Breast Cancer
Conditions
Brief summary
An open-label randomized Phase II study in order to explore two different sequential anthracycline-based neoadjuvant treatment regimens in female patients with primary, operable breast cancer (T2-T4/N0-2/M0).
Interventions
DRUGpemetrexed
500 mg/m\^2, intravenous (IV), every 21 days, 4 cycles (1-4)
DRUGcyclophosphamide
600 mg/m2, intravenous (IV), every 21 days, 4 cycles (1-4)
DRUGdoxorubicin
60 mg/m\^2, intravenous (IV), every 21 days, 4 cycles (1-4)
DRUGdocetaxel
100 mg/m\^2, intravenous (IV), every 21 days, 4 cycles (5-8)
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed diagnosis of primary early breast cancer, tumor size greater than or equal to 2 centimeters (cm), of Stages T2-T4/N0-2. * Performance status 0-2 Eastern Cooperative Oncology Group (ECOG). * Adequate organ function (bone marrow, hepatic, renal, cardiac).
Exclusion criteria
* Prior anthracyclines as part of prior anticancer therapy. * Concurrent antitumor therapy. * Second primary malignancy. * Serious concomitant systemic disorder. * Pre-existing sensorial or motor neuropathy * Grade 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Pathological Complete Response | surgery after eight 21-day cycles of chemotherapy | pathological assessment of tissue removed during surgery to determine if tumor tissue is still present after chemotherapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Clinical Tumor Response After the First Sequence of Chemotherapy | Cycles 1-4 (21-day cycles) | The number of participants with a clinical tumor response based on measurement of tumor size after the first sequence of chemotherapy, without a second confirmatory tumor measurement, per protocol. |
| Number of Participants With a Clinical Tumor Response After the Second Sequence of Chemotherapy | Cycles 5-8 (21-day cycles) | The number of participants with a clinical tumor response based on measurement of tumor size after the second sequence of chemotherapy, without a second confirmatory tumor measurement required, per protocol. |
| Number of Patients With Histologically Negative Axillary Lymph Node Status at Surgery | surgery after eight 21-day cycles of chemotherapy | Histologically negative is defined as no malignant cells present in the axillary lymph nodes during surgery. |
| Disease-free Survival | baseline through post surgery, follow-up for 3 years post-surgery (up to 5.2 years after randomization) | Disease-free survival is defined as the time from date of study enrollment (randomization) to first date of progressive disease (PD) or death from any cause. PD per Response Evaluation Criteria In Solid Tumors (RECIST) criteria is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. For patients not known to have died as of the data cut-off date and who do not have progressive disease, disease-free survival was censored at the last contact date. |
Countries
Germany, Italy, Russia, Spain
Participant flow
Pre-assignment details
The one participant who was randomized to pemetrexed but treated with cyclophosphamide is included in the as randomized group (pemetrexed) for the purposes of the participant flow, excluded from the efficacy analyses (per the protocol), but in the as treated group (cyclophosphamide) for safety analyses.
