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
Conditions
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.
Interventions
DRUGCelecoxib
Given PO
DRUGCyclophosphamide
Given IV
DRUGDoxorubicin
Given IV
DRUGDoxorubicin Hydrochloride
Given IV
DRUGPaclitaxel
Given IV
BIOLOGICALRecombinant Interferon Alfa-2b
Given IV
DRUGRintatolimod
Given IV
Sponsors
National Center for Advancing Translational Sciences (NCATS)
Roswell Park Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Dose Limiting Toxicities | Within 21 days of treatment adminstration | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Pathological Complete Response (pCR) | Up to 4 week post-treatment (with a range of 7 to 11 weeks). | 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 | At 12 weeks post treatment initiation. | 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) | 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) 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) | 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. The median OS is estimated using standard Kaplan-Meier methods (where NR = not reached). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Interferon Alpha-2b at DL 1 Dose Level 1
Celecoxib: 200 mg orally BID on days 1-3 of weeks 1-3.
Interferon alpha-2b: None
Rintatolimod: 200 mg intravenous on days 1-3 of weeks 1-3.
Paclitaxel: 80 mg/m2 intravenous once weekly on day 1 | 1 |
| Arm 2: Interferon Alpha-2b at DL 2 Dose Level 2
Celecoxib: 200 mg orally BID on days 1-3 of weeks 1-3.
Interferon alpha-2b: 5 million units/m2 IV on days 1-3 of weeks 1-3.
Rintatolimod: 200 mg intravenous on days 1-3 of weeks 1-3.
Paclitaxel: 80 mg/m2 intravenous once weekly on day 1 | 1 |
| Arm 3: Interferon Alpha-2b at DL 3 Dose Level 3
Celecoxib: 200 mg orally BID on days 1-3 of weeks 1-3.
Interferon alpha-2b: 10 million units/m2 IV on days 1-3 of weeks 1-3.
Rintatolimod: 200 mg intravenous on days 1-3 of weeks 1-3.
Paclitaxel: 80 mg/m2 intravenous once weekly on day 1 | 4 |
| Arm 4: Interferon Alpha-2b at DL 4 Dose Level 4
Celecoxib: 200 mg orally BID on days 1-3 of weeks 1-3.
Interferon alpha-2b: 20 million units/m2 IV on days 1-3 of weeks 1-3.
Rintatolimod: 200 mg intravenous on days 1-3 of weeks 1-3.
Paclitaxel: 80 mg/m2 intravenous once weekly on day 1 | 3 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Arm 4: Interferon Alpha-2b at DL 4 | Arm 1: Interferon Alpha-2b at DL 1 | Arm 3: Interferon Alpha-2b at DL 3 | Arm 2: Interferon Alpha-2b at DL 2 |
|---|---|---|---|---|---|
| Age, Continuous | 47.6 years STANDARD_DEVIATION 7.2 | 52.6 years STANDARD_DEVIATION 4.6 | 47.0 years STANDARD_DEVIATION 0 | 45.7 years STANDARD_DEVIATION 8.7 | 40.5 years STANDARD_DEVIATION 0 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 8 Participants | 3 Participants | 0 Participants | 4 Participants | 1 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Laterality Left Breast | 4 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Laterality Right Breast | 5 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants |
| Overall American Joint Committee on Cancer (AJCC) Stage Stage I | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Overall American Joint Committee on Cancer (AJCC) Stage Stage II | 3 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants |
| Overall American Joint Committee on Cancer (AJCC) Stage Stage III | 5 Participants | 2 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 3 Participants | 1 Participants | 3 Participants | 1 Participants |
| Region of Enrollment United States | 9 participants | 3 participants | 1 participants | 4 participants | 1 participants |
| Sex: Female, Male Female | 9 Participants | 3 Participants | 1 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 1 | 0 / 1 | 1 / 4 | 0 / 3 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 4 / 4 | 3 / 3 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 | 1 / 4 | 1 / 3 |
Outcome results
Primary
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
Time frame: Within 21 days of treatment adminstration
Population: 1 patient was not DLT evaluable in DL3.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Interferon Alpha-2b at DL 1 | Number of Patients With Dose Limiting Toxicities | 0 Participants |
| Arm 2: Interferon Alpha-2b at DL 2 | Number of Patients With Dose Limiting Toxicities | 0 Participants |
| Arm 3: Interferon Alpha-2b at DL 3 | Number of Patients With Dose Limiting Toxicities | 0 Participants |
| Arm 4: Interferon Alpha-2b at DL 4 | Number of Patients With Dose Limiting Toxicities | 0 Participants |
Secondary
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.
