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Chemokine Modulation Therapy and Standard Chemotherapy Before Surgery for the Treatment of Early Stage Triple Negative Breast Cancer

NCT04081389

Description:

This phase I trial studies how well chemokine modulation therapy and standard chemotherapy given before surgery work in treating patients with early stage triple negative breast cancer. Chemokine modulation therapy, including celecoxib, recombinant interferon alfa-2b, and rintatolimod, may stimulate the immune system and stop tumor cells from growing. Drugs used in standard chemotherapy, such as paclitaxel, doxorubicin, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemokine modulation therapy together with standard chemotherapy may work better than giving either therapy alone in treating patients with triple negative breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Chemokine Modulation Therapy and Standard Chemotherapy Before Surgery for the Treatment of Early Stage Triple Negative Breast Cancer
  • Official Title: Phase Ib/II Clinical Trial Assessing the Combination of Chemokine Modulation With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: I 73718
  • SECONDARY ID: NCI-2019-05299
  • SECONDARY ID: I 73718
  • SECONDARY ID: P30CA016056
  • NCT ID: NCT04081389

Conditions

  • Anatomic Stage 0 Breast Cancer AJCC v8
  • Anatomic Stage I Breast Cancer AJCC v8
  • Anatomic Stage IA Breast Cancer AJCC v8
  • Anatomic Stage IB Breast Cancer AJCC v8
  • Anatomic Stage II Breast Cancer AJCC v8
  • Anatomic Stage IIA Breast Cancer AJCC v8
  • Anatomic Stage IIB Breast Cancer AJCC v8
  • Early-Stage Breast Carcinoma
  • Estrogen Receptor Negative
  • HER2/Neu Negative
  • Progesterone Receptor Negative
  • Prognostic Stage 0 Breast Cancer AJCC v8
  • Prognostic Stage I Breast Cancer AJCC v8
  • Prognostic Stage IA Breast Cancer AJCC v8
  • Prognostic Stage IB Breast Cancer AJCC v8
  • Prognostic Stage II Breast Cancer AJCC v8
  • Prognostic Stage IIA Breast Cancer AJCC v8
  • Prognostic Stage IIB Breast Cancer AJCC v8
  • Triple-Negative Breast Carcinoma

Interventions

DrugSynonymsArms
CelecoxibBenzenesulfonamide, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-, Celebrex, SC-58635, YM 177Arm A (CKM weeks 1-3, doxorubicin, cyclophosphamide)
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Arm A (CKM weeks 1-3, doxorubicin, cyclophosphamide)
DoxorubicinAdriablastin, Hydroxydaunomycin, Hydroxyl Daunorubicin, HydroxyldaunorubicinArm A (CKM weeks 1-3, doxorubicin, cyclophosphamide)
Doxorubicin Hydrochloride5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin HCl, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, RubexArm A (CKM weeks 1-3, doxorubicin, cyclophosphamide)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm A (CKM weeks 1-3, doxorubicin, cyclophosphamide)
Recombinant Interferon Alfa-2bAlfatronol, Glucoferon, Heberon Alfa, IFN alpha-2B, Interferon alfa 2b, Interferon Alfa-2B, Interferon Alpha-2b, Intron A, Sch 30500, Urifron, ViraferonArm A (CKM weeks 1-3, doxorubicin, cyclophosphamide)
RintatolimodAmpligen, AtvogenArm A (CKM weeks 1-3, doxorubicin, cyclophosphamide)

Purpose

This phase Ib/II trial studies how well chemokine modulation therapy and standard chemotherapy given before surgery work in treating patients with early stage triple negative breast cancer. Chemokine modulation therapy, including celecoxib, recombinant interferon alfa-2b, and rintatolimod, may stimulate the immune system and stop tumor cells from growing. Drugs used in standard chemotherapy, such as paclitaxel, doxorubicin, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemokine modulation therapy together with standard chemotherapy may work better than giving either therapy alone in treating patients with triple negative breast cancer.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine whether adding chemokine-modulatory (CKM) regimen to standard neoadjuvant
      paclitaxel increases the number of tumor-infiltrating CD8+ cytotoxic T lymphocytes (CTLs)
      compared to treatment with paclitaxel alone in early stage triple negative breast cancer.

      SECONDARY OBJECTIVES:

      I. To examine the safety and tolerability profile of the combination of rintatolimod,
      celecoxib +/- recombinant interferon alfa-2b (interferon alpha-2b), when given as CKM along
      with chemotherapy in the neoadjuvant setting in early stage triple negative breast cancer
      using the Cancer Therapy Evaluation Program (CTEP) National Cancer Institute (NCI) Common
      Terminology Criteria for Adverse Events (CTCAE version 5.0).

      II. Improvement in pathological complete response (CR) at the end of chemotherapy from 26% to
      50%.

      III. To assess complete breast magnetic resonance imaging (MRI) response after 12 weeks.

      IV. Determine three and five-year recurrence-free survival and overall survival.

      EXPLORATORY OBJECTIVES:

      I. To compare baseline, and post 3 doses of CKM + paclitaxel or paclitaxel monotherapy, and
      end of treatment changes in the intratumoral levels of biomarkers such as tumor-infiltrating
      T-cell subsets, myeloid derived suppressor cells (MDSC), chemokines, and immune-regulatory
      factors.

