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

Primary Purpose

Anatomic Stage 0 Breast Cancer AJCC v8, Anatomic Stage I Breast Cancer AJCC v8, Anatomic Stage IA Breast Cancer AJCC v8

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Celecoxib
Cyclophosphamide
Doxorubicin
Doxorubicin Hydrochloride
Paclitaxel
Recombinant Interferon Alfa-2b
Rintatolimod
Sponsored by
Roswell Park Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Anatomic Stage 0 Breast Cancer AJCC v8

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Roswell Park Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

CKM weeks 1-3, doxorubicin, cyclophosphamide)

Arm Description

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.

Outcomes

Primary Outcome Measures

Number of Patients With Dose Limiting Toxicities
Safety and toxicity will be assessed using the CTEP NCI Common Terminology Criteria for Adverse Events (CTCAE Version 5.0). The resulting dose limiting toxicity (DLT) information is used to identify the appropriate dose level of CKM and paclitaxel for future clinical exploration. The following events will be considered a DLT: The event occurs within 3 weeks following 1st dose of combination CKM + paclitaxel therapy and subsequent enrollment for dose-escalation will only proceed after the 3-week period has been completed. The toxicity has been determined by the investigator to be possibly, probably or definitely related to celecoxib, rintatolimod, interferon-α2b or paclitaxel. Any death not clearly due to th

Secondary Outcome Measures

Number of Patients With Pathological Complete Response (pCR)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI, where Complete Response (CR) corresponds to the disappearance of all target lesions.
Residual Cancer Burden Index
The calculated RCB index value is categorized as one of four RCB classes, RCB-0 to RCB-III where RCB-0 is best prognosis (no residual disease) to RCB-III a worst prognosis.
Recurrence-free Survival (RFS)
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) or any cause. RFS will be calculated from the time of treatment to event. The median RFS was estimated using standard Kaplan-Meier methods (where NR = not reached).
Overall Survival (OS)
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. The median OS is estimated using standard Kaplan-Meier methods (where NR = not reached).

Full Information

First Posted
August 27, 2019
Last Updated
August 25, 2023
Sponsor
Roswell Park Cancer Institute
Collaborators
National Center for Advancing Translational Sciences (NCATS)
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1. Study Identification

Unique Protocol Identification Number
NCT04081389
Brief Title
Chemokine Modulation Therapy and Standard Chemotherapy Before Surgery for the Treatment of Early Stage Triple Negative Breast Cancer
Official Title
Phase I Clinical Trial Assessing the Combination of Chemokine Modulation With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Completed
Study Start Date
December 6, 2019 (Actual)
Primary Completion Date
May 24, 2022 (Actual)
Study Completion Date
February 27, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Roswell Park Cancer Institute
Collaborators
National Center for Advancing Translational Sciences (NCATS)

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
9 (Actual)

8. Arms, Groups, and Interventions

Arm Title
CKM weeks 1-3, doxorubicin, cyclophosphamide)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Celecoxib
Other Intervention Name(s)
Benzenesulfonamide, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-, Celebrex, SC-58635, YM 177
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
(-)-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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Doxorubicin
Other Intervention Name(s)
Adriablastin, Hydroxydaunomycin, Hydroxyl Daunorubicin, Hydroxyldaunorubicin
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Doxorubicin Hydrochloride
Other Intervention Name(s)
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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Paclitaxel
Other Intervention Name(s)
Anzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol Konzentrat
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
Recombinant Interferon Alfa-2b
Other Intervention Name(s)
Alfatronol, Glucoferon, Heberon Alfa, IFN alpha-2B, Interferon alfa 2b, Interferon Alfa-2B, Interferon Alpha-2b, Intron A, Sch 30500, Urifron, Viraferon
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Rintatolimod
Other Intervention Name(s)
Ampligen, Atvogen
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Number of Patients With Dose Limiting Toxicities
Description
Safety and toxicity will be assessed using the CTEP NCI Common Terminology Criteria for Adverse Events (CTCAE Version 5.0). The resulting dose limiting toxicity (DLT) information is used to identify the appropriate dose level of CKM and paclitaxel for future clinical exploration. The following events will be considered a DLT: The event occurs within 3 weeks following 1st dose of combination CKM + paclitaxel therapy and subsequent enrollment for dose-escalation will only proceed after the 3-week period has been completed. The toxicity has been determined by the investigator to be possibly, probably or definitely related to celecoxib, rintatolimod, interferon-α2b or paclitaxel. Any death not clearly due to th
Time Frame
Within 21 days of treatment adminstration
Secondary Outcome Measure Information:
Title
Number of Patients With Pathological Complete Response (pCR)
Description
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI, where Complete Response (CR) corresponds to the disappearance of all target lesions.
Time Frame
Up to 4 week post-treatment (with a range of 7 to 11 weeks).
Title
Residual Cancer Burden Index
Description
The calculated RCB index value is categorized as one of four RCB classes, RCB-0 to RCB-III where RCB-0 is best prognosis (no residual disease) to RCB-III a worst prognosis.
Time Frame
At 12 weeks post treatment initiation.
Title
Recurrence-free Survival (RFS)
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) or any cause. RFS will be calculated from the time of treatment to event. The median RFS was estimated using standard Kaplan-Meier methods (where NR = not reached).
Time Frame
At 3 years
Title
Overall Survival (OS)
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. The median OS is estimated using standard Kaplan-Meier methods (where NR = not reached).
Time Frame
At 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Shipra Gandhi
Organizational Affiliation
Roswell Park Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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