Time frame: Up to 4 week post-treatment (with a range of 7 to 11 weeks).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Interferon Alpha-2b at DL 1 | Number of Patients With Pathological Complete Response (pCR) | 0 Participants |
| Arm 2: Interferon Alpha-2b at DL 2 | Number of Patients With Pathological Complete Response (pCR) | 1 Participants |
| Arm 3: Interferon Alpha-2b at DL 3 | Number of Patients With Pathological Complete Response (pCR) | 2 Participants |
| Arm 4: Interferon Alpha-2b at DL 4 | Number of Patients With Pathological Complete Response (pCR) | 2 Participants |
Secondary
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).
Time frame: At 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Interferon Alpha-2b at DL 1 | Overall Survival (OS) | 21.7 months |
| Arm 2: Interferon Alpha-2b at DL 2 | Overall Survival (OS) | NA months |
| Arm 3: Interferon Alpha-2b at DL 3 | Overall Survival (OS) | NA months |
| Arm 4: Interferon Alpha-2b at DL 4 | Overall Survival (OS) | NA months |
Secondary
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).
Time frame: At 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Interferon Alpha-2b at DL 1 | Recurrence-free Survival (RFS) | 12.0 months |
| Arm 2: Interferon Alpha-2b at DL 2 | Recurrence-free Survival (RFS) | NA months |
| Arm 3: Interferon Alpha-2b at DL 3 | Recurrence-free Survival (RFS) | 11.4 months |
| Arm 4: Interferon Alpha-2b at DL 4 | Recurrence-free Survival (RFS) | 11.5 months |
Secondary
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.
Time frame: At 12 weeks post treatment initiation.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1: Interferon Alpha-2b at DL 1 | Residual Cancer Burden Index | RCB-I | 0 Participants |
| Arm 1: Interferon Alpha-2b at DL 1 | Residual Cancer Burden Index | RCB-II | 1 Participants |
| Arm 1: Interferon Alpha-2b at DL 1 | Residual Cancer Burden Index | RCB-0 | 0 Participants |
| Arm 2: Interferon Alpha-2b at DL 2 | Residual Cancer Burden Index | RCB-0 | 1 Participants |
| Arm 2: Interferon Alpha-2b at DL 2 | Residual Cancer Burden Index | RCB-II | 0 Participants |
| Arm 2: Interferon Alpha-2b at DL 2 | Residual Cancer Burden Index | RCB-I | 0 Participants |
| Arm 3: Interferon Alpha-2b at DL 3 | Residual Cancer Burden Index | RCB-I | 1 Participants |
| Arm 3: Interferon Alpha-2b at DL 3 | Residual Cancer Burden Index | RCB-0 | 2 Participants |
| Arm 3: Interferon Alpha-2b at DL 3 | Residual Cancer Burden Index | RCB-II | 1 Participants |
| Arm 4: Interferon Alpha-2b at DL 4 | Residual Cancer Burden Index | RCB-0 | 2 Participants |
| Arm 4: Interferon Alpha-2b at DL 4 | Residual Cancer Burden Index | RCB-II | 0 Participants |
| Arm 4: Interferon Alpha-2b at DL 4 | Residual Cancer Burden Index | RCB-I | 1 Participants |