Breast Cancer
Conditions
Brief summary
The primary purpose of this study is to help answer the following research questions: * whether the chemotherapy combination therapy Pemetrexed-Carboplatin or Gemcitabine-Vinorelbine can help participants with advanced breast cancer to make the tumor smaller or disappear and for how long * to learn more about the side effects in each chemotherapy combination treatment arm * to assess how participants with advanced breast cancer report health changes while receiving any of the chemotherapy combination arm
Interventions
DRUGPemetrexed
600 mg/m\^2, administered intravenously (IV) every 21 days until disease progression or unacceptable toxicity.
DRUGCarboplatin
AUC 5 mg\*min/mL, administered IV every 21 days until disease progression or unacceptable toxicity.
DRUGGemcitabine
1200 mg/m\^2 gemcitabine, administered IV on day 1 and day 8 every 21 days until disease progression or unacceptable toxicity.
DRUGVinorelbine
30 mg/m\^2 vinorelbine administered IV on day 1 and day 8 every 21 days until disease progression or unacceptable toxicity.
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Females with histologic or cytologic diagnosis of advanced breast cancer. Lesions should not be amenable to surgery or radiation of curative intent. * Performance status of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG) performance status scale. * One prior chemotherapy containing anthracyclines as (neo)adjuvant or palliative 1st-line treatment. * One prior chemotherapy containing taxanes as (neo) adjuvant or palliative 1st-line treatment. * Prior radiation therapy is allowed to less than 25% of the bone marrow. Participants must have recovered from the toxic effects of the treatment prior to study enrollment (except for alopecia). Prior radiotherapy must be completed 30 days before study entry. Lesions that have been radiated cannot be included as sites of measurable disease unless clear tumor progression has been documented in these lesions since the end of radiation therapy. * At least one uni-dimensionally measurable lesion meeting Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Positron emission tomography \[PET\] scans and ultrasounds may not be used. * Antitumoral hormonal treatment must be discontinued prior to enrollment. * Estimated life expectancy of at least 3 months. * Participant compliance and geographic proximity that allow adequate follow-up. * Adequate organ function * Female participants of childbearing potential must test negative for pregnancy within 7 days of enrollment based on a urine and/or serum pregnancy test and agree to use a reliable method of birth control during and for 6 months following the last dose of study drug. * Participants must sign an informed consent document. * Female participants must be at least 18 years of age.
Exclusion criteria
* Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry. * Have previously completed or withdrawn from this study or any other study investigating Pemetrexed, Gemcitabine, Carboplatin or Vinorelbine * Have received more than one line of chemotherapy in Metastatic Breast Cancer. Participants having received more than one combination of anthracycline plus taxane. * Are pregnant or breast-feeding. * Have serious concomitant systemic disorders (e.g., active infection) that, in the opinion of the investigator, would compromise the safety of the participant or compromise the participant's ability to complete the study. * Have a prior malignancy other than breast cancer, carcinoma in situ of the cervix, or nonmelanoma skin cancer, unless that prior malignancy was diagnosed and definitively treated at least 5 years previously with no subsequent evidence of recurrence. * Are unable to interrupt aspirin or other nonsteroidal anti-inflammatory agents for a 5-day period (8-day period for long-acting agents such as piroxicam), unless the Creatinine Clearance is greater than or equal to 80 ml/min. * Have central nervous system (CNS) metastases. * Have clinically relevant (by physical exam) third-space fluid collections (for example, ascites or pleural effusions) that cannot be controlled by drainage or other procedures prior to study entry. * Are unable or unwilling to take