Metastatic Pancreatic Adenocarcinoma, Recurrent Pancreatic Carcinoma, Stage III Pancreatic Cancer, Stage IV Pancreatic Cancer
Conditions
Brief summary
This phase Ib/II trial studies the side effects and best dose of bispecific antibody armed activated T-cells when given together with aldesleukin and sargramostim and to see how well they work in treating patients with pancreatic cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced) or other places in the body (metastatic). Bispecific antibody armed activated T-cells are the patient's own T cells that are coated with a bispecific antibody comprising 2 antibodies chemically joined together. These antibodies have specific targets and binding properties that may give the T cells a greater ability to seek out, attach to, and kill more cancer cells.
Detailed description
PRIMARY OBJECTIVES: I. Confirm in a single dose phase I (3 to 6 patients \[pts\]) that 8 infusions of 10\^10 epidermal growth factor receptor (EGFR) bispecific antibody armed activated T cells (BATs) given twice per week in combination with interleukin (IL)-2 (aldesleukin) (300,000 IU/m\^2/day) and granulocyte-macrophage colony stimulating factor (GM-CSF) (sargramostim) (250 ug/m\^2/twice weekly) beginning 3 days before the 1st infusion and ending on the day of the last infusion is safe. II. Perform a phase II clinical trial to estimate the clinical efficacy of 8 infusions of 10\^10 EGFR BATs in combination with IL-2 and GM-CSF in 39 evaluable pts (including the 3-6 pts in the single dose phase I). SECONDARY OBJECTIVES: I. Determine if infusions of EGFR BATs significantly increase cellular or humoral anti-pancreatic cancer (PC) responses by peripheral blood mononuclear cells (PBMC) at different time points after last EGFR BATs infusion and if those responses persist beyond 2 months (mos). II. Obtain original tumor paraffin blocks prior to treatment and evaluate blocks for cluster of differentiation (CD)3, CD4, CD8, programmed cell death (PD)1/programmed cell death ligand (PDL)1, monocytes subpopulations, myeloid-derived suppressor cells (MDSC), and cytoplasmic interferon (IFN)-gamma and IL-10 by immunohistochemical staining to quantitate type and number of tumor infiltrating lymphocytes (TILs) in the tumor microenvironment to estimate whether the type and number correlate with clinical responses. III. To determine the time to progression (TTP). OUTLINE: This is a phase Ib, dose-escalation study of anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells followed by a phase II study. Patients receive one of the following standard chemotherapy regimens at the discretion of the treating physician: gemcitabine hydrochloride intravenously (IV) over 30 minutes; gemcitabine hydrochloride IV over 30 minutes and paclitaxel albumin-stabilized nanoparticle formulation IV over 30-40 minutes; oxaliplatin IV over 2 hours, fluorouracil IV over 46 hours and leucovorin calcium IV over 2 hours; or fluorouracil IV over 46 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV, and oxaliplatin IV over 2 hours. Approximately 2 weeks after standard chemotherapy completion, patients receive anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells IV over 5-30 minutes twice weekly for 4 weeks. Patients also receive aldesleukin subcutaneously (SC) and sargramostim SC on day -3 before the first anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells infusion and continuing twice weekly until the final infusion. After completion of study treatment, patients are followed up for 18 months.