Participants by arm
| Arm | Count |
|---|---|
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel pemetrexed: 500 mg/m\^2, intravenous (IV), every 21 days, 4 cycles (1-4) doxorubicin: 60 mg/m\^2, intravenous (IV), every 21 days, 4 cycles (1-4) docetaxel: 100 mg/m\^2, intravenous (IV), every 21 days, 4 cycles (5-8) | 135 |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel cyclophosphamide: 600 mg/m\^2, intravenous (IV), every 21 days, 4 cycles (1-4) doxorubicin: 60 mg/m\^2, intravenous (IV), every 21 days, 4 cycles (1-4) docetaxel: 100 mg/m\^2, intravenous (IV), every 21 days, 4 cycles (5-8) | 122 |
| Total | 257 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 9 |
| Overall Study | Physician Decision | 3 | 3 |
| Overall Study | Progressive Disease | 7 | 3 |
| Overall Study | Sponsor Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 1 |
Baseline characteristics
| Characteristic | Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Total |
|---|---|---|---|
| Age Continuous | 49.9 years STANDARD_DEVIATION 10.2 | 49.5 years STANDARD_DEVIATION 9.7 | 49.7 years STANDARD_DEVIATION 10 |
| Eastern Cooperative Oncology Group Performance Status Grade 0 - Fully active | 131 participants | 113 participants | 244 participants |
| Eastern Cooperative Oncology Group Performance Status Grade 1- Ambulatory; strenuous activity restricted | 1 participants | 4 participants | 5 participants |
| Eastern Cooperative Oncology Group Performance Status Status Unknown | 3 participants | 5 participants | 8 participants |
| Estrogen and Progesterone Receptor Status At least one positive | 90 participants | 78 participants | 168 participants |
| Estrogen and Progesterone Receptor Status Both negative | 45 participants | 44 participants | 89 participants |
| Menopausal Status Peri-Menopausal | 6 participants | 7 participants | 13 participants |
| Menopausal Status Post-Menopausal | 60 participants | 48 participants | 108 participants |
| Menopausal Status Pre-Menopausal | 69 participants | 66 participants | 135 participants |
| Menopausal Status Unknown | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity Caucasian | 135 participants | 119 participants | 254 participants |
| Race/Ethnicity Hispanic | 0 participants | 3 participants | 3 participants |
| Region of Enrollment Germany | 74 participants | 71 participants | 145 participants |
| Region of Enrollment Italy | 11 participants | 8 participants | 19 participants |
| Region of Enrollment Russian Federation | 14 participants | 14 participants | 28 participants |
| Region of Enrollment Spain | 36 participants | 29 participants | 65 participants |
| Sex: Female, Male Female | 135 Participants | 122 Participants | 257 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 134 / 134 | 120 / 123 |
| serious Total, serious adverse events | 15 / 134 | 25 / 123 |
Outcome results
Primary
Number of Participants With a Pathological Complete Response
pathological assessment of tissue removed during surgery to determine if tumor tissue is still present after chemotherapy
Time frame: surgery after eight 21-day cycles of chemotherapy
Population: Participants meeting the following criteria qualify for pathological tumor response:~* Histologic diagnosis of primary operable breast cancer~* No concurrent antitumor therapy~* Specimen for evaluation of pathological response obtained upon surgery~* Treatment with at least one dose of study drug of the assigned study regimen.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Pathological Complete Response | Pathological Complete Response | 21 participants |
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Pathological Complete Response | Tumor Cells Still Present | 99 participants |
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Pathological Complete Response | Not evaluable | 7 participants |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Pathological Complete Response | Pathological Complete Response | 24 participants |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Pathological Complete Response | Tumor Cells Still Present | 89 participants |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Pathological Complete Response | Not evaluable | 6 participants |
Comparison: Confidence Interval for pathological complete response in the Pemetrexed treatment arm.95% CI: [10.5, 24.2]
Comparison: Confidence Interval for pathological complete response in the Cyclophosphamide treatment group.95% CI: [13.4, 28.5]
Secondary
Disease-free Survival
Disease-free survival is defined as the time from date of study enrollment (randomization) to first date of progressive disease (PD) or death from any cause. PD per Response Evaluation Criteria In Solid Tumors (RECIST) criteria is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. For patients not known to have died as of the data cut-off date and who do not have progressive disease, disease-free survival was censored at the last contact date.
Time frame: baseline through post surgery, follow-up for 3 years post-surgery (up to 5.2 years after randomization)
Population: All randomized participants. In the Pemetrexed plus Doxorubicin, Followed by Docetaxel arm, 99 participants were censored. In the Cyclophosphamide plus Doxorubicin, Followed by Docetaxel arm, 94 participants were censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Disease-free Survival | NA months |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Disease-free Survival | NA months |
Secondary
Number of Participants With a Clinical Tumor Response After the First Sequence of Chemotherapy
The number of participants with a clinical tumor response based on measurement of tumor size after the first sequence of chemotherapy, without a second confirmatory tumor measurement, per protocol.
