BMS-813160 With Nivolumab and Gemcitabine and Nab-paclitaxel in Borderline Resectable and Locally Advanced Pancreatic Ductal Adenocarcinoma (PDAC)

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Drug: BMS-813160
* Drug: Nivolumab
* Drug: Gemcitabine
* Drug: Nab-paclitaxel
* Procedure: Biopsy
* Procedure: Peripheral blood


Participation Criteria
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Eligibility Criteria
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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) AST(SGOT)/ALT(SGPT) ≤ 3 x IULN Serum albumin ≥ 3g/dL Creatinine ≤ 1.5 x IULN OR creatinine clearance ≥ 40 mL/min by Cockcroft-Gault for patients with creatinine levels above institutional normal Women of childbearing potential and men must agree to use at least two forms of contraception (hormonal, barrier method of birth control, abstinence, and must include barrier method) prior to study entry, for the duration of study participation, and through 5 months (for women) or 7 months (for men) after the last dose of treatment on this study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Able to understand and willing to sign an IRB approved written informed consent document. All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to Grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v5.0) or baseline before administration of study treatment. Participants with toxicities attributed to prior anti-cancer therapy that are not expected to resolve and result in long lasting sequelae, such as neuropathy after platinum-based therapy, are permitted to enroll. 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. Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry and again within 24 hours prior to first treatment. Known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (by PCR). Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. Anti-retroviral agents are known to have potential adverse pharmacokinetic interactions with nivolumab and/or BMS-813160. IN addition, patients not on anti-retroviral agents, regardless of HIV viral load, are at increased risk of lethal infections with marrow-suppressive therapy including chemotherapy. Testing for HIV must be performed at sites mandated by local requirements. Requires continued use of warfarin for anticoagulation and cannot stop warfarin or be safely switched to another anticoagulant. Current or recent (within 3 months of study treatment administration) gastrointestinal disease or conditions that could interfere with the swallowing or absorption of study medication or inability to tolerate oral medication. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral anti-bacterial, anti-viral, or anti-fungal therapy ≤ 7 days prior to administration of study medication; immunosuppression; autoimmune conditions; underlying pulmonary disease; or psychiatric illness/social situations that would limit compliance with study requirements. Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected treatment-related pulmonary toxicity. Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following: Myocardial infarction or stroke/transient ischemic attack within the past 6 months Uncontrolled angina within the past 3 months Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes) QT interval corrected for heart rate using Fridericia's formula (QTcF) prolongation > 480 msec History of other clinically significant heart disease (e.g. cardiomyopathy, congestive heart failure with NYHA functional classification III-IV, pericarditis, significant pericardial effusion, or myocarditis) Major surgery within 28 days prior to the first study treatment. Participants must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study treatment. Concurrent use of oral or intravenous medications or food which may interfere with BMS-813160 including any strong inhibitors or inducers of CYP3A4 or P-gp is not allowed. These include but are not limited to Class I antiarrhythmics (eg, quinidine, procainamide, dysopiramide, lidocaine, phenytoin, mexiletine, tocainide, flecainide, propafenone, moricizine), Grapefruit and Seville oranges.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part A: 16 patients will be randomized to 1:1 to control or experimental arm through block randomization without stratification factors. After 8 evaluable patients have been enrolled and treated on the control arm, subsequent patients are enrolled only into the experimental arm.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A - Experimental Dose Level 0<br>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 | Drug: BMS-813160<br>* BMS-813160 will be supplied by Bristol Myers Squibb<br>Drug: Nivolumab<br>* Nivolumab will be supplied by Bristol Myers Squibb<br>* Other names: Opdivo;Drug: Gemcitabine<br>* Gemcitabine will be given as per routine care from commercial supply.<br>* Other names: Gemzar;Drug: Nab-paclitaxel<br>* Nab-paclitaxel will be given as per routine care from commercial supply.<br>* Other names: Abraxane;Procedure: Biopsy<br>* Pre-treatment, end of cycle 2, end of treatment for patients who progress or otherwise do not go to surgery, and surgery for patients who do go to surgery<br>Procedure: Peripheral blood<br>* -Cycle 1 Day 1 before treatment begins, after 2 cycles of treatment +/- 3 days of mandatory tumor biopsy, end of treatment for patients who progress or otherwise do not go to surgery, and no more than 24 hours prior to time of surgery (if applicable)<br>|
| Active Comparator: Part A - Control (chemotherapy only)<br>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 | Drug: Gemcitabine<br>* Gemcitabine will be given as per routine care from commercial supply.<br>* Other names: Gemzar;Drug: Nab-paclitaxel<br>* Nab-paclitaxel will be given as per routine care from commercial supply.<br>* Other names: Abraxane;Procedure: Biopsy<br>* Pre-treatment, end of cycle 2, end of treatment for patients who progress or otherwise do not go to surgery, and surgery for patients who do go to surgery<br>Procedure: Peripheral blood<br>* -Cycle 1 Day 1 before treatment begins, after 2 cycles of treatment +/- 3 days of mandatory tumor biopsy, end of treatment for patients who progress or otherwise do not go to surgery, and no more than 24 hours prior to time of surgery (if applicable)<br>|
| Experimental: Part B - Dose expansion<br>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 | Drug: BMS-813160<br>* BMS-813160 will be supplied by Bristol Myers Squibb<br>Drug: Nivolumab<br>* Nivolumab will be supplied by Bristol Myers Squibb<br>* Other names: Opdivo;Drug: Gemcitabine<br>* Gemcitabine will be given as per routine care from commercial supply.<br>* Other names: Gemzar;Drug: Nab-paclitaxel<br>* Nab-paclitaxel will be given as per routine care from commercial supply.<br>* Other names: Abraxane;Procedure: Biopsy<br>* Pre-treatment, end of cycle 2, end of treatment for patients who progress or otherwise do not go to surgery, and surgery for patients who do go to surgery<br>Procedure: Peripheral blood<br>* -Cycle 1 Day 1 before treatment begins, after 2 cycles of treatment +/- 3 days of mandatory tumor biopsy, end of treatment for patients who progress or otherwise do not go to surgery, and no more than 24 hours prior to time of surgery (if applicable)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (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 | -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. | Through 100 days after completion of treatment (approximately 7.5 months) | 
| (Part B and Part A Experimental Dose Level 0 Only): Objective Response Rate | 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. | Through completion of treatment (approximately 4 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (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) | PFS is defined as the days from the date of treatment and death or progression, which occurs first. Patients alive without progression or lost to follow-up are censored at the last follow-up. Progressive disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | Through 3 years after surgical resection or off treatment | 
| (Part B and Part A Experimental Dose Level 0 Only): Overall Survival (OS) | OS is defined as days from date of treatment to date of death within 3 years after surgical resection. Patients alive or lost to follow-up are censored at the last treatment on study or 3 years after surgical resection, regardless of subsequent treatment received. | Through 3 years after surgical resection or off treatment |