Breast Cancer
Conditions
Keywords
stage IV breast cancer, Human epidermal growth factor (HER2)-negative breast cancer, triple-negative breast cancer, hormone-resistant breast cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as cisplatin and paclitaxel, 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 cisplatin and paclitaxel together with everolimus may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects of giving cisplatin and paclitaxel together with everolimus and to see how well it works in treating patients with metastatic breast cancer.
Detailed description
OBJECTIVES: Primary * Safety profile of cisplatin, paclitaxel, and everolimus (RAD001) in patients with metastatic breast cancer. (Phase I) * Progression-free survival (Phase II) Secondary * Overall response rate * Time to progression * Number of patients with worst-grade toxicities Tertiary * To determine p53, p63, p73, and phosphatase and tensin homolog (PTEN) levels by immunohistochemistry (IHC). * To screen for exon 9 (E542K and E545K), exon 20 (H1047R), and phosphatidylinositol 3-kinase (PI3K) (p110α) mutations in DNA extracted from paraffin blocks. * To correlate IHC results with clinical outcome and with the different subtypes of breast cancer determined by molecular classification (basal-type vs luminal A vs luminal B) based on microarrays of RNA extracted from formalin-fixed paraffin-embedded blocks. * To generate microarrays of RNA extracted from fresh-frozen core biopsies (when available) to identify a pretreatment gene signature that mirrors the established p63 and p73 gene signatures that predict response to treatment. OUTLINE: This is a multicenter study. Patients receive oral everolimus once daily on days 1-28 and cisplatin IV over 1 hour and paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Tumor tissue samples are collected at baseline for correlative studies. After completion of study treatment, patients are followed up at 4 weeks.
Interventions
DRUGcisplatin
Given through a vein in the arm 1 time a week for 3 weeks, then a one week break and then begin the process again.
DRUGeverolimus
Taken daily by mouth.
DRUGpaclitaxel
Given through a vein in the arm 1 time a week for 3 weeks, then a one week break and then begin the process again.
OTHERlaboratory biomarker analysis
Blood collection
Sponsors
National Cancer Institute (NCI)
Vanderbilt-Ingram Cancer Center
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
DISEASE CHARACTERISTICS: * Histologically confirmed invasive mammary carcinoma * Stage IV disease * Basal-like disease (triple-negative, hormone-refractory, HER2-negative) * No locally recurrent breast cancer * No symptomatic brain metastases * Patients with a history of brain metastases are eligible provided they are clinically stable for \> 3 weeks after completion of radiotherapy and are not taking steroids or therapeutic anticonvulsants that are cytochrome P450 3A4 (CYP3A4) modifiers * Patients with asymptomatic brain metastases are eligible provided they are not taking prophylactic anticonvulsants that are CYP3A4 modifiers PATIENT CHARACTERISTICS: * Pre- or post-menopausal * European Cooperative Oncology Group (ECOG) performance status 0-1 * Life expectancy ≥ 6 months * Absolute neutrophil count (ANC) ≥ 1,000/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Creatinine ≤ 1.5 times upper limit of normal (ULN) * Total bilirubin ≤ 1.5 times ULN (≤ 3 times ULN in the presence of liver metastasis) * Direct bilirubin will be measured in patients with Gilbert syndrome * serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) ≤ 1.5 times ULN (≤ 3 times ULN in the presence of liver metastasis) * Alkaline phosphatase ≤ 3 times ULN (in the presence of liver metastasis) * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective barrier contraception during and for 3 months after completion of study treatment * Able to swallow and retain oral medication * No malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel * No concurrent uncontrolled illness including, but not limited to, any of the following: * Ongoing or active infection requiring parenteral antibiotics * Impaired lung function (chronic obstructive pulmonary disease or lung conditions requiring oxygen therapy) * New York Heart Association class III-IV congestive heart failure * Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within the past 6 months * Uncontrolled hypertension (systolic BP \> 180 mm Hg or diastolic BP \> 100 mm Hg, found on 2 consecutive measurements separated by a 1-week period and despite adequate medical support) * Clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or requires treatment \[grade 3 according to NCI