Breast Cancer
Conditions
Keywords
Breast Cancer, Triple-Negative, Paclitaxel, Carboplatin, Sunitinib, Sutent, Neoadjuvant
Brief summary
This trial will examine the combination of sunitinib plus paclitaxel and carboplatin as neoadjuvant treatment for locally advanced breast cancer.
Detailed description
This open label, Phase I/II trial is designed to evaluate the combination of sunitinib plus paclitaxel and carboplatin as neoadjuvant treatment for locally advanced breast cancer. The Phase I portion of this study will determine the maximum tolerated dose (MTD) of paclitaxel, sunitinib and carboplatin that can be used together as neoadjuvant treatment in patients with locally advanced breast cancer. The MTD identified in the Phase I portion of the study will be used in the Phase II portion which will evaluate the efficacy, safety, and tolerability of neoadjuvant sunitinib/paclitaxel/carboplatin given for 6 cycles in patients with locally advanced breast cancer.
Interventions
DRUGPaclitaxel
IV infusion per institutional guidelines on Days 1, 8 and 15 of a 28 day cycle as follows depending on dose level (DL): DL1- 70 mg/m2, DL2- 80 mg/m2, DL3- 80mg/m2, DL4- 80mg/m2, DL-1- 70mg/m2, DL-2- 60mg/m2
DRUGCarboplatin
IV infusion per institutional guidelines Day 1 of a 28 day cycle as follows depending on dose level (DL): DL1- AUC=5, DL2- AUC=5, DL3- AUC=6, DL4- AUC=6, DL-1- AUC=4, DL-2- AUC=4
DRUGSunitinib
By mouth (PO) once daily on days 1-21 of a 28 day cycle as follows depending on dose level (DL): DL1- 25mg, DL2-25mg, DL3- 25mg, DL4- 37.5mg, DL-1- 25mg, DL-2- 25mg. Maintenance therapy of 25mg daily
Sponsors
Pfizer
SCRI Development Innovations, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Female patients, age ≥18 years 2. Histologically confirmed invasive ER-, PR-, and HER2-negative (triple-negative) adenocarcinoma of the breast 3. Triple-negative tumors are defined as: * For HER2-negative: * Fluorescence in situ hybridization (FISH)-negative (defined by ratio \<2.2) OR * Immunohistochemical (IHC) 0, IHC 1+, OR * IHC 2+ or IHC 3+ and FISH-negative (defined by ratio \<2.2) * For ER- and PR-negative: \<10% tumor staining by immunohistochemistry (IHC) 4. Primary palpable disease confined to a breast and axilla on physical examination. For patients without clinically suspicious axillary adenopathy, the primary tumor must be larger than 2 cm in diameter by physical exam or imaging studies (clinical T2-T3, N0-N1, M0). For patients with clinically suspicious axillary adenopathy, the primary breast tumor can be any size (clinical T1-3, N1-2, M0). T1N0M0 lesions are excluded. Patients with metastatic disease are excluded. 5. Patients without clearly defined palpable breast mass or axillary lymph nodes but radiographically measurable tumor masses are eligible. Accepted procedures for measuring breast disease are mammography, MRI, and breast ultrasound. Patients with lesions measurable only by imaging will require repeat imaging after 3 cycles and prior to surgery 6. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 7. Neuropathy grade \<1 by the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v 3.0) 8. Resolution of all acute effects of surgical procedures to grade ≤1. For patients who had, or will have sentinel lymph node and/or axillary dissection prior to initiation of study treatment, completion at least 4 weeks prior to starting study treatment and well-healed wound is required 9. Adequate hematologic function with: * Absolute neutrophil count (ANC) \>1500/μL * Platelets ≥100,000/μL * Hemoglobin ≥10 g/dL 10. Adequate hepatic and renal function with: * Serum bilirubin ≤ the institutional upper limit of normal (ULN) * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x institutional ULN * Alkaline phosphatase ≤2.5 x institutional ULN * Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥40 mL/min 11. Left ventricular ejection fraction (LVEF) ≥50% by multigated acquisition (MUGA) or echocardiogram (ECHO) 12. Bilateral, synchronous breast cancer is allowed if one primary tumor meets the inclusion criteria 13. Knowledge of the investigational nature of the study and ability to provide consent for study participation 14. Ability and willingness to comply with study visits, treatment, testing, and other study procedures
Exclusion criteria