      II. To evaluate longitudinal changes of blood biomarkers such as peripheral T-cell subsets,
      myeloid derived suppressor cells (MDSC), expression of chemokine and other immune genes,
      circulating immune mediators.

      III. To correlate these findings with pathological CR at the time of resection, progression
      free survival (PFS) and overall survival (OS).

      IV. Comparison of response assessment criteria for a prospective analysis.

      OUTLINE: This is a phase Ib, dose-escalation study of recombinant interferon alfa-2b followed
      by a phase II study.

      PHASE I: Patients receive celecoxib orally (PO) twice daily (BID), recombinant interferon
      alfa-2b intravenously (IV) over 20 minutes (omitted in lowest dose level), and rintatolimod
      IV on days 1-3 of weeks 1-3, as well as paclitaxel IV over 1 hour once weekly on day 1.
      Treatment continues for a total of 12 weeks in the absence of disease progression or
      unacceptable toxicity. 1-3 weeks after last dose of paclitaxel, patients receive doxorubicin
      IV over 10 minutes and cyclophosphamide IV over 30 minutes. Treatment repeats every 2 weeks
      for 4 cycles in the absence of disease progression or unacceptable toxicity.

      PHASE II: Patients are randomized to 1 of 2 arms.

      ARM A: Patients receive celecoxib PO BID, recombinant interferon alfa-2b IV over 20 minutes,
      and rintatolimod IV on days 1-3 of weeks 1-3, as well as paclitaxel IV over 1 hour once
      weekly on day 1. Treatment continues for a total of 12 weeks in the absence of disease
      progression or unacceptable toxicity. 1-3 weeks after last dose of paclitaxel, patients
      receive doxorubicin IV over 10 minutes and cyclophosphamide IV over 30 minutes. Treatment
      repeats every 2 weeks for 4 cycles in the absence of disease progression or unacceptable
      toxicity.

      ARM B: Patients receive celecoxib PO BID, recombinant interferon alfa-2b IV over 20 minutes,
      and rintatolimod IV on days 1-3 of weeks 4-6, as well as paclitaxel IV over 1 hour once
      weekly on day 1. Treatment continues for 12 weeks in the absence of disease progression or
      unacceptable toxicity. 1-3 weeks after last dose of paclitaxel, patients receive doxorubicin
      IV over 10 minutes and cyclophosphamide IV over 30 minutes. Treatment repeats every 2 weeks
      for 4 cycles in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 2 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (CKM weeks 1-3, doxorubicin, cyclophosphamide)ExperimentalPatients receive celecoxib PO BID, recombinant interferon alfa-2b IV over 20 minutes, and rintatolimod IV on days 1-3 of weeks 1-3, as well as paclitaxel IV over 1 hour once weekly on day 1. Treatment continues for a total of 12 weeks in the absence of disease progression or unacceptable toxicity. 1-3 weeks after last dose of paclitaxel, patients receive doxorubicin IV over 10 minutes and cyclophosphamide IV over 30 minutes. Treatment repeats every 2 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity.
  • Celecoxib
  • Cyclophosphamide
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Paclitaxel
  • Recombinant Interferon Alfa-2b
  • Rintatolimod
Arm B (CKM weeks 4-6, doxorubicin, cyclophosphamide)ExperimentalPatients receive celecoxib PO BID, recombinant interferon alfa-2b IV over 20 minutes, and rintatolimod IV on days 1-3 of weeks 4-6, as well as paclitaxel IV over 1 hour once weekly on day 1. Treatment continues for 12 weeks in the absence of disease progression or unacceptable toxicity. 1-3 weeks after last dose of paclitaxel, patients receive doxorubicin IV over 10 minutes and cyclophosphamide IV over 30 minutes. Treatment repeats every 2 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity.
  • Celecoxib
  • Cyclophosphamide
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Paclitaxel
  • Recombinant Interferon Alfa-2b
  • Rintatolimod

Eligibility Criteria

        Inclusion Criteria:

          -  Have pathologically confirmed diagnosis of resectable triple negative breast cancer

          -  Must have clinically or radiographically measurable disease (discrete lesion only,
             enhancement is not included) in the breast after diagnostic biopsy, defined as longest
             diameter greater than or equal to 2 cm. Multi-centric disease is allowed if 1 lesion
             is >= 2 cm

          -  Prior therapy: No prior cytotoxic regimens are allowed for this malignancy.
             Participants may not have had prior chemotherapy, other targeted anticancer therapies,
             or prior radiation therapy to the ipsilateral breast for this malignancy. Prior
             bis-phosphonate therapy is allowed

          -  Patient eligible for surgery as determined by patient?s surgeon

          -  Patient has lesion that can be biopsied and is willing to undergo the procedure as
             part of the protocol

          -  Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2

          -  Participants of child-bearing potential must agree to use adequate contraceptive
             methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study
             entry. Should a woman become pregnant or suspect she is pregnant while she or her
             partner is participating in this study, she should inform her treating physician
             immediately

