A Phase I/II Study to Evaluate the Tolerability and Efficacy of BMS-813160 (CCR2/5 Inhibitor) With Nivolumab and Gemcitabine and Nab-paclitaxel in Borderline Resectable and Locally Advanced Pancreatic Ductal Adenocarcinoma (PDAC)
Overview
- Phase
- Phase 1
- Intervention
- BMS-813160
- Conditions
- Pancreatic Ductal Adenocarcinoma
- Sponsor
- Washington University School of Medicine
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- (Part A Experimental Dose Level 0 Only) Safety of the Combination of BMS-813160 Plus Nivolumab Plus Gemcitabine Plus Nab-paclitaxel as Measured by Frequency, Type, and Severity of Adverse Events
- Status
- Completed
- Last Updated
- 9 months ago
Overview
Brief Summary
The purpose of this research study is to learn more about a new combination of drugs being given to treat pancreatic cancer. The drugs being tested are BMS-813160, nivolumab, gemcitabine, and nab-paclitaxel. The investigators will be looking at both the side effects and the way the disease responds to treatment.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically or cytologically confirmed locally advanced or borderline resectable pancreatic ductal adenocarcinoma. Patients with clinical suspicion of pancreatic adenocarcinoma can be enrolled for pre-treatment biopsy, and must be histologically confirmed to have adenocarcinoma before being treated on study. Patients with squamous carcinoma, adenosquamous carcinoma or neuroendocrine tumor will be excluded. Tumor Biopsy can be omitted, if deemed by PI and treatment physician, that it may incur immediate, excessive health risks to patients. This determination (rationale and discussion with PI and treating physician) should be clearly documented in the screening visit notes.
- •Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan or MRI.
- •At least 18 years of age.
- •ECOG performance status ≤ 1
- •Normal bone marrow and organ function as defined below:
- •Leukocytes ≥ 2,000/mcL
- •Absolute neutrophil count ≥ 1,500/mcl
- •Hemoglobin ≥ 8.5 g/dL
- •Platelets ≥ 100,000/mcl
- •Total bilirubin ≤ 1.5 x IULN (except participants with Gilbert's Syndrome who must have normal direct bilirubin)
Exclusion Criteria
- •Prior exposure to chemotherapy or radiation for the disease to be treated on this trial not allowed.
- •Previous malignancies (except non-melanoma skin cancers, and in situ bladder, gastric, colorectal, endometrial, cervical/dysplasia, melanoma, or breast cancers) unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period. Other active malignancy requiring concurrent intervention
- •Currently receiving any other investigational agents, or exposure to any investigational drug or placebo within 4 weeks of study treatment
- •A history of allergic reactions attributed to compounds of similar chemical or biologic composition to BMS-813160, nivolumab, gemcitabine, paclitaxel, nab-paclitaxel, or other agents used in the study.
- •Prior exposure to anti-PD-1, anti-PD-L1, CCR2/5, or anti-CTLA4 antibodies.
- •Taking immunomodulatory agents (including steroids and NSAIDs). A wash-out period of at least 4 weeks or 5 half-lives, whichever is shorter, is required for patients receiving immunomodulatory agents at the time of enrollment.
- •Note: daily use of low dose aspirin (e.g. 81 mg PO QD) is not considered an immunomodulatory agent and patients are still eligible for enrollment despite taking such medication at a low dose
- •Participants with active, known or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, euthyroid participants with a history of Grave's disease (participants with suspected autoimmune thyroid disorders must be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid stimulating immunoglobulin prior to first dose of study treatment), psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll after discussing with the Principal Investigator
- •Participants with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of study treatment except for adrenal replacement steroid doses \> 10 mg daily prednisone equivalent in the absence of active autoimmune disease. Note: treatment with a short course of steroids (\< 5 days) up to 7 days prior to initiating study treatment is permitted.
- •History of allogeneic organ or stem cell transplant.
