Pancreatic Cancer
Conditions
Keywords
Pancreas vaccine, immunotherapy, antibody, PD-1, IMC-CS4, Pembrolizumab, GVAX, Borderline Resectable, CY, Cyclophosphamide, Adenocarcinoma, Neoplasms
Brief summary
The purpose of this study is to evaluate whether combining cyclophosphamide (CY), pembrolizumab, GVAX and IMC-CS4 is effective and safe in patients with borderline resectable pancreatic cancer.
Detailed description
This was a single center, open label, pilot study to evaluate the safety and intratumoral immune response of neoadjuvant/adjuvant triplet immunotherapy: CY/GVAX, Pembrolizumab, and IMC-CS4 in patients with resectable or borderline resectable Pancreatic ductal adenocarcinoma. Patients received the combination of CY/GVAX with pembrolizumab and IMC-CS4 following completion of standard neoadjuvant chemotherapy (with or without radiation). Immunotherapy agents were given prior to and after surgical resection. Patients receive neoadjuvant immunotherapy consisting of cyclophosphamide and pembrolizumab on day 1, IMC-CS4 on days 1, 8, and 15, and GVAX on day 2 of Cycles 1 and 2 (3 weeks/cycle). Patients will then undergo pancreaticoduodenectomy 2-3 weeks later, followed by standard of care adjuvant chemotherapy at the discretion of the primary oncologist. Patients may then receive 4 cycles (3 weeks/cycle) of adjuvant immunotherapy (same regimen as Cycles 1 and 2). Disease free patients may receive an additional 12 booster cycles (3 weeks/cycle) of immunotherapy consisting of pembrolizumab on day 1 of all 12 booster cycles, as well as cyclophosphamide on day 1 and GVAX on day 2 of the 6th and 12th booster cycle.
Interventions
DRUGCyclophosphamide
200 mg/m\^2, intravenous (IV) infusion Patients receive neoadjuvant immunotherapy consisting of cyclophosphamide and pembrolizumab on day 1, IMC-CS4 on days 1, 8, and 15, and GVAX on day 2 of Cycles 1 and 2 (3 weeks/cycle). Patients will then undergo pancreaticoduodenectomy 2-3 weeks later, followed by standard of care adjuvant chemotherapy at the discretion of the primary oncologist. Patients may then receive 4 cycles (3 weeks/cycle) of adjuvant immunotherapy (same regimen as Cycles 1 and 2). Disease free patients may receive an additional 12 booster cycles (3 weeks/cycle) of immunotherapy consisting of pembrolizumab on day 1 of all 12 booster cycles, as well as cyclophosphamide on day 1 and GVAX on day 2 of the 6th and 12th booster cycle.
DRUGGVAX Pancreas Vaccine (GVAX)
5x10\^8 cells, six intradermal (ID) injections Patients receive neoadjuvant immunotherapy consisting of cyclophosphamide and pembrolizumab on day 1, IMC-CS4 on days 1, 8, and 15, and GVAX on day 2 of Cycles 1 and 2 (3 weeks/cycle). Patients will then undergo pancreaticoduodenectomy 2-3 weeks later, followed by standard of care adjuvant chemotherapy at the discretion of the primary oncologist. Patients may then receive 4 cycles (3 weeks/cycle) of adjuvant immunotherapy (same regimen as Cycles 1 and 2). Disease free patients may receive an additional 12 booster cycles (3 weeks/cycle) of immunotherapy consisting of pembrolizumab on day 1 of all 12 booster cycles, as well as cyclophosphamide on day 1 and GVAX on day 2 of the 6th and 12th booster cycle.