          -  Ability to swallow and retain oral medication

          -  Ability to undergo magnetic resonance imaging (MRI)

          -  Platelets >= 75,000/uL

          -  Hemoglobin >= 9 g/dL

          -  Absolute neutrophil count (ANC) >= 1500/uL

          -  Total bilirubin =< institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
             ALT (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 X institutional upper limit
             of normal (ULN)

          -  Creatinine < ULN OR creatinine clearance >= 50 mL/min per Cockcroft-Gault equation for
             patients with creatinine levels greater than ULN

          -  Left ventricular ejection fraction (LVEF) >= 55%; if LVEF is < 55% and patient is
             otherwise study-eligible, the principal investigator (PI) will discuss with
             cardiologist if patient is eligible to receive doxorubicin and participate in study

          -  Participant or legal representative must understand the investigational nature of this
             study and sign an Independent Ethics Committee/Institutional Review Board approved
             written informed consent form prior to receiving any study related procedure

        Exclusion Criteria:

          -  Patients currently treated with systemic immunosuppressive agents, including steroids,
             are ineligible until 3 weeks after removal from immunosuppressive treatment

          -  Patients with active autoimmune disease, requiring ongoing immunosuppressive therapy
             or history of transplantation

          -  Diagnosis of invasive carcinoma within the last 3 years

          -  Inflammatory breast cancer will be excluded from the study

          -  Participants who have metallic surgical implants that are not compatible with an MRI
             machine are not eligible

          -  Pregnant or nursing female participants

          -  Unwilling or unable to follow protocol requirements

          -  Patients with known serious mood disorders. (Major depression is an exclusion. Other
             stable mood disorders on stable therapy for > 6 months may be allowed after
             consultation with PI)

          -  Cardiac risk factors including:

               -  Patients experiencing cardiac event(s) (acute coronary syndrome, myocardial
                  infarction, or ischemia) within 3 months of signing consent

               -  Patients with a New York Heart Association classification of III or IV

          -  History of upper gastrointestinal ulceration, upper gastrointestinal bleeding, or
             upper gastrointestinal perforation within the past 3 years

          -  Prior allergic reaction or hypersensitivity to nonsteroidal anti-inflammatory drugs
             (NSAIDs) or any drugs administered on protocol

          -  Patients are ineligible if they plan on regular use of NSAIDs at any dose more than 2
             times per week (on average) or aspirin at more than 325 mg at least three times per
             week, on average. Low-dose aspirin not exceeding 100 mg/day is permitted. Patients who
             agree to stop regular NSAIDs or higher dose aspirin are eligible and no wash out
             period is required

          -  Any condition which in the investigator?s opinion deems the participant an unsuitable
             candidate to receive study drug
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Tumor-infiltrating CD8+ cytotoxic T lymphocyte (CTL)s
Time Frame:Baseline (Pre-treatment)
Safety Issue:
Description:Will compare the tumor-infiltrating CD8+ CTLs in the pre-treatment and w week posttreatment biopsy samples of early stage triple negative breast cancer tissue following neo-adjuvant chemotherapy with paclitaxel with/without chemokine modulation (CKM): rintatolimod (a selective toll-like receptor-3 agonist), celecoxib + interferon (IFN)-alpha.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 3 years
Safety Issue:
Description:Will analyze safety and tolerability of the combination of CKM with chemotherapy according to Common Terminology Criteria for Adverse Events version 5. Will be summarized by grade using frequencies and relative frequencies.
Measure:Improvement in pathological complete response (CR)
Time Frame:Up to 4 week post-treatment
Safety Issue:
Description:Improvement in pathological CR from 26% to 50% between the pre treatment biopsy and post-treatment surgical tissue will be assessed.
Measure:Complete breast magnetic resonance imaging (MRI) response
Time Frame:After 12 weeks
Safety Issue:
Description:
Measure:Recurrence-free survival (RFS)
Time Frame:At 3 years
Safety Issue:
Description:RFS is defined as local/regional invasive recurrence, invasive ipsilateral breast tumor recurrence, distant recurrence, inoperable (meaning no surgery because of progression), and/or death from breast cancer (per standard of care according to physician discretion). RFS will be calculated from the time of treatment to event.
Measure:RFS
Time Frame:At 5 years
Safety Issue:
Description:RFS is defined as local/regional invasive recurrence, invasive ipsilateral breast tumor recurrence, distant recurrence, inoperable (meaning no surgery because of progression), and/or death from breast cancer (per standard of care according to physician discretion). RFS will be calculated from the time of treatment to event.
Measure:Overall survival (OS)
Time Frame:At 3 years
Safety Issue:
Description:OS is defined by death from breast cancer, non-breast cancer, unknown, or any other cause and will be calculated from the time of study entry to event.
Measure:OS
Time Frame:At 5 years
Safety Issue:
Description:OS is defined by death from breast cancer, non-breast cancer, unknown, or any other cause and will be calculated from the time of study entry to event.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Roswell Park Cancer Institute

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