Arms & Interventions
Part A - Experimental Dose Level 0
* BMS-813160 300 mg twice per day * Nivolumab 30-minute intravenous (IV) infusion at a flat dose of 480 mg on Day 1 of each 28-day cycle * Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Post-treatment biopsy at the end of cycle 2 * Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cyclesore cycles
Intervention: BMS-813160
Part A - Experimental Dose Level 0
* BMS-813160 300 mg twice per day * Nivolumab 30-minute intravenous (IV) infusion at a flat dose of 480 mg on Day 1 of each 28-day cycle * Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Post-treatment biopsy at the end of cycle 2 * Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cyclesore cycles
Intervention: Nivolumab
Part A - Experimental Dose Level 0
* BMS-813160 300 mg twice per day * Nivolumab 30-minute intravenous (IV) infusion at a flat dose of 480 mg on Day 1 of each 28-day cycle * Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Post-treatment biopsy at the end of cycle 2 * Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cyclesore cycles
Intervention: Gemcitabine
Part A - Experimental Dose Level 0
* BMS-813160 300 mg twice per day * Nivolumab 30-minute intravenous (IV) infusion at a flat dose of 480 mg on Day 1 of each 28-day cycle * Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Post-treatment biopsy at the end of cycle 2 * Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cyclesore cycles
Intervention: Nab-paclitaxel
Part A - Experimental Dose Level 0
* BMS-813160 300 mg twice per day * Nivolumab 30-minute intravenous (IV) infusion at a flat dose of 480 mg on Day 1 of each 28-day cycle * Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Post-treatment biopsy at the end of cycle 2 * Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cyclesore cycles
Intervention: Biopsy
Part A - Experimental Dose Level 0
* BMS-813160 300 mg twice per day * Nivolumab 30-minute intravenous (IV) infusion at a flat dose of 480 mg on Day 1 of each 28-day cycle * Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Post-treatment biopsy at the end of cycle 2 * Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cyclesore cycles
Intervention: Peripheral blood
Part A - Control (chemotherapy only)
* Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Post treatment biopsy at the end of cycle 2 * Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cycles
Intervention: Gemcitabine
Part A - Control (chemotherapy only)
* Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Post treatment biopsy at the end of cycle 2 * Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cycles
Intervention: Nab-paclitaxel
Part A - Control (chemotherapy only)
* Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Post treatment biopsy at the end of cycle 2 * Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cycles
Intervention: Biopsy
Part A - Control (chemotherapy only)
* Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Post treatment biopsy at the end of cycle 2 * Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cycles
Intervention: Peripheral blood
Part B - Dose expansion
* BMS-813160 300 mg twice per day * Nivolumab 30-minute IV infusion at a flat dose of 480 mg on Day 1 of each 28-day cycle * Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Post-treatment biopsy at the end of cycle 2 * Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cycles
Intervention: BMS-813160
Part B - Dose expansion
* BMS-813160 300 mg twice per day * Nivolumab 30-minute IV infusion at a flat dose of 480 mg on Day 1 of each 28-day cycle * Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Post-treatment biopsy at the end of cycle 2 * Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cycles
Intervention: Nivolumab
Part B - Dose expansion
* BMS-813160 300 mg twice per day * Nivolumab 30-minute IV infusion at a flat dose of 480 mg on Day 1 of each 28-day cycle * Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Post-treatment biopsy at the end of cycle 2 * Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cycles
Intervention: Gemcitabine
Part B - Dose expansion
* BMS-813160 300 mg twice per day * Nivolumab 30-minute IV infusion at a flat dose of 480 mg on Day 1 of each 28-day cycle * Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Post-treatment biopsy at the end of cycle 2 * Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cycles
Intervention: Nab-paclitaxel
Part B - Dose expansion
* BMS-813160 300 mg twice per day * Nivolumab 30-minute IV infusion at a flat dose of 480 mg on Day 1 of each 28-day cycle * Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Post-treatment biopsy at the end of cycle 2 * Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cycles
Intervention: Biopsy
Part B - Dose expansion
* BMS-813160 300 mg twice per day * Nivolumab 30-minute IV infusion at a flat dose of 480 mg on Day 1 of each 28-day cycle * Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle * Post-treatment biopsy at the end of cycle 2 * Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cycles
Intervention: Peripheral blood
Outcomes
Primary Outcomes
(Part A Experimental Dose Level 0 Only) Safety of the Combination of BMS-813160 Plus Nivolumab Plus Gemcitabine Plus Nab-paclitaxel as Measured by Frequency, Type, and Severity of Adverse Events
Time Frame: Through 100 days after completion of treatment (approximately 7.5 months)
-The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.
(Part B and Part A Experimental Dose Level 0 Only): Objective Response Rate
Time Frame: Through completion of treatment (approximately 4 months)
* Objective response rate (ORR) is defined as number of participants with complete response or partial response. * Complete Response (CR): Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Normalization of tumor marker level. * Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Secondary Outcomes
- (Part B and Part A Experimental Dose Level 0 Only): Percentage of Patients Whose Disease Becomes Resectable After Treatment(Completion of treatment (approximately 4 months))
- (Part B and Part A Experimental Dose Level 0 Only): Progression-free Survival (PFS)(Through completion of follow-up (median length of follow-up 12.15 months, full range 0.43-44.10 months))
- (Part B and Part A Experimental Dose Level 0 Only): Overall Survival (OS)(Through completion of follow-up (median length of follow-up 17.63 months, full range 0.43-64.47 months))