DRUGPembrolizumab
200 mg, intravenous (IV) infusion Patients receive neoadjuvant immunotherapy consisting of cyclophosphamide and pembrolizumab on day 1, IMC-CS4 on days 1, 8, and 15, and GVAX on day 2 of Cycles 1 and 2 (3 weeks/cycle). Patients will then undergo pancreaticoduodenectomy 2-3 weeks later, followed by standard of care adjuvant chemotherapy at the discretion of the primary oncologist. Patients may then receive 4 cycles (3 weeks/cycle) of adjuvant immunotherapy (same regimen as Cycles 1 and 2). Disease free patients may receive an additional 12 booster cycles (3 weeks/cycle) of immunotherapy consisting of pembrolizumab on day 1 of all 12 booster cycles, as well as cyclophosphamide on day 1 and GVAX on day 2 of the 6th and 12th booster cycle.
DRUGIMC-CS4
75 mg (dose level 1) or 100 mg (dose level 2), intravenous (IV) infusion Patients receive neoadjuvant immunotherapy consisting of cyclophosphamide and pembrolizumab on day 1, IMC-CS4 on days 1, 8, and 15, and GVAX on day 2 of Cycles 1 and 2 (3 weeks/cycle). Patients will then undergo pancreaticoduodenectomy 2-3 weeks later, followed by standard of care adjuvant chemotherapy at the discretion of the primary oncologist. Patients may then receive 4 cycles (3 weeks/cycle) of adjuvant immunotherapy (same regimen as Cycles 1 and 2). Disease free patients may receive an additional 12 booster cycles (3 weeks/cycle) of immunotherapy consisting of pembrolizumab on day 1 of all 12 booster cycles, as well as cyclophosphamide on day 1 and GVAX on day 2 of the 6th and 12th booster cycle.
Sponsors
Merck Sharp & Dohme LLC
Eli Lilly and Company
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
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
* Have histologically or cytologically proven adenocarcinoma of the pancreas. * Patient's acceptance to have a core biopsy. * Presence of at least one measurable lesion. * Must not have metastatic disease. * Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>20 mm with conventional techniques or as \>10 mm with spiral CT scan. See Section 10.1.2 for the evaluation of measurable disease. * Must have received last dose of stereotactic body radiotherapy no longer than 28 days prior to enrollment. * Must have received last dose of chemotherapy at least 14 days or longer prior to entry into the study. * Age \>18 years. * ECOG performance status 0-1. * Patient's blood, kidney and liver function must within normal limits * Must use an acceptable form of birth control while on study. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Currently is participating or has participated in a study using any investigational therapy within the past 28 days or is currently using an investigational device. * Major surgery 28 days prior to study entry excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, and biliary stent placement. * Used any systemic steroids, immunosuppressant medications and anti-neoplastic treatment in the past 14 days. * Prior treatment with immunotherapy agents (including, but not limited to: IL-2, interferon, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, anti-CD40, or anti-CTLA-4 antibodies). * Used any growth factors including, but not limited to, granulocyte-colony stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days of study drug administration. Use of such agents while on study is also prohibited. * Received any prophylactic vaccine within 14 days of first dose of study drug or received a live vaccine within 30 days of study treatment. * Currently have or have history of certain study-specified heart, liver, kidney, lung, neurological, psychological, immune or other medical conditions. * History of any autoimmune disease: inflammatory bowel disease, (including ulcerative colitis and Crohn's Disease), rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus (SLE) autoimmune vasculitis (e.g., Wegener's Granulomatosis), CNS or motor neuropathy considered to be of autoimmune origin (e.g., Guillian-Barre Syndrome, Myasthenia Gravis, Multiple Sclerosis). Patients with thyroid disease will be allowed. * Has history of (non-infectious) pneumonitis that required steroids, history or evidence of interstitial lung disease or active, non-infectious pneumonitis. * Has a pulse oximetry \< 92% on room air. * Evidence of ascites on imaging. * Requires the use of home oxygen. * Have known history of infection with HIV, hepatitis B, or hepatitis C. * Have been diagnosed with another cancer in the past 5 years (except for superficial bladder cancer, non-melanoma skin cancers, or a low grade prostate cancer not requiring therapy) * History of severe hypersensitivity reaction to any monoclonal antibody. * Known or suspected hypersensitivity to GM-CSF, hetastarch, corn, dimethyl sulfoxide, fetal bovine serum, trypsin (porcine origin), yeast or any other component of GVAX pancreas vaccine. * Pregnant