a hormone that is known to stimulate bone marrow to make more white blood cells. CCL21 is a chemokine (protein) that helps to recruit T cells (a type of white blood cell that helps to protect the body from infections) and leads to hyper-responsive T cells. This leads to heightened immune responses when T cells are exposed to both CCL21 and antigen (a substance that when introduced into the body lead to production of an antibody)-presenting cells (A cell that can present antigen in a form that T cells can recognize it ). The induction of a strong cell-mediated immune response is the type of immunity expected to be most involved in controlling cancer cell growth. A randomized trial of a vaccine consisting of the GM.CD40L bystander cells and an equivalent number of allogeneic (taken from different individuals) tumor cells plus or minus CCL21 is proposed.
Interventions
BIOLOGICALPhase I - GM.CD40L.CCL21 Vaccinations
This is a dual-agent, Phase I study with an expansion of each group at the recommended Phase II dose. Participants are entered in cohorts of 3 at the first dose level. Doses are not escalated over the course of treatment of an individual patient. Phase I: Participants receive the GM.CD40L.CCL21 vaccine in a standard 3+3 design.
BIOLOGICALPhase II - GM.CD40L cells Vaccinations
Patients randomized to Arm A will receive vaccinations on 3 occasions, at 2 week intervals. 7.5 X 10\^6 irradiated H1944 tumor cells, 7.5 X 10\^6 irradiated H2122 cells, and containing 15 X 10\^6 GM.CD40L cells (1.1 mL) will be injected intradermally into 4 separate sites (0.25 ml injected at each site), in bilateral proximal upper and lower extremities (in the regions of the axillary and inguinal nodal basins). Patients will be restaged approximately 2 weeks after vaccine 3. If patients show no sign of disease progression, patients will then be vaccinated at 4-week intervals.
BIOLOGICALPhase II - GM.CD40L.CCL21 Vaccinations
This is a dual-agent, Phase I study with an expansion of each group at the recommended Phase II dose. Participants are entered in cohorts of 3 at the first dose level. Doses are not escalated over the course of treatment of an individual patient. Phase II: Participants are randomized to one of the 2 arms (ratio 1:1): GM.CD40L versus GM.CD40L.CCL21. Patients in Arm B will receive vaccines at the same dose and schedule as described for patients in Arm A. In addition, their vaccine will include H1944 cells expressing CCL21. Note for patients on Arms A and B: the use of steroid medication is to be avoided for 4 weeks before to the initiation of vaccine therapy and during the vaccine treatment period.
Sponsors
Bankhead-Coley Florida Biomedical Research Program
James and Esther King Biomedical Research Program
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
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 * Patients must have received and completed first line therapy * Eastern Cooperative Oncology Group (ECOG) performance status of 0, or 1 * No external beam radiation therapy within 2 weeks of first vaccine administration * No stereotactic radiation therapy within 3 days of first vaccine * No targeted therapy within 2 weeks of first vaccine administration * No immunomodulatory therapy within 2 weeks of first vaccine administration * No chemotherapy within 4 weeks of first vaccine administration * During Screening period, 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): * White blood count (WBC) \> 3,000/mm³ and absolute neutrophil count (ANC) \>/= 1500/mm³ * Platelets \> 100,000/mm³ * Hematocrit \> 25% * Bilirubin \< 2.0 mg/dL * Creatinine \< 2.0 mg/dL, or creatinine clearance \> 60 mL/min * Patients will be tested for 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 ≥20 mm. With spiral computed tomography (CT) scan, lesion must be ≥10 mm in at least one dimension.
Exclusion criteria
* Symptomatic brain metastasis or Uncontrolled central nervous system (CNS) metastasis will not be permitted. * Any acute medical problems requiring active intervention * Current corticosteroid (other than replacement doses in patients who are hypo-adrenal) or other immunosuppressive therapy * Any other pre-existing immunodeficiency condition (including known human immunodeficiency virus \[HIV\] infection) * Any known pre-existing autoimmune disorder * History of a second malignancy within the previous 2 years (except non-melanoma skin cancer and cervical in-situ) * Patients who have had major surgery without full recovery or major surgery within three weeks of the start of vaccine treatment * 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 * Patients with other significant diseases or disorders that, in the Investigator's opinion, would exclude them from the study. * Patients who at the discretion of the investigator are deemed to have rapidly progressive disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Recommend Phase II Dose (RPDII) | Up to 6 Months | Highest dose level of GMCD40L vaccine in combination with CCL21 that induced dose limiting toxicity (DLT) in fewer than 33% of patients. DLT: Intervention-specific acute toxicity; i.e., occurrence within 28 days of drug administration, according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), V 4: 1.) that precludes further dose escalation. Participants are entered in cohorts of 3 at the first dose level. Doses are not escalated over the course of treatment of an individual patient. If 2 or more patients experience toxicity in dose level 1 (30X10\^6 cells per injection), dose de-escalation will occur. Dose level -1 will be defined by 10 % reduction of cells administered from dose level 1 and follow the same rules. It is not feasible to escalate the dose of the vaccine beyond 30X10\^6 cells per injection; therefore the Maximum Tolerated Dose (MTD) may not be reached in this study. In that case, the highest dose level will be used in the phase II component. |
| Phase II: Progression Free Survival (PFS) | Up to 6 Months | PFS is measured as the time from start of treatment to progression or death. 6 month progression free survival will be estimated from available clinical and radiographic assessments and RECIST 1.1 will be used to make tumor measurements. Progressive Disease (PD) = 20% increase in the sum of the longest diameter of target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate | Up to 12 Months | Response according to Response Evaluation in Solid Tumors (RECIST) 1.1. Complete Response (CR): Complete disappearance of all measurable and non-measurable disease; No new lesions. Partial Response (PR): Applies only to patients with at least one measurable lesion; Greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions. Progressive Disease (PD): 20% or greater increase in the sum of longest diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline. Unequivocal progression of non-measurable disease in the opinion of the treating physician (an explanation must be provided). Appearance of any new lesion/site. Stable Disease (SD): Does not qualify for CR, PR, Progression or Symptomatic Deterioration; All target measurable lesions must be assessed using the same techniques as baseline. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at Moffitt Cancer Center between April 2012 and June 2015.
