Breast Neoplasm
Conditions
Keywords
cancer, breast, metastatic, triple negative
Brief summary
The primary objective of this study is to determine whether overall response to cetuximab combined with cisplatin is better than overall response to cisplatin alone together with showing that the overall response for cetuximab and cisplatin was above a pre-specified threshold of 0.2 in the treatment of triple negative metastatic breast cancer. The secondary objective of this study is to compare the differences between the two treatment groups using the following criteria : Progression-Free Survival (PFS) Time, Overall Survival (OS), Time to Response (TTR) and Safety.
Interventions
Subjects will receive an initial dose of cetuximab 400 milligram per square meter (mg/m\^2) followed by weekly doses of 250 mg/m\^2. All doses will be given by intravenous (IV) infusion. Subjects will receive cisplatin (75 mg/m\^2 IV on Day 1) every 3 weeks, with a maximum of 6 cycles. Administration of the Investigational Medicinal Product (IMP) will be stopped upon the first occurrence of disease progression, unacceptable toxicity or withdrawal of consent.
DRUGcisplatin
Subjects will receive cisplatin (75 mg/m\^2 IV on Day 1) every 3 weeks, with a maximum of 6 cycles. Subjects have the option of receiving cetuximab plus cisplatin at progression within the first 6 cycles, or cetuximab alone at progression after the 6 cycles. Administration of the IMP will be stopped upon the first occurrence of disease progression (except in cisplatin arm where switch to cetuximab plus cisplatin, or cetuximab alone is possible), unacceptable toxicity or withdrawal of consent.
Sponsors
Merck KGaA, Darmstadt, Germany
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 confirmed diagnosis of metastatic breast cancer (Stage IV) * Estrogen Receptor \[ER\] negative, PgR negative and HER2 less than 3+ expression by immunohistochemistry (IHC) * No more than 1 prior chemotherapy received for treating this metastatic breast cancer * No more than 1 prior anthracycline and/or taxane regimen (either adjuvant or metastatic setting) * Other protocol-defined inclusion criteria may apply
Exclusion criteria
* Prior platinum agent * Prior mitomycin * Known history of brain metastases * Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response (BOR) | Evaluations were performed every 6 weeks until progression reported between day of first participant randomized, 20 June 2007, until cut-off date, 31 July 2009 | Percentage of participants with best overall (objective) response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) Time | Time from randomization to disease progression, death or last tumour assessment, reported between day of first participant randomized, 20 June 2007, until cut-off date, 31 July 2009 | The PFS was defined as the duration from randomization until radiological progression according to investigator (based on RECIST) or death due to any cause. Only deaths within 85 days of last tumor assessment were considered. Participants without event were censored on the date of last tumor assessment. |
| Overall Survival (OS) Time | Time from randomization to death or last day known to be alive, reported between day of first participant randomized, 20 June 2007, until cut-off date, 05 April 2010 | The OS time was defined as the time from randomization to death. Participants without event were censored at the last date known to be alive or at the clinical cut-off date, whatever was earlier. |
| Time to Response (TTR) | Time from the first dose of study treatment (cetuximab or cisplatin) to first assessment of CR or PR, reported between day of first participant randomized, 20 June 2007, until cut-off date, 31 July 2009 | The TTR was determined for participants whose confirmed BOR (based on RECIST) was either a CR or a PR . It was defined as the time from the first dose study treatment until the date of the first assessment of confirmed CR or PR. |
| Safety- Number of Participants Experiencing Any Adverse Event (AE) | Time from first dose up to 30 days after last dose of study treatment, reported between day of first dose of study treatment, 20 June 2007, until cut-off date 05 April 2010 | Number of participants experiencing any AE. AEs: Any untoward medical occurrence in the form of signs, clinically significant abnormalities in laboratory findings, diseases, symptoms, or worsening of complications. |
Countries
Australia, Austria, Belgium, Germany, Ireland, Israel, Italy, New Zealand, Portugal, Spain, United Kingdom
Participant flow
Pre-assignment details
Following a mandate of the Spanish health authority, data from all participants at site 0904 (Spain) were excluded from analyses due to evidence of misconduct, with significant deviations from Good Clinical Practice guidelines. Therefore, 173 of the 181 randomized participants were considered in the full analysis set (FAS).