or breastfeeding women. * Positive pregnancy test during the study. * Women sexually active with a fertile man and of childbearing potential unwilling or unable to use an acceptable method to avoid pregnancy for the entire study and for up to 120 days after the last dose of study drug. * Unwilling or unable to follow the study schedule for any reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With a Treatment-related Immunologic Effect | 8 weeks | Treatment-related immunologic effect is defined as an 80% or greater increase in the number of CD8+ T cells (and at least 1.8 times the baseline median absolute deviation) in surgically resected tumor tissue in comparison to the baseline biopsy in subjects that received at least 1 dose of neoadjuvant combination immunotherapy and underwent a R0, R1, or R2 surgical resection. |
| Safety of the Combination of GVAX Pancreas Vaccine (With CY), Pembrolizumab, and a Macrophage Targeting Agent (CSF1R Inhibitor IMC-CS4) in Patients With Resectable or Borderline Resectable Pancreatic Cancer (BRPC) Prior to and Following Surgery | 25 months | Number of subjects that experienced a grade 3 or higher study drug related adverse event |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immune-related Objective Response Rate (irORR) | Up to 10 weeks from baseline irRC read | Immune-related Objective Response Rate (irORR) is defined as the number of patients achieving a complete response (irCR) or partial response (irPR) based on immune related response criteria (irRC) following the study immunotherapy prior to surgical resection. Per irRC criteria, Complete Response (irCR) is the disappearance of all target lesions, Partial Response (irPR) is a decrease in tumor burden by 50% or greater. |
| Overall Survival (OS) | 44 months | OS will be measured from date of first dose until death or end of follow-up (OS will be censored on the date the subject was last known to be alive for subjects without documentation of death at the time of analysis). Estimation based on the Kaplan-Meier curve. |
| Pathologic Response Rate | 8 weeks | Pathologic response as determined by surgical margins status at the time of surgery and response to neoadjuvant treatment per surgical specimen assessment (participants with \<10% residual viable tumor is reported). |
| Surgical Resectability Rate | 8 weeks | Surgical resectability after neoadjuvant therapy as determined by the number of patients able to undergo surgical resection. |
| Disease Free Survival (DFS) | 37 months | DFS is defined as time from fist dose of study drug to the date of progression or death. Subjects were censored at the date of last scan if alive at the time of analyses or if the subject's date of death was greater than 3 months after last scan. Estimation based on the Kaplan-Meier curve. |
Countries
United States
Participant flow
Pre-assignment details
2 participants were excluded from analysis because they did not receive the study drug.
Participants by arm
| Arm | Count |
|---|---|
| Cyclophosphamide, GVAX, Pembrolizumab and IMC-CS4 Cyclophosphamide: 200 mg/m\^2, intravenous (IV) infusion GVAX: 5x10\^8 cells, six intradermal (ID) injections Pembrolizumab: 200 mg, intravenous (IV) infusion IMC-CS4: 75 mg (dose level 1) or 100 mg (dose level 2), intravenous (IV) infusion
Patients receive neoadjuvant immunotherapy consisting of cyclophosphamide and pembrolizumab on day 1, IMC-CS4 on days 1, 8, and 15, and GVAX on day 2 of Cycles 1 and 2 (3 weeks/cycle). Patients will then undergo pancreaticoduodenectomy 2-3 weeks later, followed by standard of care adjuvant chemotherapy at the discretion of the primary oncologist. Patients may then receive 4 cycles (3 weeks/cycle) of adjuvant immunotherapy (same regimen as Cycles 1 and 2). Disease free patients may receive an additional 12 booster cycles (3 weeks/cycle) of immunotherapy consisting of pembrolizumab on day 1 of all 12 booster cycles, as well as cyclophosphamide on day 1 and GVAX on day 2 of the 6th and 12th booster cycle. | 9 |
| Total | 9 |
Baseline characteristics
| Characteristic | Cyclophosphamide, GVAX, Pembrolizumab and IMC-CS4 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 1 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment United States | 9 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 9 |
| other Total, other adverse events | 9 / 9 |
| serious Total, serious adverse events | 5 / 9 |
Outcome results
Primary
Number of Patients With a Treatment-related Immunologic Effect
Treatment-related immunologic effect is defined as an 80% or greater increase in the number of CD8+ T cells (and at least 1.8 times the baseline median absolute deviation) in surgically resected tumor tissue in comparison to the baseline biopsy in subjects that received at least 1 dose of neoadjuvant combination immunotherapy and underwent a R0, R1, or R2 surgical resection.
