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

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ClinicalTrials.gov Identifier: NCT04081389
Recruitment Status : Recruiting
First Posted : September 9, 2019
Last Update Posted : September 13, 2021
Sponsor:
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Tracking Information
First Submitted Date  ICMJE August 27, 2019
First Posted Date  ICMJE September 9, 2019
Last Update Posted Date September 13, 2021
Actual Study Start Date  ICMJE December 6, 2019
Estimated Primary Completion Date July 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 6, 2019)
  • Tumor-infiltrating CD8+ cytotoxic T lymphocyte (CTL)s [ Time Frame: Baseline (Pre-treatment) ]
    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.
  • Tumor-infiltrating CD8+ cytotoxic T lymphocyte (CTL)s [ Time Frame: 4 week post-treatment ]
    Will compare the tumor-infiltrating CD8+ CTLs in the pre-treatment and 4 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 6, 2019)
  • Incidence of adverse events [ Time Frame: Up to 3 years ]
    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.
  • Improvement in pathological complete response (CR) [ Time Frame: Up to 4 week post-treatment ]
    Improvement in pathological CR from 26% to 50% between the pre treatment biopsy and post-treatment surgical tissue will be assessed.
  • Complete breast magnetic resonance imaging (MRI) response [ Time Frame: After 12 weeks ]
  • Recurrence-free survival (RFS) [ Time Frame: At 3 years ]
    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.
  • RFS [ Time Frame: At 5 years ]
    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.
  • Overall survival (OS) [ Time Frame: At 3 years ]
    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.
  • OS [ Time Frame: At 5 years ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: September 6, 2019)
  • Biomarker analysis [ Time Frame: Up to 3 years ]
    Change in intratumoral levels of biomarkers using immunofluorescent and IHC stainings
  • Clinical course of the disease [ Time Frame: Up to 3 years ]
    Will correlate markers and their change over treatment with the clinical course of the disease post-surgery.
 
Descriptive Information
Brief Title  ICMJE Chemokine Modulation Therapy and Standard Chemotherapy Before Surgery for the Treatment of Early Stage Triple Negative Breast Cancer
Official Title  ICMJE Phase I Clinical Trial Assessing the Combination of Chemokine Modulation With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
Brief Summary 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.
Detailed Description

PRIMARY OBJECTIVE:

I. To examine the safety and tolerability profile of the combination of rintatolimod celecoxib +/- interferon alpha-2b, when given as CKM along with chemotherapy in the neoadjuvant setting in early stage triple negative breast cancer.

II To identify the appropriate dose level of CKM and paclitaxel for future clinical exploration.

SECONDARY OBJECTIVES:

II. • Evaluate the effect of neoadjuvant CKM + paclitaxel on pathological response and breast MRI response in early stage triple negative breast cancer patients.

III. • Evaluate the overall and recurrence-free survival in early stage triple negative breast cancer patients that received neoadjuvant CKM + paclitaxel.

EXPLORATORY OBJECTIVES:

I• 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 and correlate them with the clinical course post surgery.

II• Comparison of response assessment criteria for a prospective analysis using RECIST 1.1. and irRECIST

  • Evaluate changes in the intratumoral levels of biomarkers, such as, peripheral T-cell subsets, myeloid derived suppressor cells (MDSC), chemokines, and immune-regulatory factors (pre- vs post-CKM + paclitaxel treatment).

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

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.

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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Drug: Celecoxib
    Given PO
    Other Names:
    • Benzenesulfonamide, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
    • Celebrex
    • SC-58635
    • YM 177
  • Drug: Cyclophosphamide
    Given IV
    Other Names:
    • (-)-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- 138719
  • Drug: Doxorubicin
    Given IV
    Other Names:
    • Adriablastin
    • Hydroxydaunomycin
    • Hydroxyl Daunorubicin
    • Hydroxyldaunorubicin
  • Drug: Doxorubicin Hydrochloride
    Given IV
    Other Names:
    • 5,12-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
    • Rubex
  • Drug: Paclitaxel
    Given IV
    Other Names:
    • Anzatax
    • Asotax
    • Bristaxol
    • Praxel
    • Taxol
    • Taxol Konzentrat
  • Biological: Recombinant Interferon Alfa-2b
    Given IV
    Other Names:
    • Alfatronol
    • Glucoferon
    • Heberon Alfa
    • IFN alpha-2B
    • Interferon alfa 2b
    • Interferon Alfa-2B
    • Interferon Alpha-2b
    • Intron A
    • Sch 30500
    • Urifron
    • Viraferon
  • Drug: Rintatolimod
    Given IV
    Other Names:
    • Ampligen
    • Atvogen
Study Arms  ICMJE Experimental: CKM weeks 1-3, doxorubicin, cyclophosphamide)
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.
Interventions:
  • Drug: Celecoxib
  • Drug: Cyclophosphamide
  • Drug: Doxorubicin
  • Drug: Doxorubicin Hydrochloride
  • Drug: Paclitaxel
  • Biological: Recombinant Interferon Alfa-2b
  • Drug: Rintatolimod
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 4, 2019)
24
Original Estimated Enrollment  ICMJE
 (submitted: September 6, 2019)
42
Estimated Study Completion Date  ICMJE July 30, 2023
Estimated Primary Completion Date July 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Have pathologically confirmed diagnosis of resectable triple negative breast cancer (ASCO/CAP guidelines will be used to define triple negative breast cancer)
  • Must have measurable disease. Multi-centric disease is allowed. If patient has another lesion which is biopsied with ER/PR positive it will be Physician discretion for this eligibility criteria.
  • 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 must have a lesion that amendable to biopsy, unless inaccessible and with PI approval
  • 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 >= 100,000/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
  • Participants on this study will be counseled on and are willing to use adequate contraceptive methods

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
  • Any history of allergy to sulfonamides
  • Any history of autoimmune hepatitis
  • Grade 1 or higher neuropathy
  • Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04081389
Other Study ID Numbers  ICMJE I 73718
NCI-2019-05299 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
I 73718 ( Other Identifier: Roswell Park Cancer Institute )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Roswell Park Cancer Institute
Study Sponsor  ICMJE Roswell Park Cancer Institute
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Shipra Gandhi Roswell Park Cancer Institute
PRS Account Roswell Park Cancer Institute
Verification Date September 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP