Metastatic Breastcancer
Conditions
Keywords
Metastatic, Breast, Cancer, HER2-negative Stage IV, No previous chemotherapy
Brief summary
Longer first line chemotherapy duration has recently been associated with a modest, but significant improvement in overall survival and a clinically meaningful and statistically significant improvement in progression-free survival, in metastatic breast cancer patients. Prolonging chemotherapy until disease progression, however, must be weighed against the detrimental effects of continuous chemotherapy delivery. The SNAP trial seeks to improve the tolerability of prolonged chemotherapy administration strategy by studying alternative treatment schedules, while preserving and possibly improving treatment efficacy in this disease setting. The availability of a new nanoparticle albumin-bound taxane, nab-Paclitaxel (Abraxane®), represents an opportunity to test this hypothesis. Nab-Paclitaxel has been developed in an attempt to reduce the toxicity associated with standard taxane administration (caused by the use of chemical solvents) while increasing antitumor efficacy. The SNAP randomized phase II trial evaluates three schedules of nab-Paclitaxel as prolonged chemotherapy administration strategy. Each of three arms will be compared to a historical reference of seven-month median progression-free survival (PFS) based on the most recent trial with docetaxel as control arm to determine whether any of the three arms are worthy of further investigation.
Interventions
DRUGnab-Paclitaxel
Induction phase: 3 cycles of nab-Paclitaxel days 1, 8, 15. Maintenance phase with three maintenance schedules of nab-Paclitaxel (same total dose per cycle, different number of administrations)
Sponsors
ETOP IBCSG Partners Foundation
Breast International Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed HER2-negative metastatic (stage IV) breast cancer. * Measurable or non-measurable, but radiologically evaluable, disease according to RECIST 1.1 criteria. * Female aged 18 years or older. * Life expectancy \> 3 months. * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. * Either ER-positive or ER-negative disease. Patients with ER-positive disease must be endocrine resistant, defined as having failed at least one prior endocrine therapy for breast cancer, or must be candidates for first-line chemotherapy. * If previously treated with a taxane or anthracycline in the neoadjuvant or adjuvant setting, the period from end of treatment to disease recurrence must have been \> 12 months (\> 365 days). * Radiation therapy, if given and regardless of site, must be completed at least 2 weeks prior to randomization. * Normal hematologic status. * Normal renal function. * Normal liver function. * Normal cardiac function. * Women of childbearing potential: documented negative pregnancy test within 2 weeks prior to randomization, and acceptable birth control during the duration of the trial therapy and for a period of 6 months following the last administration of study drug. * Written Informed Consent (IC) must be signed and dated by the patient and the Investigator prior to randomization. * Completed baseline Quality of Life Form. * The patient has been informed of and agrees to data transfer and handling, in accordance with national data protection guidelines. * Availability of an formalin fixed paraffin embedded (FFPE) block from the primary tumor (breast lesion) for submission to central pathology review and for translational research. * Written consent to pathology material submission, signed and dated by the patient and the Investigator prior to randomization.
Exclusion criteria
* Any prior chemotherapy for metastatic breast cancer. * Presence of central nervous system (CNS) metastasis. * Peripheral neuropathy grade 2 or higher (CTCAE version 4). * Significant uncontrolled cardiac disease (i.e. unstable angina, recent myocardial infarction within prior 6 months), patients classified as having a New York Heart Association (NYHA) class III or IV congestive heart failure. * Pregnant or lactating. * Prior history of non-breast malignancy (except for adequately controlled basal cell carcinoma of the skin, carcinoma in situ of the cervix, in situ carcinoma of the bladder). * Any concurrent condition which in the Investigator's opinion makes it inappropriate for the patient to participate in the trial or which would jeopardize compliance with the protocol. * Contraindications or known hypersensitivity to the study medication or excipients. * The use of any anti-cancer investigational agents within 30 days prior to expected start of trial treatment. * Inability or unwillingness to abide by the study protocol or cooperate fully with the Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Reported after 18.2 months median follow-up since randomization | Time from randomization until objective disease progression \[progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions\] or death, whichever occurs first. For patients without progression, follow-up was censored at the date of last disease assessment without progression, unless death occurred within a short period of time (12 weeks) following the date last known progression-free, in which case the death was counted as a PFS event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Reported after 18.2 months median follow-up since randomization | Time from randomization until death from any cause, or censored at date last known alive |
| Changes in Physical Well-being (Change From Day 1 of Cycle 4 to Day 1 of Cycle 6) | Assessed from day 1 of cycle 4 through day 1 of cycle 12 | Primary quality of life=physical well being; endpoint based on the GLQ 8. The indicator was in Linear Analogue Self-Assessment (LASA) format ranging 0-100 (0=as bad as it can be, 100=as good as it can be). |
| Feasibility of Treatment: Number of Participants Completed Treatment According to the Protocol for at Least 24 Weeks | Baseline to 24 weeks follow-up | Whether or not the patient completed treatment according to the protocol for at least 24 weeks. Patients who progressed within 24 weeks were considered as not completing. |
| Disease Control: Overall Response of Stable Disease for a Duration of ≥24 Weeks | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 18 months | Overall response of stable disease (or non-CR/non-PD for patients with non-measurable disease) for a duration of ≥24 weeks, or better (i.e., partial or complete response) according to RECIST criteria \[Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.\] |
| Best Overall Response | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 18 months | Best response according to RECIST 1.1 criteria \[assessed by MRI\] recorded from the start of treatment across all time points until end of study treatment. Confirmation of partial or complete response by an additional scan was not requested in this trial. |
Countries
Belgium, Ireland, Italy, Slovenia, Spain, Switzerland
Contacts
STUDY_CHAIRAlessandra Gennari, MD
Division of Medical Oncology, E.O. Galliera, Genoa, Italy
STUDY_CHAIRGuy Jerusalem, MD, PhD
CHU Sart Tilman and University of Liège, Liège, Belgium
Participant flow
Recruitment details
255 patients were randomized between 16April2013 and 7August2015 at 35 centers in 5 countries.
Participants by arm
| Arm | Count |
|---|---|
| A: Nab-Paclitaxel 150 mg/m2 Days 1,15 Arm A: Induction\* nab-Paclitaxel 125 mg/m2 on days 1,8,15 every 28 days for 3 cycles followed by maintenance nab-Paclitaxel 150 mg/m2 administered on days 1, 15 of each 28-day cycle (total 300mg/m2 per cycle) until progression or unacceptable toxicity.
\*Following Amendment 1, the dose in the induction phase dose in all three arms was reduced to 125 mg/m² from 150 mg/m².
nab-Paclitaxel: Induction phase: 3 cycles of nab-Paclitaxel days 1, 8, 15. Maintenance phase with three maintenance schedules of nab-Paclitaxel (same total dose per cycle, different number of administrations) | 83 |
| B: Nab-Paclitaxel 100 mg/m2 Days 1,8,15 Arm B: Induction\* nab-Paclitaxel 125 mg/m2 on days 1,8,15 every 28 days for 3 cycles followed by maintenance nab-Paclitaxel 100 mg/m2 administered on days 1, 8, 15 of each 28-day cycle (total 300mg/m2 per cycle) until progression or unacceptable toxicity.
\*Following Amendment 1, the dose in the induction phase dose in all three arms was reduced to 125 mg/m² from 150 mg/m².
nab-Paclitaxel: Induction phase: 3 cycles of nab-Paclitaxel days 1, 8, 15. Maintenance phase with three maintenance schedules of nab-Paclitaxel (same total dose per cycle, different number of administrations) | 86 |
| C: Nab-Paclitaxel 75 mg/m2 Days 1,8,15,22 Arm C: Induction\* nab-Paclitaxel 125 mg/m2 on days 1,8,15 every 28 days for 3 cycles followed by maintenance nab-Paclitaxel 75 mg/m2 administered on days 1, 8, 15, 22 of each 28-day cycle (total 300mg/m2 per cycle) until progression or unacceptable toxicity.
\*Following Amendment 1, the dose in the induction phase dose in all three arms was reduced to 125 mg/m² from 150 mg/m².
nab-Paclitaxel: Induction phase: 3 cycles of nab-Paclitaxel days 1, 8, 15. Maintenance phase with three maintenance schedules of nab-Paclitaxel (same total dose per cycle, different number of administrations) | 86 |
| Total | 255 |
Baseline characteristics
| Characteristic | A: Nab-Paclitaxel 150 mg/m2 Days 1,15 | Total | C: Nab-Paclitaxel 75 mg/m2 Days 1,8,15,22 | B: Nab-Paclitaxel 100 mg/m2 Days 1,8,15 |
|---|---|---|---|---|
| Age, Continuous | 58 years | 58 years | 60 years | 56 years |
| ER Status Negative | 11 Participants | 45 Participants | 17 Participants | 17 Participants |
| ER Status Positive | 72 Participants | 210 Participants | 69 Participants | 69 Participants |
| Prior Taxanes No | 57 Participants | 175 Participants | 60 Participants | 58 Participants |
| Prior Taxanes Yes | 26 Participants | 80 Participants | 26 Participants | 28 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White/Caucasian | 83 Participants | 253 Participants | 85 Participants | 85 Participants |
| Region of Enrollment Belgium | 10 participants | 33 participants | 11 participants | 10 participants |
| Region of Enrollment Ireland | 21 participants | 61 participants | 18 participants | 22 participants |
| Region of Enrollment Italy | 12 participants | 40 participants | 12 participants | 16 participants |
| Region of Enrollment Slovenia | 3 participants | 7 participants | 3 participants | 1 participants |
| Region of Enrollment Spain | 17 participants | 42 participants | 13 participants | 12 participants |
| Region of Enrollment Switzerland | 20 participants | 75 participants | 29 participants | 25 participants |
| Sex: Female, Male Female | 83 Participants | 255 Participants | 86 Participants | 86 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Type of Radiologically Evaluable Disease Measurable | 68 Participants | 210 Participants | 69 Participants | 73 Participants |
| Type of Radiologically Evaluable Disease Non-measurable only | 15 Participants | 45 Participants | 17 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| other Total, other adverse events | 78 / 83 | 83 / 86 | 80 / 86 |
| serious Total, serious adverse events | 51 / 83 | 43 / 86 | 57 / 86 |
Outcome results
Primary
Progression-free Survival
Time from randomization until objective disease progression \[progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions\] or death, whichever occurs first. For patients without progression, follow-up was censored at the date of last disease assessment without progression, unless death occurred within a short period of time (12 weeks) following the date last known progression-free, in which case the death was counted as a PFS event.
Time frame: Reported after 18.2 months median follow-up since randomization
Population: Intention-to-treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A: Nab-Paclitaxel 150 mg/m2 Days 1,15 | Progression-free Survival | 7.9 months |
| B: Nab-Paclitaxel 100 mg/m2 Days 1,8,15 | Progression-free Survival | 9.0 months |
| C: Nab-Paclitaxel 75 mg/m2 Days 1,8,15,22 | Progression-free Survival | 8.5 months |
Comparison: For each arm separately, PFS was compared to the historic PFS of first-line docetaxel using a one-sample one-sided log-rank test, of the null hypothesis, H0: median PFS≤7 months vs. H1: median PFS\>7 months.p-value: 0.12Log Rank
Comparison: For each arm separately, PFS was compared to the historic PFS of first-line docetaxel using a one-sample one-sided log-rank test, of the null hypothesis, H0: median PFS≤7 months vs. H1: median PFS\>7 months.p-value: 0.03Log Rank
Comparison: For each arm separately, PFS was compared to the historic PFS of first-line docetaxel using a one-sample one-sided log-rank test, of the null hypothesis, H0: median PFS≤7 months vs. H1: median PFS\>7 months.p-value: 0.2Log Rank
Secondary
Best Overall Response
Best response according to RECIST 1.1 criteria \[assessed by MRI\] recorded from the start of treatment across all time points until end of study treatment. Confirmation of partial or complete response by an additional scan was not requested in this trial.
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 18 months
Population: Intention to treat population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| A: Nab-Paclitaxel 150 mg/m2 Days 1,15 | Best Overall Response | Progressive Disease (PD) | 3 Participants |
| A: Nab-Paclitaxel 150 mg/m2 Days 1,15 | Best Overall Response | Stable Disease (SD)/Non-CR/Non-PD | 39 Participants |
| A: Nab-Paclitaxel 150 mg/m2 Days 1,15 | Best Overall Response | Complete Response (CR) | 5 Participants |
| A: Nab-Paclitaxel 150 mg/m2 Days 1,15 | Best Overall Response | Partial Response (PR) | 34 Participants |
| A: Nab-Paclitaxel 150 mg/m2 Days 1,15 | Best Overall Response | Not Evaluable (NE) | 2 Participants |
| B: Nab-Paclitaxel 100 mg/m2 Days 1,8,15 | Best Overall Response | Stable Disease (SD)/Non-CR/Non-PD | 33 Participants |
| B: Nab-Paclitaxel 100 mg/m2 Days 1,8,15 | Best Overall Response | Complete Response (CR) | 6 Participants |
| B: Nab-Paclitaxel 100 mg/m2 Days 1,8,15 | Best Overall Response | Partial Response (PR) | 41 Participants |
| B: Nab-Paclitaxel 100 mg/m2 Days 1,8,15 | Best Overall Response | Progressive Disease (PD) | 5 Participants |
| B: Nab-Paclitaxel 100 mg/m2 Days 1,8,15 | Best Overall Response | Not Evaluable (NE) | 1 Participants |
| C: Nab-Paclitaxel 75 mg/m2 Days 1,8,15,22 | Best Overall Response | Not Evaluable (NE) | 5 Participants |
| C: Nab-Paclitaxel 75 mg/m2 Days 1,8,15,22 | Best Overall Response | Progressive Disease (PD) | 11 Participants |
| C: Nab-Paclitaxel 75 mg/m2 Days 1,8,15,22 | Best Overall Response | Complete Response (CR) | 4 Participants |
| C: Nab-Paclitaxel 75 mg/m2 Days 1,8,15,22 | Best Overall Response | Stable Disease (SD)/Non-CR/Non-PD | 31 Participants |
| C: Nab-Paclitaxel 75 mg/m2 Days 1,8,15,22 | Best Overall Response | Partial Response (PR) | 35 Participants |
Secondary
Changes in Physical Well-being (Change From Day 1 of Cycle 4 to Day 1 of Cycle 6)
Primary quality of life=physical well being; endpoint based on the GLQ 8. The indicator was in Linear Analogue Self-Assessment (LASA) format ranging 0-100 (0=as bad as it can be, 100=as good as it can be).
Time frame: Assessed from day 1 of cycle 4 through day 1 of cycle 12
Population: Patients who started the maintenance phase of treatment (cycle 4)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| A: Nab-Paclitaxel 150 mg/m2 Days 1,15 | Changes in Physical Well-being (Change From Day 1 of Cycle 4 to Day 1 of Cycle 6) | -2 units on a scale |
| B: Nab-Paclitaxel 100 mg/m2 Days 1,8,15 | Changes in Physical Well-being (Change From Day 1 of Cycle 4 to Day 1 of Cycle 6) | 1 units on a scale |
| C: Nab-Paclitaxel 75 mg/m2 Days 1,8,15,22 | Changes in Physical Well-being (Change From Day 1 of Cycle 4 to Day 1 of Cycle 6) | 4 units on a scale |
Secondary
Disease Control: Overall Response of Stable Disease for a Duration of ≥24 Weeks
Overall response of stable disease (or non-CR/non-PD for patients with non-measurable disease) for a duration of ≥24 weeks, or better (i.e., partial or complete response) according to RECIST criteria \[Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.\]
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 18 months
Population: Intention to treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| A: Nab-Paclitaxel 150 mg/m2 Days 1,15 | Disease Control: Overall Response of Stable Disease for a Duration of ≥24 Weeks | 54 Participants |
| B: Nab-Paclitaxel 100 mg/m2 Days 1,8,15 | Disease Control: Overall Response of Stable Disease for a Duration of ≥24 Weeks | 59 Participants |
| C: Nab-Paclitaxel 75 mg/m2 Days 1,8,15,22 | Disease Control: Overall Response of Stable Disease for a Duration of ≥24 Weeks | 52 Participants |
Secondary
Feasibility of Treatment: Number of Participants Completed Treatment According to the Protocol for at Least 24 Weeks
Whether or not the patient completed treatment according to the protocol for at least 24 weeks. Patients who progressed within 24 weeks were considered as not completing.
Time frame: Baseline to 24 weeks follow-up
Population: Intention to treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| A: Nab-Paclitaxel 150 mg/m2 Days 1,15 | Feasibility of Treatment: Number of Participants Completed Treatment According to the Protocol for at Least 24 Weeks | 40 Participants |
| B: Nab-Paclitaxel 100 mg/m2 Days 1,8,15 | Feasibility of Treatment: Number of Participants Completed Treatment According to the Protocol for at Least 24 Weeks | 43 Participants |
| C: Nab-Paclitaxel 75 mg/m2 Days 1,8,15,22 | Feasibility of Treatment: Number of Participants Completed Treatment According to the Protocol for at Least 24 Weeks | 44 Participants |
Secondary
Overall Survival
Time from randomization until death from any cause, or censored at date last known alive
Time frame: Reported after 18.2 months median follow-up since randomization
Population: Intention to treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A: Nab-Paclitaxel 150 mg/m2 Days 1,15 | Overall Survival | 25.8 months |
| B: Nab-Paclitaxel 100 mg/m2 Days 1,8,15 | Overall Survival | 26.2 months |
| C: Nab-Paclitaxel 75 mg/m2 Days 1,8,15,22 | Overall Survival | 25.5 months |