Interventions
BIOLOGICALAldesleukin
Given SC
BIOLOGICALAntibody Therapy
Given anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells IV
DRUGFluorouracil
Given IV
DRUGGemcitabine Hydrochloride
Given IV
DRUGIrinotecan Hydrochloride
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGLeucovorin Calcium
Given IV
DRUGOxaliplatin
Given IV
DRUGPaclitaxel Albumin-Stabilized Nanoparticle Formulation
Given IV
BIOLOGICALSargramostim
Given SC
Sponsors
National Cancer Institute (NCI)
Barbara Ann Karmanos Cancer 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
* Histological or cytological proof of pancreatic adenocarcinoma; must have locally advanced or metastatic pancreatic cancer who have received at least first line chemotherapy and may have responding, stable or progressive disease * Expected survival \>= 3 months * Karnofsky performance scale (KPS) \>= 70% or Southwestern Oncology Group (SWOG) performance status 0 or 1 * Absolute neutrophil count (ANC) \>= 1,000/mm\^3 * Lymphocyte count \>= 400/mm\^3 * Platelet count \>= 75,000/mm\^3 * Hemoglobin \>= 8 g/dL * Serum creatinine \< 2.0 mg/dl, creatinine clearance \>= 50 ml/mm (can be calculated or measured) * Total bilirubin =\< 2 mg/dl (biliary stent is allowed) * Serum glutamate pyruvate transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) \< 5.0 times normal * Left ventricular ejection fraction (LVEF) \>= 45% at rest (multigated acquisition scan \[MUGA\] or echocardiogram \[Echo\]) * Females of childbearing potential, and males, must be willing to use an effective method of contraception * Females of childbearing potential must have a negative pregnancy test within 7 days of being registered for protocol therapy
Exclusion criteria
* Any chemotherapy related toxicities from prior treatment (\> grade 2 per Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\]4.0) * Known hypersensitivity to cetuximab or other EGFR antibody * Treatment with any investigational agent within 14 days prior to being registered for protocol therapy * Symptomatic brain metastasis * Chronic treatment with systemic steroids or another immuno-suppressive agent * Serious non-healing wound, ulcer, bone fracture, major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to being registered for protocol therapy * Active liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis * Known human immunodeficiency virus (HIV) infection * Active bleeding or a pathological condition that is associated with a high risk of bleeding (therapeutic anticoagulation is allowed) * Has an active infection requiring systemic therapy * A serious uncontrolled medical disorder that in the opinion of the investigator may be jeopardized by the treatment with protocol therapy * Females must not be breastfeeding * Patient (Pt) may be excluded if, in the opinion of the principal investigator (PI) and investigator team, the pt is not capable of being compliant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Overall Survival (OS) | Up to 18 months | Descriptive statistics (point and exact 90% confidence interval estimates from the resultant Kaplan-Meier curve) will be generated for OS. The median OS will be estimated on an intention-to-treat basis (using all registered patients), and on a response-evaluable basis (using all patients who completed all BAT infusions) using the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Biomarker Analysis (Including CD3, CD4, CD8, PD1, PDL1, Monocytes, MDSC, IFN-gamma, IL-10, and TILs) Assessed Using Immunohistochemistry | Up to 18 months | Each biomarker and computed biomarker will be evaluated for normality and transformed (including non-parametric) if necessary to achieve normality. Summary statistics (including means, medians, and standard deviations) will be produced for each variable and subsequently associate each variable with OS using Cox regression. In addition, a threshold for each variable associating with OS will be defined using classification and regression trees. The tumor will be stained for inflammatory biomarkers. Specifically, T cells with undergo cytoplasmic staining for IFN and IL-10 and the level and ratio of these markers will be evaluated. |
| Incidence of Toxicity (CTCAE Version 4.0) | Up to 18 months | Toxicity rates will be estimated using all treated patients. |
| Progression Free Survival (PFS) | Up to 18 months | Descriptive statistics (point and exact 90% confidence interval estimates from the resultant Kaplan-Meier curve) will be generated for PFS. The median PFS will be estimated on an intention-to-treat basis (using all registered patients), and on a response-evaluable basis (using all patients who completed all BAT infusions) using the Kaplan-Meier method. |
| Quantitative Immune Response | Up to 18 months | For the quantitative immune response variables, summary statistics (including means, medians, and standard deviations) will be produced pre- and post-BATs treatment. Subsequent analyses will compare the immune response variables (after a suitable transformation, if necessary) pre- and post-treatment using a paired t-test (or Wilcoxon sign ranked test if the data are not approximately normally distributed). To explore whether immune responses associate with clinical responses, the association between the baseline of each biomarker and clinical endpoints (such as response, or OS) will be analyze |
| TTP | Up to 18 months | To explore whether immune responses associate with clinical responses, the association between the baseline of each biomarker and clinical endpoints (such as response, or OS) will be analyzed using logistic regression for binary endpoints and Cox regression for time to event endpoints. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Anti-CD3 x Anti-EGFR BATs) Patients receive one of the following standard chemotherapy regimens at the discretion of the treating physician: gemcitabine hydrochloride IV over 30 minutes; gemcitabine hydrochloride IV over 30 minutes and paclitaxel albumin-stabilized nanoparticle formulation IV over 30-40 minutes; oxaliplatin IV over 2 hours, fluorouracil IV over 46 hours and leucovorin calcium IV over 2 hours; or fluorouracil IV over 46 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV, and oxaliplatin IV over 2 hours. Approximately 2 weeks after standard chemotherapy completion, patients receive anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells IV over 5-30 minutes twice weekly for 4 weeks. Patients also receive aldesleukin SC and sargramostim SC on day -3 before the first anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells infusion and continuing twice weekly until the final infusion.