1. Previous treatment for this breast cancer 2. Previous treatment with paclitaxel or carboplatin 3. Previous treatment with sunitinib or other angiogenic inhibitors (including, but not limited to bevacizumab, sorafenib, thalidomide) 4. Any of the following within the 12 months prior to starting study treatment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, cerebrovascular accident including transient ischemic attack, or pulmonary embolus 5. Uncontrolled hypertension (blood pressure \>150/100 mmHg despite optimal medical therapy) 6. Ongoing cardiac dysrhythmias grade ≥2, atrial fibrillation of any grade, or prolongation of the QTc interval to \>470 msec 7. Major surgery, significant traumatic injury, or radiation therapy within 4 weeks of starting study treatment. An interval of at least 1week is required following minor surgical procedures, with the exception of placement of a vascular access device 8. Grade 3 hemorrhage within 4 weeks of starting study treatment 9. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication 10. Known human immunodeficiency virus (HIV) infection or other serious infection 11. Concomitant treatment with drugs having proarrhythmic potential including terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide, and flecainide 12. Concurrent use of the potent CYP3A4 inhibitors ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine and voriconazole and CYP3A4 inducers rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, St. John's Wort, and dexamethasone. Use of dexamethasone for study premedication is allowed. Grapefruit and grapefruit juice is prohibited. Alternative therapies should be used when available. If use of a potent CYP3A4 inhibitor or inducer is necessary, this must be approved by the Study Chair 13. Known or suspected hypersensitivity to drugs containing Cremophor®EL (polyoxyethylated castor oil) such as cyclosporine or teniposide 14. Pregnancy or breast-feeding. Negative serum pregnancy test is required within 7 days prior to first study treatment (Day 1, Cycle ) for all women of childbearing potential. Patients of childbearing potential must agree to use a birth control method that is approved by their study physician while receiving study treatment and for three months after the last dose of study treatment. Patients must agree to not breast-feed while receiving study treatment 15. Concurrent treatment with an ovarian hormonal replacement therapy or with hormonal agents such as raloxifene, tamoxifen or other selective estrogen receptor modulator (SERM). Patients must have discontinued use of such agents prior to beginning study treatment 16. History of malignancy treated with curative intent within the previous 5 years with the exception of skin cancer, cervical carcinoma in situ, or follicular thyroid cancer. Patients with previous invasive cancers (including breast cancer) are eligible if the treatment was completed more than 5 years prior to initiating current study treatment, and there is no evidence of recurrent disease 17. Use of any investigational agent within 30 days of administration of the first dose of study drug or concurrent treatment on another clinical study 18. Requirement for radiation therapy concurrent with study anticancer treatment. Patients who require breast or chest wall radiation therapy after surgery are eligible, but will have maintenance sunitinib interrupted while receiving radiation 19. Any other disease(s), psychiatric condition, metabolic dysfunction, or findings from a physical examination or clinical laboratory test result that would cause reasonable suspicion of a disease or condition, that contraindicates the use of study drugs, that may increase the risk associated with study participation, that may affect the interpretation of the results, or that would make the patient inappropriate for this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: The Number of Subjects Exhibiting Pathologic Complete Response to Neoadjuvant Treatment With Sunitinib/Paclitaxel/Carboplatin | at weeks 26-30 | Pathologic complete response (PCR) is defined as no residual invasive breast cancer in final breast or axillary lymph node samples. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Days 1, 8, and 15 of each 4-week cycle up to 24 weeks during neoadjuvant treatment, and every 4 weeks during maintenance treatment | Assessments will be made through analysis of reported incidence of treatment-emergent adverse events (AEs) and serious adverse events (SAEs) at the phase II dose |
| Overall Response Rate (ORR) | Days 1, 8 and 15 of each cycle, minimum of 12 weeks | Assessed by clinical, radiologic and surgical determinations before and after neoadjuvant therapy. Measurable lesions will be defined by RECIST criteria v1.1. |
| Disease-free Survival | every 4 weeks from date of surgery until treatment discontinuation or death, expected average 18 months | Defined as the time between day of surgery to first documented disease occurrence or death due to any cause. |
| Overall Survival (OS) | 24 months | Defined as the time between Day 1 Cycle 1 to time of death from any cause. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited at multiple dose levels into the Dose Escalation (Phase I) portion of this study to determine the safest dose of this regimen (MTD- Maximum Tolerated Dose). Upon determination of this dose, patients being treated at the MTD proceeded to the Dose Expansion (Phase II) portion of the study and additional patients were recruited