Participants by arm
| Arm | Count |
|---|---|
| Cisplatin and Cetuximab Cisplatin 75 milligram per square meter (mg/m\^2) intravenous (IV) infusion administered on Day 1 until every 3 weeks with a maximum of 6 cycles and cetuximab initially 400 mg/m\^2 followed by 250 mg/m\^2 IV infusion weekly. Participants who demonstrated at least stable disease (SD) up to 6 cycles of cisplatin continued treatment with cetuximab only until progressive disease (PD) or occurrence of unacceptable toxicity. | 115 |
| Cisplatin Cisplatin 75 mg/m\^2 IV infusion administered on Day 1 until every 3 weeks with a maximum of 6 cycles until the first occurrence of PD, unacceptable toxicity or withdrawal of consent. | 58 |
| Total | 173 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 2 |
| Overall Study | Death | 4 | 3 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other | 3 | 0 |
| Overall Study | Progressive Disease | 86 | 42 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Randomized but not treated | 1 | 1 |
| Overall Study | Symptomatic Deterioration | 2 | 3 |
| Overall Study | Withdrawal by Subject | 6 | 2 |
Baseline characteristics
| Characteristic | Cisplatin and Cetuximab | Cisplatin | Total |
|---|---|---|---|
| Age, Continuous | 52.9 years STANDARD_DEVIATION 12.53 | 51.7 years STANDARD_DEVIATION 10.67 | 52.5 years STANDARD_DEVIATION 11.92 |
| Age, Customized < 65 years | 93 participants | 51 participants | 144 participants |
| Age, Customized >= 65 years | 22 participants | 7 participants | 29 participants |
| Duration from initial breast cancer diagnosis to date of metastasis | 15.7 months | 15.4 months | 15.5 months |
| Duration of breast cancer from primary tumor diagnosis to informed consent | 19.2 months | 17.3 months | 18.7 months |
| Duration of metastatic breast cancer from metastasis to informed consent | 0.9 months | 0.8 months | 0.9 months |
| Naturally post menopausal participants No | 51 participants | 22 participants | 73 participants |
| Naturally post menopausal participants Yes | 64 participants | 36 participants | 100 participants |
| Participants categorized by site of metastasis Bone | 37 participants | 20 participants | 57 participants |
| Participants categorized by site of metastasis Liver | 36 participants | 17 participants | 53 participants |
| Participants categorized by site of metastasis Lung | 64 participants | 26 participants | 90 participants |
| Participants categorized by site of metastasis Lymph nodes (by medical review) | 49 participants | 22 participants | 71 participants |
| Participants categorized by site of metastasis Other | 15 participants | 8 participants | 23 participants |
| Participants categorized by site of metastasis Skin | 20 participants | 8 participants | 28 participants |
| Sex: Female, Male Female | 115 Participants | 58 Participants | 173 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 112 / 114 | 55 / 57 | 28 / 31 |
| serious Total, serious adverse events | 41 / 114 | 13 / 57 | 6 / 31 |
Outcome results
Primary
Best Overall Response (BOR)
Percentage of participants with best overall (objective) response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST).
Time frame: Evaluations were performed every 6 weeks until progression reported between day of first participant randomized, 20 June 2007, until cut-off date, 31 July 2009
Population: FAS population included all participants who were randomized as described in the pre-assignment details.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cisplatin and Cetuximab | Best Overall Response (BOR) | 20.0 percentage of participants |
| Cisplatin | Best Overall Response (BOR) | 10.3 percentage of participants |
p-value: 0.110995% CI: [0.809, 5.591]Cochran-Mantel-Haenszel
Secondary
Overall Survival (OS) Time
The OS time was defined as the time from randomization to death. Participants without event were censored at the last date known to be alive or at the clinical cut-off date, whatever was earlier.
Time frame: Time from randomization to death or last day known to be alive, reported between day of first participant randomized, 20 June 2007, until cut-off date, 05 April 2010
Population: FAS population included all participants who were randomized as described in the pre-assignment details.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cisplatin and Cetuximab | Overall Survival (OS) Time | 12.9 months |
| Cisplatin | Overall Survival (OS) Time | 9.4 months |
p-value: 0.312195% CI: [0.561, 1.204]Log Rank
Secondary
Progression-Free Survival (PFS) Time
The PFS was defined as the duration from randomization until radiological progression according to investigator (based on RECIST) or death due to any cause. Only deaths within 85 days of last tumor assessment were considered. Participants without event were censored on the date of last tumor assessment.
Time frame: Time from randomization to disease progression, death or last tumour assessment, reported between day of first participant randomized, 20 June 2007, until cut-off date, 31 July 2009
Population: FAS population included all participants who were randomized as described in the pre-assignment details.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cisplatin and Cetuximab | Progression-Free Survival (PFS) Time | 3.7 months |
| Cisplatin | Progression-Free Survival (PFS) Time | 1.5 months |
p-value: 0.032495% CI: [0.47, 0.969]Log Rank
Secondary
Safety- Number of Participants Experiencing Any Adverse Event (AE)
Number of participants experiencing any AE. AEs: Any untoward medical occurrence in the form of signs, clinically significant abnormalities in laboratory findings, diseases, symptoms, or worsening of complications.
Time frame: Time from first dose up to 30 days after last dose of study treatment, reported between day of first dose of study treatment, 20 June 2007, until cut-off date 05 April 2010
Population: Safety population included all the participants who received at least 1 dose of study medication (that is cisplatin or cetuximab).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cisplatin and Cetuximab | Safety- Number of Participants Experiencing Any Adverse Event (AE) | 114 participants |
| Cisplatin | Safety- Number of Participants Experiencing Any Adverse Event (AE) | 57 participants |
Secondary
Time to Response (TTR)
The TTR was determined for participants whose confirmed BOR (based on RECIST) was either a CR or a PR . It was defined as the time from the first dose study treatment until the date of the first assessment of confirmed CR or PR.
Time frame: Time from the first dose of study treatment (cetuximab or cisplatin) to first assessment of CR or PR, reported between day of first participant randomized, 20 June 2007, until cut-off date, 31 July 2009
Population: FAS population included all participants who were randomized as described in the pre-assignment details.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cisplatin and Cetuximab | Time to Response (TTR) | 1.4 months |
| Cisplatin | Time to Response (TTR) | 1.3 months |
p-value: 0.599395% CI: [0.262, 2.17]Log Rank