Metastatic Breast Cancer
Conditions
Keywords
Breast cancer, Cancer of the breast, Human mammary carcinoma, HER-2, Metastatic, everolimus, trastuzumab, paclitaxel
Brief summary
Phase I: will look at different dose levels and regimens of everolimus combined with weekly trastuzumab and paclitaxel therapy in patients with HER-2 overexpressing metastatic breast cancer. Phase II: will assess the efficacy and safety of the 10mg daily dose of everolimus combined with weekly trastuzumab and paclitaxel therapy in patients with HER-2 overexpressing metastatic breast cancer.
Interventions
DRUGEverolimus
Everolimus (RAD001) was supplied as tablets in 3 different dosage strengths, 2.5, 5, and 10 mg. The drug was packaged in blisters containing 10 tablets per blister. Blisters and packaging labels were compliant with local regulations and were printed in local language.
DRUGTrastuzumab
Commercially-available trastuzumab was used in this study. A 4 mg/kg loading dose was administered, intra-venous (IV), over 90 minutes on Day 1 (if patient was not already receiving trastuzumab); this was followed by weekly trastuzumab 2 mg/kg IV administered over 30 minutes. For patients who continued to receive trastuzumab and everolimus after completion/discontinuation of chemotherapy in the core treatment phase, trastuzumab may have been administered once every 3 weeks at a dose of 6 mg/kg. PT = Paclitaxel & Trastuzumab
DRUGPaclitaxel
Commercially-available paclitaxel was used in this study. Paclitaxel infusion was administered on Days 1, 8, and 15 of each 28-day cycle, after administration of trastuzumab. Paclitaxel (80 mg/m2) was administered as a 60-minute continuous IV infusion after standard premedication. Patients received paclitaxel for 6 cycles. At the investigator's discretion, treatment with paclitaxel could continue beyond 6 cycles.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female or male patients ≥ 18 years old with WHO performance status ≤ 1 * HER-2 over-expressing metastatic breast cancer cells confirmed by histology * Progressive disease on prior trastuzumab alone/or in combination with other anticancer agents, or relapsed any time after completion of this therapy (phase l) * Patient resistance to trastuzumab and taxanes (Phase ll) * Measurable disease according to RECIST (Phase ll) * Patients neurologically stable with adequate bone marrow, liver and renal function
Exclusion criteria
* Patients receiving endocrine therapy for breast cancer ≤ 2 weeks prior to study treatment start * Patients currently receiving chemotherapy, immunotherapy or radiotherapy or who have received these ≤ 4 weeks prior to study treatment start or patients who have received lapatinib ≤ 2 weeks prior to study treatment start * Patients who have previously received mTOR inhibitors Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: Overall Response Rate | every 8 - 9 weeks until disease progression or a new lesion is identified | The primary objective of this phase II study was to evaluate the efficacy of the dose level/regimen of everolimus recommended from the Phase I with trastuzumab and paclitaxel (PT) therapy in patients with HER2-overexpressing metastatic breast cancer whose disease progressed on/after trastuzumab mono-and/or combination therapy based on the evaluation of objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Objective response rate (ORR) was defined as the proportion of patients with a best overall response (BOR) of complete response (CR) or partial response (PR). Only patients with measurable disease (the presence of at least one measurable lesion) at baseline were included in the study. CR = Disappearance of all target lesions; PR = At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Best Overall Response (BOR) | every 8 - 9 weeks until disease progression or a new lesion is identified | BOR was determined based on investigator assessment of overall lesion response using RECIST criteria guidelines. BOR = objective responses rate (ORR), disease control rate (DCR) or clinical benefit rate (CBR). ORR = (complete response (CR) or partial response(PR); DCR = (CR or PR or Stable disease (SD); CBR = (CR or PR or SD \>= 24 weeks).CR = Disappearance of all target lesions; PR = At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for partial disease (PD). PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline. |
| Phase II: Progression Free Survival (PFS) | every 8 - 9 weeks until disease progression or a new lesion is identified | PFS is defined as the time from start of treatment to the date of first documented progression or death due to any cause. If a patient has not had an event, PFS will be censored at the date of last adequate tumor assessment. |
| Phase II: Overall Survival (OS) | every 3 months until death | Overall survival (OS) is defined as the time from start of treatment to the date of death due to any cause. If a patient is not known to have died, survival was censored at the last date of contact. OS was to be reported at extension and after 3-year follow-up. The Kaplan-Meier median was used to analyze the OS. |
Countries
Belgium, France, Netherlands, Spain, United States
Participant flow
Pre-assignment details
Based on the results of the Phase I portion of this study, in addition to all available information on daily and weekly everolimus regimen in breast cancer and other tumors, all patients in the Phase II portion of the study were allocated to one arm to receive the recommended everolimus dose of 10 mg daily in combination with PT.