folic acid, vitamin B12 supplementation, or dexamethasone. * Concurrent administration of any other antitumor therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response Rate | Baseline up to 30 days of follow-up after 21 cycles of treatment | Participants with best overall response determined from complete response (CR) or partial response (PR) according to Response Criteria in Solid Tumors (RECIST) criteria. For CR or PR, best response must be confirmed. A second assessment performed at 28 days. Two determinations of CR before progression required for rate to=CR. Evaluations include: CR=Disappearance of lesions. PR=≥30% size decrease of lesions. Progressive Disease (PD)=≥20% size increase of lesions. Stable Disease (SD)=Not enough shrinkage for PR nor enough increase for PD. Overall Response Rate=PR+CR/Qualified Participants\*100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | Time of response to progressive disease (up to 19 months) | DOR-RECIST criteria of (Complete Response \[CR =Disappearance of lesions\] or Partial Response \[PR=≥30% size decrease of lesions\]) is defined as time from the date when measurement criteria are met for CR or PR until the date of first observation of progressive disease (PD) or death from study disease. For participants who die from causes other than study disease and without PD, DOR will be censored at the date of death. For participants who have not died as of the data cut-off date who are without PD, DOR was censored at last contact date. |
| Time to Progressive Disease (PD) | Baseline to measured PD (up to 25.1 months) | Time to PD is defined as the time from the date of study enrollment to the first documented date of PD or death from study disease. For participants who die from causes other than study disease and without PD, time to PD was censored at the date of death. For participants not known to have died as of the data cut-off date and do not have PD, time to PD was censored at the last contact date. For participants who received subsequent chemotherapy (after discontinuation from the study chemotherapy) prior to disease progression, time to PD was censored at the date of subsequent chemotherapy. |
| Time To Treatment Failure (TTTF) | Baseline to end of treatment (up to 21.9 months) | TTTF is defined as the time from date of study enrollment to the first documented date of death, PD, or study treatment discontinuation due to adverse event (AE). For participants not known to have discontinued as of the data cut-off date, TTTF is censored at the last contact date. For participants who discontinued for reasons other than death, PD, or AE, TTTF is censored at the date of discontinuation. |
| Time to Response | Baseline to response (up to 7.8 months) | Time to response (Complete Response(CR) or Partial Response (PR) is defined as the time from the date of study enrollment to the first date when the measurement criteria are met for complete response or partial response (whichever status is recorded first). CR=Disappearance of target lesions lesions. PR=≥30% size decrease of lesions. |
| Number of Participants With Adverse Events (AE) | every cycle up to twenty-one 21-day cycles (plus 30 days of follow-up) | A listing of adverse events is presented in the Reported Adverse Event Module. |
Countries
Germany, Italy, South Africa, Spain, Turkey (Türkiye)
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pemetrexed/Carboplatin Pemetrexed 600 mg/m\^2 was administered intravenously over approximately 10 minutes on Day 1. Carboplatin was given over approximately 30 minutes on Day 1 beginning after the end of the Pemetrexed infusion, consistent with a target of AUC 5.0 mg\*min/mL. The cycle of treatment was 21 days. | 69 |
| Gemcitabine/Vinorelbine Vinorelbine 30 mg/m\^2 was given over approximately 6-10 minutes on Day 1 and Day 8.
Gemcitabine 1200 mg/m\^2 was given over approximately 30 minutes on Day 1 and Day 8 beginning after the end of the Vinorelbine infusion. The cycle of treatment was 21 days. | 66 |
| Total | 135 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 7 |
| Overall Study | Death due to Study Disease | 1 | 0 |
| Overall Study | Entry Criteria Not Met | 1 | 2 |
| Overall Study | Physician Decision | 17 | 12 |