Pre-assignment details
Three participants were enrolled in the Phase I portion of the study, followed by seventy participants enrolled in the Randomized Phase II portion of the study.
Participants by arm
| Arm | Count |
|---|---|
| Phase I Vaccinations Participants enrolled in the Phase I trial will receive GM.CD40L.CCL21 vaccinations on 3 occasions, at 2 week intervals. | 3 |
| Phase II Arm A Vaccinations Arm A participants will receive GM.CD40L cells vaccinations on 3 occasions, at 2 week intervals. | 37 |
| Phase II Arm B Vaccinations Arm B participants will receive GM.CD40L.CCL21 vaccinations on 3 occasions, at 2 week intervals. | 33 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 0 | 2 | 0 |
| Overall Study | Disease Progression | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Phase II Arm A Vaccinations | Phase II Arm B Vaccinations | Phase I Vaccinations | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 21 Participants | 23 Participants | 2 Participants | 46 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 10 Participants | 1 Participants | 27 Participants |
| Age, Continuous | 62 years | 65 years | 68 years | 62 years |
| Region of Enrollment United States | 37 Participants | 33 Participants | 3 Participants | 73 Participants |
| Sex: Female, Male Female | 19 Participants | 19 Participants | 0 Participants | 38 Participants |
| Sex: Female, Male Male | 18 Participants | 14 Participants | 3 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 35 / 37 | 33 / 33 |
| serious Total, serious adverse events | 1 / 3 | 14 / 37 | 7 / 33 |
Outcome results
Primary
Phase II: Progression Free Survival (PFS)
PFS is measured as the time from start of treatment to progression or death. 6 month progression free survival will be estimated from available clinical and radiographic assessments and RECIST 1.1 will be used to make tumor measurements. Progressive Disease (PD) = 20% increase in the sum of the longest diameter of target lesions.
Time frame: Up to 6 Months
Population: A Phase II participants evaluable at time of analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I GM.CD40L.CCL21 Vaccinations | Phase II: Progression Free Survival (PFS) | 2.4 months |
| Phase II Arm B GM.CD40L.CCL21 Vaccinations | Phase II: Progression Free Survival (PFS) | 3.1 months |
Primary
Phase I: Recommend Phase II Dose (RPDII)
Highest dose level of GMCD40L vaccine in combination with CCL21 that induced dose limiting toxicity (DLT) in fewer than 33% of patients. DLT: Intervention-specific acute toxicity; i.e., occurrence within 28 days of drug administration, according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), V 4: 1.) that precludes further dose escalation. Participants are entered in cohorts of 3 at the first dose level. Doses are not escalated over the course of treatment of an individual patient. If 2 or more patients experience toxicity in dose level 1 (30X10\^6 cells per injection), dose de-escalation will occur. Dose level -1 will be defined by 10 % reduction of cells administered from dose level 1 and follow the same rules. It is not feasible to escalate the dose of the vaccine beyond 30X10\^6 cells per injection; therefore the Maximum Tolerated Dose (MTD) may not be reached in this study. In that case, the highest dose level will be used in the phase II component.
Time frame: Up to 6 Months
Population: All Phase I Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I GM.CD40L.CCL21 Vaccinations | Phase I: Recommend Phase II Dose (RPDII) | 1 Recommend Phase II Dose Level |
Secondary
Response Rate
Response according to Response Evaluation in Solid Tumors (RECIST) 1.1. Complete Response (CR): Complete disappearance of all measurable and non-measurable disease; No new lesions. Partial Response (PR): Applies only to patients with at least one measurable lesion; Greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions. Progressive Disease (PD): 20% or greater increase in the sum of longest diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline. Unequivocal progression of non-measurable disease in the opinion of the treating physician (an explanation must be provided). Appearance of any new lesion/site. Stable Disease (SD): Does not qualify for CR, PR, Progression or Symptomatic Deterioration; All target measurable lesions must be assessed using the same techniques as baseline.
Time frame: Up to 12 Months
Population: All Phase II participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I GM.CD40L.CCL21 Vaccinations | Response Rate | Progressive Disease | 19 Participants |
| Phase I GM.CD40L.CCL21 Vaccinations | Response Rate | Complete Response | 0 Participants |
| Phase I GM.CD40L.CCL21 Vaccinations | Response Rate | Stable Disease | 18 Participants |
| Phase I GM.CD40L.CCL21 Vaccinations | Response Rate | Partial Response | 0 Participants |
| Phase II Arm B GM.CD40L.CCL21 Vaccinations | Response Rate | Stable Disease | 12 Participants |
| Phase II Arm B GM.CD40L.CCL21 Vaccinations | Response Rate | Partial Response | 0 Participants |
| Phase II Arm B GM.CD40L.CCL21 Vaccinations | Response Rate | Progressive Disease | 20 Participants |
| Phase II Arm B GM.CD40L.CCL21 Vaccinations | Response Rate | Complete Response | 0 Participants |