Breast Cancer
Conditions
Keywords
stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer, HER2-negative breast cancer, recurrent breast cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as paclitaxel albumin-stabilized nanoparticle formulation, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving paclitaxel albumin-stabilized nanoparticle formulation together with everolimus may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of everolimus when given together with paclitaxel albumin-stabilized nanoparticle formulation and to see how well it works in treating women with locally advanced or metastatic breast cancer.
Detailed description
OBJECTIVES: Primary * To determine the maximum tolerated dose and recommended phase II dose of everolimus when administered in combination with paclitaxel albumin-stabilized nanoparticle formulation in women with locally advanced or metastatic breast cancer. (Phase I) * To determine the antitumor activity of this regimen, as measured by clinical tumor response according to RECIST criteria, in these patients. (Phase II) Secondary * To determine the safety and tolerability of everolimus when administered at the recommended phase II dose in combination with paclitaxel albumin-stabilized nanoparticle formulation in these patients. OUTLINE: This is a multicenter, phase I dose-escalation study of everolimus followed by a phase II study. Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients also receive oral everolimus once daily or once every other day on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.
Interventions
DRUGeverolimus
Orally administered RAD001 will be initiated at 5 mg daily. Each cohort Phase I: administration will proceed based on escalation criteria. RAD001 will be given initially once every day. Doses will be adjusted per the dosing regimen for each cohort throughout the Phase I portion of the study
DRUGabraxane
Doses of Abraxane will be calculated on Day 1 of each cycle using the patient's actual weight in the determination of body surface area. A variance of 5% of the calculated total dose will be allowed.
Sponsors
National Cancer Institute (NCI)
Rutgers, The State University of New Jersey
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed breast cancer * Locally recurrent or metastatic disease * Not amenable to surgery or radiotherapy * HER2/neu-negative disease * Has ≥ 1 measurable lesion, as defined by RECIST criteria * No non-measurable lesions (e.g., pleural effusion or ascites) other than bone metastases * Bone metastases as the sole site of disease allowed provided there are ≥ 2 lytic bone lesions by x-ray, CT scan, or MRI * Lesions irradiated in the advanced setting are not considered sites of measurable disease unless clear tumor progression has been documented in these lesions since the completion of radiotherapy * No bilateral diffuse lymphangitis carcinomatosa of the lung (\> 50% of lung involvement) or evidence of liver metastases estimated as involving \> one third of the liver by sonogram and/or CT scan * No unstable CNS metastases * Hormone receptor status not specified PATIENT CHARACTERISTICS: * Menopausal status not specified * ECOG performance status 0-2 * Life expectancy ≥ 3 months * ANC ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Hemoglobin \> 9 g/dL * Serum bilirubin ≤ 1.5 times upper limit of normal (ULN) * ALT and AST ≤ 2.5 times ULN (≤ 5 times ULN in patients with liver metastases) * INR \< 1.5 times ULN * Serum creatinine ≤ 1.5 mg/dL * Fasting serum cholesterol ≤ 300 mg/dL (or 7.75 mmol/L) (levels outside this threshold allowed provided statin therapy is initiated) * Fasting triglycerides ≤ 2.5 times ULN (levels outside this threshold allowed provided statin therapy is initiated) * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * Oral, implantable, or injectable contraceptives are not considered effective contraception * No ascites or encephalopathy due to liver disease * No neuropathy ≥ grade 2 * No impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of everolimus, including any of the following: * Ulcerative disease * Uncontrolled nausea, vomiting, or diarrhea * Malabsorption syndrome * No active, bleeding diathesis * No known HIV seropositivity * No known hypersensitivity to everolimus or sirolimus (rapamycin), paclitaxel albumin-stabilized nanoparticle formulation, or lactose * No history of noncompliance to medical regimens * No severe and/or uncontrolled medical condition or other condition that could affect study participation, including any of the following: * Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within the past 6 months, or serious uncontrolled cardiac arrhythmia * Severely impaired lung function * Active (acute or chronic) or uncontrolled infections or disorders * Nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by study treatment * Liver disease (e.g., cirrhosis, chronic active hepatitis, or chronic persistent hepatitis) * No other malignancies within the past 5 years, except curatively treated carcinoma in situ of the cervix or nonmelanoma skin cancer PRIOR CONCURRENT THERAPY: * Prior systemic endocrine therapy for advanced breast cancer allowed * No prior chemotherapy for advanced breast cancer * Prior adjuvant chemotherapy allowed * No prior small bowel resection * More than 5 days since prior strong CYP3A inhibitors or inducers (e.g., rifabutin, rifampin, clarithromycin, ketoconazole, itraconazole, voriconazole, ritonavir, or telithromycin) * More than 30 days since prior radiotherapy and recovered (alopecia allowed) * Prior localized radiotherapy for analgesic purposes allowed provided radiotherapy has been completed and the patient's condition is stabilized * No prior radiotherapy to ≥ 25% of the bone marrow * More than 30 days since prior investigational drugs * More than 1 week since prior and no concurrent immunization with attenuated live vaccines * No concurrent oral anti-vitamin K medication, except low-dose coumadin * No concurrent systemic steroids or other immunosuppressive agents as chronic therapy * Topical applications, inhaled sprays, eye drops, or local injections allowed * A short duration (\< 2 weeks) of systemic corticosteroids allowed * No concurrent hormone replacement therapy, topical estrogens (including any intra-vaginal preparations), megestrol acetate, or selective estrogen-receptor modulators (e.g., raloxifene) * No other concurrent investigational or anticancer agents * Concurrent antiangiogenic agents allowed * Concurrent bisphosphonates allowed
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To Determine the Maximum Tolerated Dose (MTD) of RAD001 in Combination of Weekly Abraxane and Determine the Phase II Dose of RAD001. | 5 yrs |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited through the Rutgers Cancer Institute of New Jersey Oncology Group. They study was open to accrual on 07/15/2009 and closed to accrual on 01/07/2014.