Participants by arm
| Arm | Count |
|---|---|
| Phase I - RAD001 5mg + PT, Daily Daily dosing schedule of Everolimus 5mg plus Paclitaxel plus Trastuzumab. PT = Paclitaxel & Trastuzumab | 6 |
| Phase I - RAD001 10mg + PT, Daily Daily dosing schedule of Everolimus 10mg plus Paclitaxel plus Trastuzumab. PT = Paclitaxel & Trastuzumab | 17 |
| Phase I - RAD001 30mg + PT, Weekly Weekly dosing schedule of Everolimus 30mg plus Paclitaxel plus Trastuzumab. PT = Paclitaxel & Trastuzumab. | 10 |
| Phase II - RAD001 10mg + PT, Daily Daily dosing schedule of Everolimus 10mg plus Paclitaxel plus Trastuzumab. PT = Paclitaxel & Trastuzumab | 55 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Phase I - Core Phase | Adverse Event | 1 | 3 | 1 | 0 |
| Phase I - Core Phase | Death | 0 | 1 | 0 | 0 |
| Phase I - Core Phase | Disease Progression | 0 | 6 | 2 | 0 |
| Phase I - Extension Phase | Adverse Event | 0 | 1 | 1 | 0 |
| Phase I - Extension Phase | Disease Progression | 5 | 5 | 6 | 0 |
| Phase II - Core Phase | Adverse Event | 0 | 0 | 0 | 8 |
| Phase II - Core Phase | Disease Progression | 0 | 0 | 0 | 16 |
| Phase II - Core Phase | Withdrawal by Subject | 0 | 0 | 0 | 3 |
| Phase II - Extension Phase | Adverse Event | 0 | 0 | 0 | 2 |
| Phase II - Extension Phase | Disease Progression | 0 | 0 | 0 | 21 |
Baseline characteristics
| Characteristic | Phase I - RAD001 5mg + PT, Daily | Phase I - RAD001 10mg + PT, Daily | Phase I - RAD001 30mg + PT, Weekly | Phase II - RAD001 10mg + PT, Daily | Total |
|---|---|---|---|---|---|
| Age, Customized Phase I : < 65 | 6 Participants | 13 Participants | 6 Participants | 0 Participants | 25 Participants |
| Age, Customized Phase I : >= 65 | 0 Participants | 4 Participants | 4 Participants | 0 Participants | 8 Participants |
| Age, Customized Phase II : < 65 | 0 Participants | 0 Participants | 0 Participants | 49 Participants | 49 Participants |
| Age, Customized Phase II : >= 65 | 0 Participants | 0 Participants | 0 Participants | 6 Participants | 6 Participants |
| Sex/Gender, Customized Phase I- Female | 6 Participants | 17 Participants | 10 Participants | 0 Participants | 33 Participants |
| Sex/Gender, Customized Phase II - Female | 0 Participants | 0 Participants | 0 Participants | 55 Participants | 55 Participants |
| Who Performance Status 0 | 4 Participants | 5 Participants | 4 Participants | 36 Participants | 49 Participants |
| Who Performance Status 1 | 2 Participants | 12 Participants | 6 Participants | 19 Participants | 39 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 17 / 17 | 10 / 10 | 55 / 55 |
| serious Total, serious adverse events | 3 / 6 | 6 / 17 | 7 / 10 | 26 / 55 |
Outcome results
Primary
Phase II: Overall Response Rate
The primary objective of this phase II study was to evaluate the efficacy of the dose level/regimen of everolimus recommended from the Phase I with trastuzumab and paclitaxel (PT) therapy in patients with HER2-overexpressing metastatic breast cancer whose disease progressed on/after trastuzumab mono-and/or combination therapy based on the evaluation of objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Objective response rate (ORR) was defined as the proportion of patients with a best overall response (BOR) of complete response (CR) or partial response (PR). Only patients with measurable disease (the presence of at least one measurable lesion) at baseline were included in the study. CR = Disappearance of all target lesions; PR = At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.