Common Toxicity Criteria for Adverse Events v3.0\]) * Uncontrolled diabetes (hyperosmolar state, ketoacidosis, etc.) * Psychiatric illness or social situations that would compromise patient safety or limit compliance with study requirements including maintenance of a compliance/pill diary * No symptomatic neuropathy ≥ grade 2 * No other invasive cancer within the past 5 years except for completely resected basal cell or squamous cell carcinoma of the skin or successfully treated cervical carcinoma in situ * No hypersensitivity to paclitaxel or drugs using the vehicle Cremophor, Chinese hamster ovary cell products, or other recombinant human antibodies * No history of hepatitis B or C PRIOR CONCURRENT THERAPY: * See Disease Characteristics * Recovered from prior therapy * Prior total cumulative life-time dose of doxorubicin ≤ 360 mg/m\^2 or epirubicin ≤ 640 mg/m\^2 * No more than 4 prior chemotherapy treatments in the metastatic setting (not including endocrine therapy or single-agent biologic therapy) * At least 2 weeks since prior investigational drugs * At least 14 days since prior and no concurrent herbal or dietary supplements * At least 14 days since prior and no concurrent CYP3A4 inducers * At least 7 days since prior and no concurrent CYP3A4 inhibitors * Concurrent radiotherapy to painful bone metastases or areas of impending bone fracture allowed provided radiotherapy is initiated before study entry * No other concurrent anticancer therapy (chemotherapy, radiotherapy, surgery, immunotherapy, hormonal therapy, biologic therapy)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Feasible Dose in Milligrams Per Meter Squared of Body Surface Area (mg/m2) of Cisplatin and Paclitaxel for Women With Metastatic Breast Cancer | at 8 weeks | The recommended dose for the Phase II trial will be the most prevalent dose delivered per week in Phase I that allows for safe and feasible administration of the medications.The maximum tolerated dose (MTD) is defined as the dose preceding that at which 2 or more of 3 patients experience dose-limiting toxicity (DLT) during the initial cycle of therapy. DLTs include Common Toxicity Criteria (CTC) Grade 4 neutropenia (absolute neutrophil count \[ANC\] \< 0.5 x 10 9/L for \> 5 days), febrile neutropenia (ANC \< 1.0 x 10 0/L with fever \> 38.5 degrees Centigrade) or documented infection associated with Grade 3-4 neutropenia, CTC Grade 4 thrombocytopenia \< 25 x 10 9/L or CTC Grade 3 \< 50-25 x 10 9/L thrombocytopenia with bleeding, and Grade 3-4 non-hematologic toxicity despite symptomatic therapy. |
| Maximum Feasible Dose in mg of RAD001 (Everolimus)for Women With Metastatic Breast Cancer | at 8 weeks | The recommended dose for the Phase II trial will be the most prevalent dose delivered per day in Phase I that allows for safe and feasible administration the medication. The MTD is defined as the dose preceding that at which 2 or more of 3 patients experience dose-limiting toxicity (DLT) during the initial cycle of therapy. DLTs include Common Toxicity Criteria (CTC) Grade 4 neutropenia (absolute neutrophil count \[ANC\] \< 0.5 x 10 9/L for \> 5 days), febrile neutropenia (ANC \< 1.0 x 10 0/L with fever \> 38.5 degrees Centigrade) or documented infection associated with Grade 3-4 neutropenia, CTC Grade 4 thrombocytopenia \< 25 x 10 9/L or CTC Grade 3 \< 50-25 x 10 9/L thrombocytopenia with bleeding, and Grade 3-4 non-hematologic toxicity despite symptomatic therapy |
| Patients With Progression-free Survival | at 6 months | Patients who had not experienced disease progression and who were alive at 6 months after study entry |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patients With Overall Response | every 12 weeks | Per Response Evaluation Criteria in Solid Tumor (RECIST) criteria v. 1.0: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) \> 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) \> 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions |
| Time to Progression | Up to 64 weeks | Duration in months from date on-study to date patient exhibited progressive disease |
| Time to Progression in Patients With Metastatic Basal-like Breast Cancer. | Up to 64 weeks | Median duration in months from on-study to disease progression in patients with metastatic basal-like breast cancer. All patients with basal-like breast cancer are negative for estrogen, progesterone, and human epidermal growth factor (HER2) receptors. |
Countries
United States
Participant flow
Recruitment details
This study opened to accrual in October 2009 and ran to June 2011.
Pre-assignment details
Fifty-seven patients consented for this study, two were determined ineligible to participate.