Pre-assignment details
We are reporting results on 27 eligible patients. One patient was deemed ineligible.
Participants by arm
| Arm | Count |
|---|---|
| Phase I Level -1 - RAD001 5mg Daily, Abraxane 60mg/m2 Phase I:
* Abraxane 60 mg/m2 will be given by IV for 30 minutes on the first day of the first three weeks of each 28 day cycle.
* RAD001 will be given by tablet (5 mg). The first group of patients will receive RAD001every day depending on side effects seen drug could be increased later to twice a day for a 28 day cycle.
Once a safe and effective drug range is established, the study moves into Phase II. | 0 |
| Phase 1 Level -2 - RAD001 5mg Every Other Day, Abraxane 60mg/m2 Phase I:
* Abraxane 60 mg/m2 will be given by IV for 30 minutes on the first day of the first three weeks of each 28 day cycle.
* RAD001 will be given by tablet (5 mg). The first group of patients will receive RAD001every other day depending on side effects seen drug could be increased later to twice a day for a 28 day cycle.
Once a safe and effective drug range is established, the study moves into Phase II. | 0 |
| Phase 1 Level 0 RAD001 5mg Daily, Abraxane 80mg/m2 Phase I:
* Abraxane 80 mg/m2 will be given by IV for 30 minutes on the first day of the first three weeks of each 28 day cycle.
* RAD001 will be given by tablet (5 mg). The first group of patients will receive RAD001 every day depending on side effects seen drug could be increased later to twice a day for a 28 day cycle.
Once a safe and effective drug range is established, the study moves into Phase II. | 3 |
| Phase 1 Level 1 RAD001 5mg Daily, Abraxane 100mg/m2 Phase I:
* Abraxane 100 mg/m2 will be given by IV for 30 minutes on the first day of the first three weeks of each 28 day cycle.
* RAD001 will be given by tablet (5 mg). The first group of patients will receive RAD001 every day depending on side effects seen drug could be increased later to twice a day for a 28 day cycle.
Once a safe and effective drug range is established, the study moves into Phase II. | 6 |
| Phase 1 Level 2 RAD001 5mg Daily, Abraxane 125mg/m2 Phase I:
* Abraxane 125 mg/m2 will be given by IV for 30 minutes on the first day of the first three weeks of each 28 day cycle.
* RAD001 will be given by tablet (5 mg). The first group of patients will receive RAD001 every day depending on side effects seen drug could be increased later to twice a day for a 28 day cycle.
Once a safe and effective drug range is established, the study moves into Phase II. | 4 |
| Phase 1 Level 3 RAD001 10mg Daily, Abraxane 125mg/m2 Phase I:
* Abraxane 125 mg/m2 will be given by IV for 30 minutes on the first day of the first three weeks of each 28 day cycle.
* RAD001 will be given by tablet (10 mg) daily. The first group of patients will receive RAD001 every day depending on side effects seen drug could be increased later to twice a day for a 28 day cycle.
Once a safe and effective drug range is established, the study moves into Phase II. | 0 |
| Phase II Phase II:
The maximum tolerated dose (established in Phase I) will be given as scheduled below and we will measure the effectiveness of the study drug combination.
* Abraxane will be given by IV (intravenous infusion) for 30 minutes on the first day of the first three weeks of each 28 day cycle (Day 1, Day 8, and Day 15 of each cycle).
* RAD001 will be given by tablet based on the dose established in the Phase I part of the study.
everolimus: Orally administered RAD001 will be initiated at 5 mg daily. Each cohort Phase I: administration will proceed based on escalation criteria. RAD001 | 14 |
| Total | 27 |
Baseline characteristics
| Characteristic | Phase I Level -1 - RAD001 5mg Daily, Abraxane 60mg/m2 | Phase 1 Level -2 - RAD001 5mg Every Other Day, Abraxane 60mg/m2 | Phase 1 Level 0 RAD001 5mg Daily, Abraxane 80mg/m2 | Phase 1 Level 1 RAD001 5mg Daily, Abraxane 100mg/m2 | Phase 1 Level 2 RAD001 5mg Daily, Abraxane 125mg/m2 | Phase 1 Level 3 RAD001 10mg Daily, Abraxane 125mg/m2 | Phase II | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 2 Participants | 4 Participants | 3 Participants | 0 Participants | 2 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 12 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 3 Participants | 5 Participants | 4 Participants | 0 Participants | 14 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 3 Participants | 2 Participants | 3 Participants | 0 Participants | 8 Participants | 16 Participants |
| Region of Enrollment United States | — | — | 3 participants | 6 participants | 4 participants | — | 14 participants | 27 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 3 Participants | 6 Participants | 4 Participants | 0 Participants | 14 Participants | 27 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 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 | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 0 | 3 / 3 | 6 / 6 | 3 / 4 | 0 / 0 | 6 / 14 |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 2 / 3 | 6 / 6 | 4 / 4 | 0 / 0 | 14 / 14 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 | 0 / 3 | 2 / 6 | 0 / 4 | 0 / 0 | 4 / 14 |
Outcome results
Primary
To Determine the Maximum Tolerated Dose (MTD) of RAD001 in Combination of Weekly Abraxane and Determine the Phase II Dose of RAD001.
Time frame: 5 yrs
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | To Determine the Maximum Tolerated Dose (MTD) of RAD001 in Combination of Weekly Abraxane and Determine the Phase II Dose of RAD001. | 5 mg |