Time frame: every 8 - 9 weeks until disease progression or a new lesion is identified
Population: The Full Analysis Set (FAS) consisted of all patients who received a least one dose of any one compound of the study treatment. Patients were analyzed according to the everolimus dose level to which they enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II - RAD001 10mg + PT, Daily | Phase II: Overall Response Rate | 21.8 Percentage of Participants |
Secondary
Phase I: Best Overall Response (BOR)
BOR was determined based on investigator assessment of overall lesion response using RECIST criteria guidelines. BOR = objective responses rate (ORR), disease control rate (DCR) or clinical benefit rate (CBR). ORR = (complete response (CR) or partial response(PR); DCR = (CR or PR or Stable disease (SD); CBR = (CR or PR or SD \>= 24 weeks).CR = Disappearance of all target lesions; PR = At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for partial disease (PD). PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.
Time frame: every 8 - 9 weeks until disease progression or a new lesion is identified
Population: The Full Analysis Set (FAS) consisted of all patients who received a least one dose of any one compound of the study treatment. Patients were analyzed according to the everolimus dose level to which they enrolled.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - RAD001 5mg + PT, Daily | Phase I: Best Overall Response (BOR) | Clinical Benefit Rate (CBR) | 83.3 Percentage of Participants |
| Phase I - RAD001 5mg + PT, Daily | Phase I: Best Overall Response (BOR) | Disease Control Rate (DCR) | 83.3 Percentage of Participants |
| Phase I - RAD001 5mg + PT, Daily | Phase I: Best Overall Response (BOR) | Objective Response Rate (ORR) | 83.3 Percentage of Participants |
| Phase I - RAD001 10mg + PT, Daily | Phase I: Best Overall Response (BOR) | Disease Control Rate (DCR) | 82.4 Percentage of Participants |
| Phase I - RAD001 10mg + PT, Daily | Phase I: Best Overall Response (BOR) | Objective Response Rate (ORR) | 23.5 Percentage of Participants |
| Phase I - RAD001 10mg + PT, Daily | Phase I: Best Overall Response (BOR) | Clinical Benefit Rate (CBR) | 47.1 Percentage of Participants |
| Phase I - RAD001 30mg + PT, Weekly | Phase I: Best Overall Response (BOR) | Objective Response Rate (ORR) | 30.0 Percentage of Participants |
| Phase I - RAD001 30mg + PT, Weekly | Phase I: Best Overall Response (BOR) | Clinical Benefit Rate (CBR) | 70.0 Percentage of Participants |
| Phase I - RAD001 30mg + PT, Weekly | Phase I: Best Overall Response (BOR) | Disease Control Rate (DCR) | 80.0 Percentage of Participants |
Secondary
Phase II: Overall Survival (OS)
Overall survival (OS) is defined as the time from start of treatment to the date of death due to any cause. If a patient is not known to have died, survival was censored at the last date of contact. OS was to be reported at extension and after 3-year follow-up. The Kaplan-Meier median was used to analyze the OS.
Time frame: every 3 months until death
Population: The Full Analysis Set (FAS) consisted of all patients who received a least one dose of any one compound of the study treatment. Patients were analyzed according to the everolimus dose level to which they enrolled.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II - RAD001 10mg + PT, Daily | Phase II: Overall Survival (OS) | 18.07 Months |
Secondary
Phase II: Progression Free Survival (PFS)
PFS is defined as the time from start of treatment to the date of first documented progression or death due to any cause. If a patient has not had an event, PFS will be censored at the date of last adequate tumor assessment.
Time frame: every 8 - 9 weeks until disease progression or a new lesion is identified
Population: The Full Analysis Set (FAS) consisted of all patients who received a least one dose of any one compound of the study treatment. Patients were analyzed according to the everolimus dose level to which they enrolled.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II - RAD001 10mg + PT, Daily | Phase II: Progression Free Survival (PFS) | 5.52 Months |