Time frame: Cycles 1-4 (21-day cycles)
Population: Participants meeting following criteria qualify for clinical tumor response:~* Histologic diagnosis of primary operable breast cancer~* No concurrent antitumor therapy up to surgery~* Presence of measurable disease as defined by RECIST.~* Treatment with at least one dose of study drug of assigned study regimen.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the First Sequence of Chemotherapy | Complete Response | 8 participants |
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the First Sequence of Chemotherapy | Partial Response | 45 participants |
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the First Sequence of Chemotherapy | Stable Disease | 49 participants |
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the First Sequence of Chemotherapy | Progressive Disease | 3 participants |
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the First Sequence of Chemotherapy | Unknown | 17 participants |
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the First Sequence of Chemotherapy | Not Done | 9 participants |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the First Sequence of Chemotherapy | Unknown | 17 participants |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the First Sequence of Chemotherapy | Complete Response | 9 participants |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the First Sequence of Chemotherapy | Progressive Disease | 2 participants |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the First Sequence of Chemotherapy | Partial Response | 43 participants |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the First Sequence of Chemotherapy | Not Done | 4 participants |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the First Sequence of Chemotherapy | Stable Disease | 44 participants |
Secondary
Number of Participants With a Clinical Tumor Response After the Second Sequence of Chemotherapy
The number of participants with a clinical tumor response based on measurement of tumor size after the second sequence of chemotherapy, without a second confirmatory tumor measurement required, per protocol.
Time frame: Cycles 5-8 (21-day cycles)
Population: Participants meeting following criteria qualify for clinical tumor response:~* Histologic diagnosis of primary operable breast cancer~* No concurrent antitumor therapy up to surgery~* Presence of measurable disease as defined by RECIST.~* Treatment with at least one dose of study drug of assigned study regimen.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the Second Sequence of Chemotherapy | Complete Tumor Response | 19 participants |
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the Second Sequence of Chemotherapy | Partial Tumor Response | 59 participants |
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the Second Sequence of Chemotherapy | Stable Disease | 35 participants |
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the Second Sequence of Chemotherapy | Progressive Disease | 2 participants |
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the Second Sequence of Chemotherapy | Unknown | 9 participants |
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the Second Sequence of Chemotherapy | Not Done | 7 participants |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the Second Sequence of Chemotherapy | Unknown | 10 participants |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the Second Sequence of Chemotherapy | Complete Tumor Response | 21 participants |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the Second Sequence of Chemotherapy | Progressive Disease | 1 participants |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the Second Sequence of Chemotherapy | Partial Tumor Response | 60 participants |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the Second Sequence of Chemotherapy | Not Done | 3 participants |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Number of Participants With a Clinical Tumor Response After the Second Sequence of Chemotherapy | Stable Disease | 24 participants |
Secondary
Number of Patients With Histologically Negative Axillary Lymph Node Status at Surgery
Histologically negative is defined as no malignant cells present in the axillary lymph nodes during surgery.
Time frame: surgery after eight 21-day cycles of chemotherapy
Population: Participants meeting the following criteria qualify for pathological tumor response:~* Histologic diagnosis of primary operable breast cancer~* No concurrent antitumor therapy~* Specimen for evaluation of pathological response obtained upon surgery~* Treatment with at least one dose of study drug of the assigned study regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pemetrexed Plus Doxorubicin, Followed by Docetaxel | Number of Patients With Histologically Negative Axillary Lymph Node Status at Surgery | 64 participants |
| Cyclophosphamide Plus Doxorubicin, Followed by Docetaxel | Number of Patients With Histologically Negative Axillary Lymph Node Status at Surgery | 63 participants |