Time frame: 8 weeks
Population: 8/9 patients were included in the analysis because obtaining pre-treatment biopsy was not possible in one patient.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cyclophosphamide, GVAX, Pembrolizumab and IMC-CS4 | Number of Patients With a Treatment-related Immunologic Effect | 6 Participants |
Primary
Safety of the Combination of GVAX Pancreas Vaccine (With CY), Pembrolizumab, and a Macrophage Targeting Agent (CSF1R Inhibitor IMC-CS4) in Patients With Resectable or Borderline Resectable Pancreatic Cancer (BRPC) Prior to and Following Surgery
Number of subjects that experienced a grade 3 or higher study drug related adverse event
Time frame: 25 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cyclophosphamide, GVAX, Pembrolizumab and IMC-CS4 | Safety of the Combination of GVAX Pancreas Vaccine (With CY), Pembrolizumab, and a Macrophage Targeting Agent (CSF1R Inhibitor IMC-CS4) in Patients With Resectable or Borderline Resectable Pancreatic Cancer (BRPC) Prior to and Following Surgery | 2 Participants |
Secondary
Disease Free Survival (DFS)
DFS is defined as time from fist dose of study drug to the date of progression or death. Subjects were censored at the date of last scan if alive at the time of analyses or if the subject's date of death was greater than 3 months after last scan. Estimation based on the Kaplan-Meier curve.
Time frame: 37 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cyclophosphamide, GVAX, Pembrolizumab and IMC-CS4 | Disease Free Survival (DFS) | 12.6 months |
Secondary
Immune-related Objective Response Rate (irORR)
Immune-related Objective Response Rate (irORR) is defined as the number of patients achieving a complete response (irCR) or partial response (irPR) based on immune related response criteria (irRC) following the study immunotherapy prior to surgical resection. Per irRC criteria, Complete Response (irCR) is the disappearance of all target lesions, Partial Response (irPR) is a decrease in tumor burden by 50% or greater.
Time frame: Up to 10 weeks from baseline irRC read
Population: 7/9 patients were evaluable for assessment by irRC criteria
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cyclophosphamide, GVAX, Pembrolizumab and IMC-CS4 | Immune-related Objective Response Rate (irORR) | 0 Participants |
Secondary
Overall Survival (OS)
OS will be measured from date of first dose until death or end of follow-up (OS will be censored on the date the subject was last known to be alive for subjects without documentation of death at the time of analysis). Estimation based on the Kaplan-Meier curve.
Time frame: 44 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cyclophosphamide, GVAX, Pembrolizumab and IMC-CS4 | Overall Survival (OS) | 20.4 months |
Secondary
Pathologic Response Rate
Pathologic response as determined by surgical margins status at the time of surgery and response to neoadjuvant treatment per surgical specimen assessment (participants with \<10% residual viable tumor is reported).
Time frame: 8 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cyclophosphamide, GVAX, Pembrolizumab and IMC-CS4 | Pathologic Response Rate | 7 Participants |
Secondary
Surgical Resectability Rate
Surgical resectability after neoadjuvant therapy as determined by the number of patients able to undergo surgical resection.
Time frame: 8 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cyclophosphamide, GVAX, Pembrolizumab and IMC-CS4 | Surgical Resectability Rate | 9 Participants |