Aldesleukin: Given SC
Antibody Therapy: Given anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells IV
Fluorouracil: Given IV
Gemcitabine Hydrochloride: Given IV
Irinotecan Hydrochloride: Given IV
Laboratory Biomarker Analysis: Correlative studies
Leucovorin Calcium: Given IV
Oxaliplatin: Given IV
Paclitaxel Albumin-Stabilized Nanoparticle Formulation: Given IV
Sargramostim: Given SC | 2 |
| Total | 2 |
Baseline characteristics
| Characteristic | Treatment (Anti-CD3 x Anti-EGFR BATs) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 63 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 2 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 2 |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 0 / 2 |
Outcome results
Primary
Median Overall Survival (OS)
Descriptive statistics (point and exact 90% confidence interval estimates from the resultant Kaplan-Meier curve) will be generated for OS. The median OS will be estimated on an intention-to-treat basis (using all registered patients), and on a response-evaluable basis (using all patients who completed all BAT infusions) using the Kaplan-Meier method.
Time frame: Up to 18 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Median Overall Survival (OS) | 0.934 years |
Secondary
Biomarker Analysis (Including CD3, CD4, CD8, PD1, PDL1, Monocytes, MDSC, IFN-gamma, IL-10, and TILs) Assessed Using Immunohistochemistry
Each biomarker and computed biomarker will be evaluated for normality and transformed (including non-parametric) if necessary to achieve normality. Summary statistics (including means, medians, and standard deviations) will be produced for each variable and subsequently associate each variable with OS using Cox regression. In addition, a threshold for each variable associating with OS will be defined using classification and regression trees. The tumor will be stained for inflammatory biomarkers. Specifically, T cells with undergo cytoplasmic staining for IFN and IL-10 and the level and ratio of these markers will be evaluated.
Time frame: Up to 18 months
Population: Analysis cannot be performed since data were not collected
Secondary
Incidence of Toxicity (CTCAE Version 4.0)
Toxicity rates will be estimated using all treated patients.
Time frame: Up to 18 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Incidence of Toxicity (CTCAE Version 4.0) | Anxiety | 1 Participants |
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Incidence of Toxicity (CTCAE Version 4.0) | Chills | 2 Participants |
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Incidence of Toxicity (CTCAE Version 4.0) | Depression | 1 Participants |
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Incidence of Toxicity (CTCAE Version 4.0) | Diarrhea | 2 Participants |
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Incidence of Toxicity (CTCAE Version 4.0) | Dizziness | 1 Participants |
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Incidence of Toxicity (CTCAE Version 4.0) | Dry Mouth | 1 Participants |
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Incidence of Toxicity (CTCAE Version 4.0) | Fatigue | 2 Participants |
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Incidence of Toxicity (CTCAE Version 4.0) | Fever | 2 Participants |
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Incidence of Toxicity (CTCAE Version 4.0) | Gastroesophageal reflux disease | 1 Participants |
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Incidence of Toxicity (CTCAE Version 4.0) | Headache | 2 Participants |
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Incidence of Toxicity (CTCAE Version 4.0) | Myalgia | 1 Participants |
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Incidence of Toxicity (CTCAE Version 4.0) | Nausea | 2 Participants |
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Incidence of Toxicity (CTCAE Version 4.0) | Rash maculo-papular | 2 Participants |
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Incidence of Toxicity (CTCAE Version 4.0) | Vomiting | 1 Participants |
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Incidence of Toxicity (CTCAE Version 4.0) | Anorexia | 1 Participants |
Secondary
Progression Free Survival (PFS)
Descriptive statistics (point and exact 90% confidence interval estimates from the resultant Kaplan-Meier curve) will be generated for PFS. The median PFS will be estimated on an intention-to-treat basis (using all registered patients), and on a response-evaluable basis (using all patients who completed all BAT infusions) using the Kaplan-Meier method.
Time frame: Up to 18 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Anti-CD3 x Anti-EGFR BATs) | Progression Free Survival (PFS) | 0.934 Years |
Secondary
Quantitative Immune Response
For the quantitative immune response variables, summary statistics (including means, medians, and standard deviations) will be produced pre- and post-BATs treatment. Subsequent analyses will compare the immune response variables (after a suitable transformation, if necessary) pre- and post-treatment using a paired t-test (or Wilcoxon sign ranked test if the data are not approximately normally distributed). To explore whether immune responses associate with clinical responses, the association between the baseline of each biomarker and clinical endpoints (such as response, or OS) will be analyze
Time frame: Up to 18 months
Population: Analysis cannot be performed since data were not collected
Secondary
TTP
To explore whether immune responses associate with clinical responses, the association between the baseline of each biomarker and clinical endpoints (such as response, or OS) will be analyzed using logistic regression for binary endpoints and Cox regression for time to event endpoints.
Time frame: Up to 18 months
Population: Analysis cannot be performed since data were not collected