Trial of Neoadjuvant and Adjuvant Nivolumab and BMS-813160 With or Without GVAX for Locally Advanced Pancreatic Ductal Adenocarcinomas.

• ClinicalTrials.gov Identifier: NCT03767582
• Recruitment Status: Recruiting
• First Posted: December 6, 2018
• Last Update Posted: February 3, 2023
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Description

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 .

Condition or disease	Intervention/treatment	Phase
Locally Advanced Pancreatic Ductal Adenocarcinoma (PDAC); Pancreatic Ductal Adenocarcinoma	Radiation: Stereotactic Body Radiation (SBRT); Drug: Nivolumab; Drug: CCR2/CCR5 dual antagonist; Drug: GVAX	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Trial of Combination Immunotherapy With Nivolumab and a CCR2/CCR5 Dual Antagonist (BMS-813160) With or Without GVAX Following Chemotherapy and Radiotherapy for Locally Advanced Pancreatic Ductal Adenocarcinomas (PDACs).
• Actual Study Start Date: December 12, 2019
• Estimated Primary Completion Date: December 2023
• Estimated Study Completion Date: December 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase I - GVAX/Nivolumab/CCR2/CCR5 dual antagonist	Radiation: Stereotactic Body Radiation (SBRT); SBRT (6.6 Gy over 5 days) will be administered between 2 to 4 weeks after chemotherapy. (Prior to surgery); Drug: Nivolumab; 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.; Other Name: OPDIVO; Drug: CCR2/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.; Other Name: BMS-813160; Drug: GVAX; 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.; Other Names: PANC 10.05 pcDNA-1/GM-Neo vaccine; PANC 6.03 pcDNA-1/GM-Neo vaccine
Experimental: Phase II - Arm A: Nivolumab/CCR2/CCR5 dual antagonist	Radiation: Stereotactic Body Radiation (SBRT); SBRT (6.6 Gy over 5 days) will be administered between 2 to 4 weeks after chemotherapy. (Prior to surgery); Drug: Nivolumab; 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.; Other Name: OPDIVO; Drug: CCR2/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.; Other Name: BMS-813160
Experimental: Phase II - Arm B: Nivolumab/GVAX/CCR2/CCR5 dual antagonist	Radiation: Stereotactic Body Radiation (SBRT); SBRT (6.6 Gy over 5 days) will be administered between 2 to 4 weeks after chemotherapy. (Prior to surgery); Drug: Nivolumab; 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.; Other Name: OPDIVO; Drug: CCR2/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.; Other Name: BMS-813160; Drug: GVAX; 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.; Other Names: PANC 10.05 pcDNA-1/GM-Neo vaccine; PANC 6.03 pcDNA-1/GM-Neo vaccine

Outcome Measures

Primary Outcome Measures :

1. Number of Participants experiencing study drug-related toxicities [ Time Frame: 3 years ]
   Number of participants who experienced study drug-related toxicities as defined by CTCAE v5.0
2. Percentage of participants treated with immunotherapy who achieve an immune response [ Time Frame: 3 years ]
   Percentage of participants who have >80% increase of infiltration of CD8+CD137+ T cells into the pancreatic ductal adenocarcinoma after treatment with immunotherapy compared to baseline before treatment.

Secondary Outcome Measures :

1. Overall survival (OS) [ Time Frame: 3 years ]
   Number of months from the time of Cycle 1, Day 1 of immunotherapy until death from any cause
2. Metastasis free survival (MFS) [ Time Frame: 3 years ]
   Number of months from the time of Cycle 1, Day 1 of immunotherapy until first documented distant metastases on imaging per RECIST 1.1 or death from any cause, whichever occurs first.
3. Local progression free survival (LPFS) Time [ Time Frame: 3 years ]
   Number of months from the time of Cycle 1, Day 1 of immunotherapy until first documented local progression or relapse from complete response on imaging (using RECIST 1.1 criteria and irRECIST criteria) or death from any cause, whichever occurs first.
4. Surgical Resectability Rate [ Time Frame: 3 years ]
   Number of participants who are able to undergo successful tumor resection (as defined by R0 and R1 resection).
5. Pathological Response Rate [ Time Frame: 3 years ]
   Number of participants who have a pathologic complete response as determined by surgical margins and residual disease.
6. Change in Quality of life score based on EORTC QLQ-C30/Pan26 [ Time Frame: Baseline, 3 years ]
   Change in quality of life from baseline will be evaluated using the European Organization for Research and Treatment of Cancer core questionnaire, pancreatic cancer module (EORTC QLQ-C30/Pan26). The QLQ-C30 includes 30 questions assessing global health status/quality of life, function, and symptoms. The PAN26 module comprises of an additional 26 questions assessing pain, dietary changes, jaundice, altered bowel habit, emotional problems related to pancreatic cancer, and other symptoms (cachexia, indigestion, flatulence, dry mouth, taste changes). The score for each item ranges from 0-100, with a higher score reflecting a better level of functioning, a better quality of life, or a worse level of symptoms.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.
• Patients cannot have had any prior therapy for the locally advanced pancreatic adenocarcinoma.
• 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:

• Have had non-FOLFIRINOX-based chemotherapy for the pancreatic cancer.
• 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.

Contacts and Locations

Contacts

Contact: Trish Brothers, RN; 410-614-3644; GIClinicalTrials@jhmi.edu

Locations

United States, Maryland

Sidney Kimmel Comprehensive Cancer Center; Recruiting

Baltimore, Maryland, United States, 21231

Contact: Trish Brothers, RN 410-614-3644 GIClinicalTrials@jhmi.edu

Sponsors and Collaborators

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Bristol-Myers Squibb

Investigators

• Principal Investigator: Lei Zheng, MD; Johns Hopkins Medical Institution

More Information

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT03767582
• Other Study ID Numbers: J18163; IRB00190660 ( Other Identifier: JHMI IRB )
• First Posted: December 6, 2018
• Last Update Posted: February 3, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:

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

Additional relevant MeSH terms:

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Nivolumab; Vaccines; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action