Locally Advanced Pancreatic Ductal Adenocarcinoma (PDAC), Pancreatic Ductal Adenocarcinoma
Conditions
Keywords
GVAX, Nivolumab, CCR2/CCR5 dual antagonist, Anti-PD-1, Cancer vaccine, Monoclonal antibody, Checkpoint inhibitor, Myeloid modulating agent, Immunotherapy, Neoadjuvant chemotherapy, Stereotactic body radiation therapy, SBRT, Pancreatic cancer, Pancreatic Ductal Adenocarcinoma, PDAC, Locally advanced pancreatic ductal adenocarcinoma, LAPC
Brief summary
The purpose of this study is to evaluate if the combination of nivolumab and a CCR2/CCR5 dual antagonist (BMS-813160) with GVAX is safe in patients with locally advanced pancreatic cancer (LAPC) who have received chemotherapy and radiotherapy, and to see if this combination therapy enhances the infiltration of CD8+CD137+ cells in PDACs .
Interventions
RADIATIONStereotactic Body Radiation (SBRT)
SBRT (6.6 Gy over 5 days) will be administered between 2 to 4 weeks after chemotherapy. (Prior to surgery)
DRUGNivolumab
Nivolumab (480 mg) will be administered IV over 30 minutes, on day 1 of cycle 1 (within 1 to 2 weeks after SBRT prior to surgery). Post - surgery Nivolumab will be given on Day 1 of cycles 2-5. Cycles are 4 weeks long.
DRUGCCR2/CCR5 dual antagonist
CCR2/CCR5 dual antagonist (150 mg capsules) will be administered orally twice a day, on days 1-28 of cycle 1 (within 1 to 2 weeks after SBRT prior to surgery). Post - surgery CCR2/CCR5 dual antagonist will be given daily on cycles 2-5. Cycles are 4 weeks long.
DRUGGVAX
Vaccine (5x10\^8 cells) will be administered on day 2 of cycle 1 (within 1 to 2 weeks after SBRT prior to surgery). Post - surgery GVAX will be given on Day 2 of cycles 2-5. Cycles are 4 weeks long. Six intradermal injections every 4 weeks.
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years. * Patients with histologically- or cytologically-proven, surgically unresectable, locally advanced pancreatic adenocarcinoma. * If the patient does not have a diagnostic biopsy that is adequate for review at our institution, the patient must agree to a research core biopsy to be performed at Johns Hopkins. * If the patient's available imaging is not adequate for review by our institution, the patient must agree to a repeat imaging to be performed at Johns Hopkins. * ECOG performance status 0 or 1 * Life expectancy greater than 3 months. * Able to swallow pills or capsules. * Patient must have adequate organ function defined by the study-specified laboratory tests. * Patients must be eligible to receive FOLFIRINOX-based chemotherapy. * Patients must be willing to be treated with stereotactic body radiation therapy (SBRT) only at Johns Hopkins Hospital. * Patients must be willing to undergo a core biopsy of the pancreatic cancer. * Patients must be willing to undergo a biopsy of the pancreatic cancer if the patient is not deemed a surgical candidate during the pre-surgical evaluation. * Must use acceptable form of birth control while on study. * Ability to understand and willingness to sign a written informed consent document.