| Overall Study | Progressive Disease | 34 | 37 |
| Overall Study | Subject Decision | 6 | 8 |
Baseline characteristics
| Characteristic | Pemetrexed/Carboplatin | Total | Gemcitabine/Vinorelbine |
|---|---|---|---|
| Age Continuous | 51.9 years STANDARD_DEVIATION 11.38 | 52.1 years STANDARD_DEVIATION 10.87 | 52.3 years STANDARD_DEVIATION 10.4 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG 0 | 39 participants | 78 participants | 39 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG 1 | 28 participants | 55 participants | 27 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG 2 | 2 participants | 2 participants | 0 participants |
| Hormonal Receptor Status Estrogen and/or Progesterone Positive | 49 participants | 93 participants | 44 participants |
| Hormonal Receptor Status Estrogen and Progesterone Negative | 19 participants | 40 participants | 21 participants |
| Hormonal Receptor Status Unknown | 1 participants | 2 participants | 1 participants |
| Human Epidermal Growth Factor Receptor 2 (HER-2/Neu) Negative | 53 participants | 102 participants | 49 participants |
| Human Epidermal Growth Factor Receptor 2 (HER-2/Neu) Not Performed | 0 participants | 1 participants | 1 participants |
| Human Epidermal Growth Factor Receptor 2 (HER-2/Neu) Positive | 12 participants | 25 participants | 13 participants |
| Human Epidermal Growth Factor Receptor 2 (HER-2/Neu) Unknown | 4 participants | 7 participants | 3 participants |
| Pathological Diagnosis Carcinoma, Ductal, Breast | 64 participants | 118 participants | 54 participants |
| Pathological Diagnosis Carcinoma, Inflammatory, Breast | 1 participants | 4 participants | 3 participants |
| Pathological Diagnosis Carcinoma, Lobular, Breast | 4 participants | 9 participants | 5 participants |
| Pathological Diagnosis Carcinoma, Mixed Cell, Breast | 0 participants | 1 participants | 1 participants |
| Pathological Diagnosis Other | 0 participants | 3 participants | 3 participants |
| Race/Ethnicity, Customized African | 1 participants | 4 participants | 3 participants |
| Race/Ethnicity, Customized Caucasian | 67 participants | 128 participants | 61 participants |
| Race/Ethnicity, Customized East Asian | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Hispanic | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized West Asian | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Germany | 9 participants | 21 participants | 12 participants |
| Region of Enrollment Israel | 9 participants | 18 participants | 9 participants |
| Region of Enrollment Italy | 16 participants | 30 participants | 14 participants |
| Region of Enrollment South Africa | 7 participants | 13 participants | 6 participants |
| Region of Enrollment Spain | 18 participants | 36 participants | 18 participants |
| Region of Enrollment Switzerland | 5 participants | 9 participants | 4 participants |
| Region of Enrollment Turkey | 5 participants | 8 participants | 3 participants |
| Sex: Female, Male Female | 69 Participants | 135 Participants | 66 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Tumor Differentiation Grade Grade I | 6 participants | 9 participants | 3 participants |
| Tumor Differentiation Grade Grade II | 25 participants | 52 participants | 27 participants |
| Tumor Differentiation Grade Grade III | 32 participants | 62 participants | 30 participants |
| Tumor Differentiation Grade Unknown | 6 participants | 12 participants | 6 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 64 / 65 | 66 / 66 |
| serious Total, serious adverse events | 18 / 65 | 22 / 66 |
Outcome results
Primary
Tumor Response Rate
Participants with best overall response determined from complete response (CR) or partial response (PR) according to Response Criteria in Solid Tumors (RECIST) criteria. For CR or PR, best response must be confirmed. A second assessment performed at 28 days. Two determinations of CR before progression required for rate to=CR. Evaluations include: CR=Disappearance of lesions. PR=≥30% size decrease of lesions. Progressive Disease (PD)=≥20% size increase of lesions. Stable Disease (SD)=Not enough shrinkage for PR nor enough increase for PD. Overall Response Rate=PR+CR/Qualified Participants\*100.