Participants by arm
| Arm | Count |
|---|---|
| RAD001 Cisplatin Paclitaxel RAD001 (Everolimus) by mouth once a day. Cisplatin intravenously (IV) weekly for 3 weeks, then 1 week of rest; paclitaxel IV weekly for 3 weeks, then 1 week of rest. One cycle = 4 weeks. | 55 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 9 |
| Overall Study | Disease Progression | 38 |
| Overall Study | Physician Decision | 4 |
| Overall Study | Still on treatment | 1 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | RAD001 Cisplatin Paclitaxel |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 47 Participants |
| Age, Continuous | 52 years STANDARD_DEVIATION 11 |
| Region of Enrollment United States | 55 participants |
| Sex: Female, Male Female | 54 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 55 / 55 |
| serious Total, serious adverse events | 9 / 55 |
Outcome results
Primary
Maximum Feasible Dose in mg of RAD001 (Everolimus)for Women With Metastatic Breast Cancer
The recommended dose for the Phase II trial will be the most prevalent dose delivered per day in Phase I that allows for safe and feasible administration the medication. The MTD is defined as the dose preceding that at which 2 or more of 3 patients experience dose-limiting toxicity (DLT) during the initial cycle of therapy. DLTs include Common Toxicity Criteria (CTC) Grade 4 neutropenia (absolute neutrophil count \[ANC\] \< 0.5 x 10 9/L for \> 5 days), febrile neutropenia (ANC \< 1.0 x 10 0/L with fever \> 38.5 degrees Centigrade) or documented infection associated with Grade 3-4 neutropenia, CTC Grade 4 thrombocytopenia \< 25 x 10 9/L or CTC Grade 3 \< 50-25 x 10 9/L thrombocytopenia with bleeding, and Grade 3-4 non-hematologic toxicity despite symptomatic therapy
Time frame: at 8 weeks
Population: Patients enrolled to determine the safety profile and recommended dose of cisplatin + RAD001 + paclitaxel in women with metastatic breast cancer
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RAD001 and Cisplatin and Paclitazel | Maximum Feasible Dose in mg of RAD001 (Everolimus)for Women With Metastatic Breast Cancer | 5 mg |
Primary
Maximum Feasible Dose in Milligrams Per Meter Squared of Body Surface Area (mg/m2) of Cisplatin and Paclitaxel for Women With Metastatic Breast Cancer
The recommended dose for the Phase II trial will be the most prevalent dose delivered per week in Phase I that allows for safe and feasible administration of the medications.The maximum tolerated dose (MTD) is defined as the dose preceding that at which 2 or more of 3 patients experience dose-limiting toxicity (DLT) during the initial cycle of therapy. DLTs include Common Toxicity Criteria (CTC) Grade 4 neutropenia (absolute neutrophil count \[ANC\] \< 0.5 x 10 9/L for \> 5 days), febrile neutropenia (ANC \< 1.0 x 10 0/L with fever \> 38.5 degrees Centigrade) or documented infection associated with Grade 3-4 neutropenia, CTC Grade 4 thrombocytopenia \< 25 x 10 9/L or CTC Grade 3 \< 50-25 x 10 9/L thrombocytopenia with bleeding, and Grade 3-4 non-hematologic toxicity despite symptomatic therapy.
Time frame: at 8 weeks
Population: Patients enrolled to determine the safety profile and recommended doses of cisplatin + paclitaxel + everolimus (RAD001) in women with metastatic breast cancer
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RAD001 and Cisplatin and Paclitazel | Maximum Feasible Dose in Milligrams Per Meter Squared of Body Surface Area (mg/m2) of Cisplatin and Paclitaxel for Women With Metastatic Breast Cancer | Cisplatin | 25 mg/m2 |
| RAD001 and Cisplatin and Paclitazel | Maximum Feasible Dose in Milligrams Per Meter Squared of Body Surface Area (mg/m2) of Cisplatin and Paclitaxel for Women With Metastatic Breast Cancer | Paclitaxel | 80 mg/m2 |
Primary
Patients With Progression-free Survival
Patients who had not experienced disease progression and who were alive at 6 months after study entry
Time frame: at 6 months
Population: Patient who received the study drugs. Four patients were not available for measurement of progression at 6 months: toxicity (3), withdrew after beginning treatment (1)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RAD001 and Cisplatin and Paclitazel | Patients With Progression-free Survival | 21 participants |
Secondary
Patients With Overall Response
Per Response Evaluation Criteria in Solid Tumor (RECIST) criteria v. 1.0: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) \> 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) \> 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions
Time frame: every 12 weeks
Population: Patients for whom an overall response could be measured. Four patients were not evaluable due to: withdrew after beginning treatment (1) and not evaluable due to only 1 cycle of treatment (3).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RAD001 and Cisplatin and Paclitazel | Patients With Overall Response | Complete Response | 1 participants |
| RAD001 and Cisplatin and Paclitazel | Patients With Overall Response | Partial Response | 12 participants |
| RAD001 and Cisplatin and Paclitazel | Patients With Overall Response | Progressive Disease | 11 participants |
| RAD001 and Cisplatin and Paclitazel | Patients With Overall Response | Stable Disease | 27 participants |
Secondary
Time to Progression
Duration in months from date on-study to date patient exhibited progressive disease
Time frame: Up to 64 weeks
Population: Patients who were available for determination of duration of time to progressive disease. Time to progression is unknown for 8 Phase II patients due to: on-treatment (1), toxicity (3), withdrew after beginning treatment (1), and no progression (3)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RAD001 and Cisplatin and Paclitazel | Time to Progression | 4.0 months |
Secondary
Time to Progression in Patients With Metastatic Basal-like Breast Cancer.
Median duration in months from on-study to disease progression in patients with metastatic basal-like breast cancer. All patients with basal-like breast cancer are negative for estrogen, progesterone, and human epidermal growth factor (HER2) receptors.
Time frame: Up to 64 weeks
Population: Patients who are negative for estrogen, progesterone and HER2 receptors. Time to progression was not determined for 5 patients in this group: toxicity (2), withdrew after beginning treatment (1), no progression (1), and on-treatment (1).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RAD001 and Cisplatin and Paclitazel | Time to Progression in Patients With Metastatic Basal-like Breast Cancer. | 4.0 months |