Exclusion criteria
* Patients cannot have had any prior therapy for the locally advanced pancreatic adenocarcinoma. * Have received any anti-neoplastic biologics, vaccines or hormonal treatment, including investigational drugs, within 28 days of the first dose of study. * History of past treatment with immunotherapy agents prior to initial enrollment into this study (including, but not limited to: IL-2, interferon, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, anti-CD40, anti-CTLA-4 or anti-CCR2/5 drugs). * Have had prior organ or tissue allograft or allogeneic bone marrow transplantation, including corneal transplants. * Is currently participating or has participated in a study of an investigational agent or using an investigational device for the treatment of cancer. * Current use of immunosuppressive medications within 14 days prior to study medications. * Have received any vaccine within 14 days prior to study medications. * Receiving growth factors including, but not limited to, granulocyte-colony stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days of the first dose of study medication. * History of any autoimmune disease. Patients with thyroid disease will be allowed. * Has a history of (non-infectious) pneumonitis or current pneumonitis. * Has a pulse oximetry \< 92% on room air. * Requires the use of home oxygen. * Patients with uncontrolled intercurrent illness including, but not limited to, myocardial infarction or stroke/transient ischemic attack within the past 6 months, uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * 12-lead electrocardiogram with QRS ≥ 120 msec, except right bundle branch block ; QTcF (QT corrected for heart rate using Fridericia's method) ≥ 480 msec, except right bundle branch block * Has an active infection requiring systemic therapy. * Infection with HIV or hepatitis B or C. * Any concurrent malignancy other than non-melanoma skin cancer, non-invasive bladder cancer, early stage prostate cancer, or carcinoma in situ of the cervix. * Current or recent (within 3 months of study treatment administration) gastrointestinal disease that could impact the absorption of study treatment. * Any gastrointestinal surgery that is likely impact upon the absorption of study treatment. * Inability to tolerate oral medication. * Unable to have blood drawn. * Have had surgery within 28 days of the first dose of study medication. * Prior use of strong/moderate CYP3A4 inhibitors or inducers within 28 days of the first dose of BMS-813160. * Prior use of Class I antiarrhythmics within 28 days of first dose of study medication. * Has ascites requiring medical management. * Presence of duodenal or gastric invasion by the tumor. * Hypersensitivity reaction to any monoclonal antibody. * Known allergy or hypersensitivity to study drugs or any of their components of the study arm that participant is enrolling. * Woman who are pregnant or breastfeeding. * Patient is unwilling or unable to follow the study schedule for any reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Study Drug-related Adverse Events | Up to 18 months | Number of participants who experienced study drug-related toxicities as defined by CTCAE v5.0 |
| Tumor Immune Response (CD8+ CD137+ Tumor Infiltration) | 7 months | Number of participants who had \>80% increase of infiltration of CD8+CD137+ T cells into their tumors after treatment with SBRT and immunotherapy. Baseline biopsies were collected at time of fiducial placement for SBRT (after completion of chemotherapy) and post-treatment tumor was collected at time of surgical resection |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 3 years | Number of months from start of immunotherapy until death from any cause |
| Metastasis Free Survival (MFS) | 3 years | Number of months from the start of immunotherapy until first documented distant metastases on radiographic imaging or death from any cause, whichever occurs first. |
| Local Progression Free Survival (LPFS) | 3 years | Number of months from the start of immunotherapy until first documented local progression on radiographic imaging or death from any cause, whichever occurs first. Local progression is defined as appearance of new lesions in the pancreas or surgical resection bed (for surgically resected patients) or clinically meaningful tumor growth in the primary pancreas tumor (for patients that were not surgically resectable). |
| Surgical Resectability Rate | 7 months | Number of participants who are able to undergo successful tumor resection (as defined by R0 and R1 resection). |
| Pathological Response Rate | 7 months | Number of participants who with a moderate, marked, or complete pathologic response after chemotherapy, SBRT, and one cycle of immunotherapy as determined by surgical margins and residual disease. Tumor response grading Complete response (grade 0): no viable residual cancer cells Marked response (grade 1): single cells or rare small groups of cancer cells Moderate response (grade 2): residual cancer outgrown by fibrosis Poor or no response (grade 3): extensive residual cancer |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAmol Narang, MD
Johns Hopkins Medical Institution
Participant flow
Pre-assignment details
Participants with locally advanced pancreatic cancer (LAPC) were enrolled on the study prior to standard of care chemotherapy and Stereotactic Body Radiation Therapy (SBRT). After completing chemotherapy and SBRT, participants were re-screened to determine if they were eligible to continue on the study and receive study drug.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 61 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Histology Grade at Diagnosis Moderately Differentiated | 2 Participants |
| Histology Grade at Diagnosis Moderate to Poorly Differentiated | 0 Participants |
| Histology Grade at Diagnosis Poorly Differentiated | 7 Participants |
| Histology Grade at Diagnosis Unknown | 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 | 4 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 | 2 Participants |
| Region of Enrollment United States | 22 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 5 / 6 | 4 / 5 | 5 / 5 | 2 / 3 |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 5 / 5 | 5 / 5 | 3 / 3 |
| serious Total, serious adverse events | 1 / 3 | 2 / 6 | 0 / 5 | 2 / 5 | 2 / 3 |
Outcome results
None listed