Time frame: Baseline up to 30 days of follow-up after 21 cycles of treatment
Population: All randomized patients who qualified for tumor response analysis by the following criteria: Females with histologic or cytologic diagnosis of advanced breast cancer previously treated with anthracyclines and taxanes. No concurrent antitumor therapy. Presence of measurable disease as defined by RECIST. Treatment with at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed/Carboplatin | Tumor Response Rate | Overall Response | 26.6 percentage of participants |
| Pemetrexed/Carboplatin | Tumor Response Rate | Complete Response | 0.0 percentage of participants |
| Pemetrexed/Carboplatin | Tumor Response Rate | Partial Response | 26.6 percentage of participants |
| Pemetrexed/Carboplatin | Tumor Response Rate | Stable Disease | 35.9 percentage of participants |
| Pemetrexed/Carboplatin | Tumor Response Rate | Progressive Disease | 26.6 percentage of participants |
| Pemetrexed/Carboplatin | Tumor Response Rate | Unknown | 10.9 percentage of participants |
| Gemcitabine/Vinorelbine | Tumor Response Rate | Progressive Disease | 27.9 percentage of participants |
| Gemcitabine/Vinorelbine | Tumor Response Rate | Overall Response | 29.5 percentage of participants |
| Gemcitabine/Vinorelbine | Tumor Response Rate | Stable Disease | 34.4 percentage of participants |
| Gemcitabine/Vinorelbine | Tumor Response Rate | Complete Response | 3.3 percentage of participants |
| Gemcitabine/Vinorelbine | Tumor Response Rate | Unknown | 8.2 percentage of participants |
| Gemcitabine/Vinorelbine | Tumor Response Rate | Partial Response | 26.2 percentage of participants |
Secondary
Duration of Response (DOR)
DOR-RECIST criteria of (Complete Response \[CR =Disappearance of lesions\] or Partial Response \[PR=≥30% size decrease of lesions\]) is defined as time from the date when measurement criteria are met for CR or PR until the date of first observation of progressive disease (PD) or death from study disease. For participants who die from causes other than study disease and without PD, DOR will be censored at the date of death. For participants who have not died as of the data cut-off date who are without PD, DOR was censored at last contact date.
Time frame: Time of response to progressive disease (up to 19 months)
Population: All randomized participants with CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed/Carboplatin | Duration of Response (DOR) | 7.7 Months |
| Gemcitabine/Vinorelbine | Duration of Response (DOR) | 7.5 Months |
Secondary
Number of Participants With Adverse Events (AE)
A listing of adverse events is presented in the Reported Adverse Event Module.
Time frame: every cycle up to twenty-one 21-day cycles (plus 30 days of follow-up)
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed/Carboplatin | Number of Participants With Adverse Events (AE) | Adverse Events | 64 participants |
| Pemetrexed/Carboplatin | Number of Participants With Adverse Events (AE) | Serious Adverse Events | 18 participants |
| Gemcitabine/Vinorelbine | Number of Participants With Adverse Events (AE) | Adverse Events | 66 participants |
| Gemcitabine/Vinorelbine | Number of Participants With Adverse Events (AE) | Serious Adverse Events | 22 participants |
Secondary
Time to Progressive Disease (PD)
Time to PD is defined as the time from the date of study enrollment to the first documented date of PD or death from study disease. For participants who die from causes other than study disease and without PD, time to PD was censored at the date of death. For participants not known to have died as of the data cut-off date and do not have PD, time to PD was censored at the last contact date. For participants who received subsequent chemotherapy (after discontinuation from the study chemotherapy) prior to disease progression, time to PD was censored at the date of subsequent chemotherapy.
Time frame: Baseline to measured PD (up to 25.1 months)
Population: All randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed/Carboplatin | Time to Progressive Disease (PD) | 5.1 Months |
| Gemcitabine/Vinorelbine | Time to Progressive Disease (PD) | 5.6 Months |
Secondary
Time to Response
Time to response (Complete Response(CR) or Partial Response (PR) is defined as the time from the date of study enrollment to the first date when the measurement criteria are met for complete response or partial response (whichever status is recorded first). CR=Disappearance of target lesions lesions. PR=≥30% size decrease of lesions.
Time frame: Baseline to response (up to 7.8 months)
Population: All randomized participants with CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed/Carboplatin | Time to Response | 1.8 Months |
| Gemcitabine/Vinorelbine | Time to Response | 1.8 Months |
Secondary
Time To Treatment Failure (TTTF)
TTTF is defined as the time from date of study enrollment to the first documented date of death, PD, or study treatment discontinuation due to adverse event (AE). For participants not known to have discontinued as of the data cut-off date, TTTF is censored at the last contact date. For participants who discontinued for reasons other than death, PD, or AE, TTTF is censored at the date of discontinuation.
Time frame: Baseline to end of treatment (up to 21.9 months)
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed/Carboplatin | Time To Treatment Failure (TTTF) | 4.8 Months |
| Gemcitabine/Vinorelbine | Time To Treatment Failure (TTTF) | 5.1 Months |