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

Phase I Clinical Trial Assessing the Combination of Chemokine Modulation With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer

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.

Study Overview

• Status: Completed
• Conditions: 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; 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; Anatomic Stage 0 Breast Cancer AJCC v8; Prognostic Stage 0 Breast Cancer AJCC v8; Early-Stage Breast Carcinoma; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Triple-Negative Breast Carcinoma
• Intervention / Treatment: Drug: Paclitaxel; Drug: Cyclophosphamide; Drug: Doxorubicin Hydrochloride; Drug: Doxorubicin; Drug: Celecoxib; Biological: Recombinant Interferon Alfa-2b; Drug: Rintatolimod

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: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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.

Drug: Paclitaxel; Given IV; Other Names: Taxol; Anzatax; Asotax; Bristaxol; Praxel; Taxol Konzentrat; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Drug: Doxorubicin Hydrochloride; Given IV; Other Names: Adriamycin; 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 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: Doxorubicin; Given IV; Other Names: Adriablastin; Hydroxydaunomycin; Hydroxyl Daunorubicin; Hydroxyldaunorubicin; Drug: Celecoxib; Given PO; Other Names: Celebrex; SC-58635; Benzenesulfonamide, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-; YM 177; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Within 21 days of treatment adminstration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 4 week post-treatment (with a range of 7 to 11 weeks).
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.	At 12 weeks post treatment initiation.
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).	At 3 years
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).	At 3 years

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Collaborators: National Center for Advancing Translational Sciences (NCATS)
• Investigators: Principal Investigator: Shipra Gandhi, Roswell Park Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2019
• Primary Completion (Actual): May 24, 2022
• Study Completion (Actual): February 27, 2023

Study Registration Dates

• First Submitted: August 27, 2019
• First Submitted That Met QC Criteria: September 6, 2019
• First Posted (Actual): September 9, 2019

Study Record Updates

• Last Update Posted (Actual): September 11, 2023
• Last Update Submitted That Met QC Criteria: August 25, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Breast Diseases; Carcinoma in Situ; Breast Neoplasms; Carcinoma; Breast Carcinoma In Situ; Triple Negative Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Carbonic Anhydrase Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cyclooxygenase 2 Inhibitors; Interferons; Interferon-alpha; Cyclophosphamide; Paclitaxel; Interferon alpha-2; Celecoxib; Albumin-Bound Paclitaxel; Doxorubicin; Liposomal doxorubicin; Daunorubicin; Benzenesulfonamide; poly(I).poly(c12,U)
• Other Study ID Numbers: I 73718 (Other Identifier: Roswell Park Cancer Institute); UL1TR001412 (U.S. NIH Grant/Contract); NCI-2019-05299 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• 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