Participants by arm
| Arm | Count |
|---|---|
| All Patients Includes all patients treated at all dose levels | 50 |
| Total | 50 |
Baseline characteristics
| Characteristic | All Patients |
|---|---|
| Age, Continuous | 53 Years |
| Baseline ECOG Performance Status ECOG Performance Status = 0 | 45 participants |
| Baseline ECOG Performance Status ECOG Performance Status = 1 | 5 participants |
| Menopausal Status Postmenopausal | 34 Participants |
| Menopausal Status Premenopausal | 16 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 36 Participants |
| Region of Enrollment United States | 50 participants |
| Sex: Female, Male Female | 50 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 41 / 41 |
| serious Total, serious adverse events | 3 / 41 |
Outcome results
Primary
Phase II: The Number of Subjects Exhibiting Pathologic Complete Response to Neoadjuvant Treatment With Sunitinib/Paclitaxel/Carboplatin
Pathologic complete response (PCR) is defined as no residual invasive breast cancer in final breast or axillary lymph node samples.
Time frame: at weeks 26-30
Population: Patients treated at Dose Level I (Phase I and Phase II) who underwent surgery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Phase II: The Number of Subjects Exhibiting Pathologic Complete Response to Neoadjuvant Treatment With Sunitinib/Paclitaxel/Carboplatin | 12 participants |
Secondary
Disease-free Survival
Defined as the time between day of surgery to first documented disease occurrence or death due to any cause.
Time frame: every 4 weeks from date of surgery until treatment discontinuation or death, expected average 18 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Disease-free Survival | Median Overall Survival | NA months |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Disease-free Survival | Median Disease-Free Survival | 15.8357 months |
Secondary
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Assessments will be made through analysis of reported incidence of treatment-emergent adverse events (AEs) and serious adverse events (SAEs) at the phase II dose
Time frame: Days 1, 8, and 15 of each 4-week cycle up to 24 weeks during neoadjuvant treatment, and every 4 weeks during maintenance treatment
Population: The safety analysis includes all eligible patients enrolled at the MTD, whether or not treatment was recieved (6 patients in Phase I were treated at the MTD, 39 patients were enrolled in Phase II, 3 were deemed ineligible after enrollment-thus 42 patients are included in the safety analysis, including 1 eligible patient who was not treated)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Neutropenia | 34 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Anemia | 30 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Thrombocytopenia | 30 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Leukopenia | 30 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Febrile neutropenia | 3 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Fatigue | 32 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Alopecia | 26 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Nausea/Vomiting | 24 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Constipation | 22 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Diarrhea | 21 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Mucositis | 17 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Dysgeusia | 17 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Peripheral neuropathy | 17 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Dyspepsia | 13 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Dyspnea | 12 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Anorexia | 10 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Fever | 9 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Bleeding | 9 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Insomnia | 9 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Pain in extremity | 9 participants |
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Skin toxicity | 9 participants |
Secondary
Overall Response Rate (ORR)
Assessed by clinical, radiologic and surgical determinations before and after neoadjuvant therapy. Measurable lesions will be defined by RECIST criteria v1.1.
Time frame: Days 1, 8 and 15 of each cycle, minimum of 12 weeks
Population: Patients who were enrolled, treated at the MTD and completed at least 3 cycles of neoadjuvant therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Overall Response Rate (ORR) | 25 participants |
Secondary
Overall Survival (OS)
Defined as the time between Day 1 Cycle 1 to time of death from any cause.
Time frame: 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II- Sunitinib/Paclitaxel/Carboplatin | Overall Survival (OS) | 0.8912 probability of overall survival at 24 m |