Clinical Trials /

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

NCT03496662

Description:

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.

Related Conditions:
  • Pancreatic Ductal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 201806007
  • SECONDARY ID: 1P50CA196510-01A1
  • NCT ID: NCT03496662

Conditions

  • Pancreatic Ductal Adenocarcinoma

Interventions

DrugSynonymsArms
BMS-813160Part A - Experimental
NivolumabOpdivoPart A - Experimental
GemcitabineGemzarPart A - Experimental
Nab-paclitaxelAbraxanePart A - Experimental

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Part A - ExperimentalExperimentalBMS-813160 daily oral pill Nivolumab will be given as a 30-minute intravenous infusion at a flat dose of 480 mg on Day 1 (+/- 2 days) of each 28-day cycle Gemcitabine will be given as a 30-minute intravenous infusion at the assigned dose on Days 1, 8, and 15 of each 28-day cycle Nab-paclitaxel will be given as a 30-40-minute intravenous infusion at the assigned dose 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
  • BMS-813160
  • Nivolumab
  • Gemcitabine
  • Nab-paclitaxel
Part A - ControlActive ComparatorGemcitabine will be given as a 30-minute intravenous infusion at the assigned dose on Days 1, 8, and 15 of each 28-day cycle Nab-paclitaxel will be given as a 30-40-minute intravenous infusion at the assigned dose 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
  • Gemcitabine
  • Nab-paclitaxel
Part B - Dose expansionExperimentalBMS-813160 daily oral pill Nivolumab will be given as a 30-minute intravenous infusion at a flat dose of 480 mg on Day 1 (+/- 2 days) of each 28-day cycle Gemcitabine will be given as a 30-minute intravenous infusion at the maximum tolerated dose on Days 1, 8, and 15 of each 28-day cycle Nab-paclitaxel will be given as a 30-40-minute intravenous infusion at the maximum tolerated dose 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
  • BMS-813160
  • Nivolumab
  • Gemcitabine
  • Nab-paclitaxel

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.

          -  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.

          -  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 medications/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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:(Part A 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:100 days after completion of treatment (approximately 7.5 months)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:(Part B only) Percentage of patients who disease becomes resectable after treatment
Time Frame:Completion of treatment (approximately 4 months)
Safety Issue:
Description:
Measure:(Part B only) Progression-free survival (PFS)
Time Frame:Through 2 years after surgical resection
Safety Issue:
Description: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. 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 progressions).
Measure:(Part B only) Overall survival (OS)
Time Frame:Through 2 years after surgical resection
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Washington University School of Medicine

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