Breast Neoplasms
Conditions
Keywords
breast neoplasm, breast cancer, breast tumor
Brief summary
The purpose of this study is to determine if E7389 is a safe and effective treatment for advanced/metastatic breast cancer.
Detailed description
The primary objective is to determine the response rate (RR) to E7389 monotherapy administered as an IV bolus of 1.4 mg/m\^2 on Days 1, 8, and 15 of a 28-Day cycle and on Days 1 and 8 of a 21-day cycle in patients with advanced/metastatic breast cancer treated with chemotherapy including an anthracycline and a taxane, with previously documented progression during or within six months following the last dose of prior chemotherapy. The secondary objectives are to evaluate: * The safety and tolerability of E7389 monotherapy in this patient population; * The antitumor activity of E7389 as determined by duration of response, time to progression, and overall survival; * Quality of life measured by the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire/tumor-related symptom improvement or worsening measured by pain intensity on a visual analog scale (VAS), analgesics consumption, weight changes and performance status (PS); * Tumor pharmacogenetics and their possible relationship to response (assessment of beta-tubulin isotype mRNA on biopsy sample) in patients who have signed a separate consent form
Interventions
DRUGE7389
The first cohort of subjects were to receive E7389 1.4 mg/m\^2 as an intravenous (IV) bolus on Days 1, 8, and 15 of a 28-day cycle. A second cohort of subjects was added and were to receive E7389 1.4 mg/m\^2 as an IV bolus on Days 1 and 8 of a 21-day cycle.
Sponsors
Eisai Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female patients with histologically or cytologically confirmed carcinoma of the breast * Patients with advanced/metastatic disease that is not amenable to curative therapy (either surgery or radiation therapy) * Patients must have measurable disease by the RECIST criteria, defined as at least one lesion that can be accurately measured in at least one diameter (at least 10 mm in longest diameter (LD) by spiral computer tomography (CT) scan, or at least 20 mm by standard techniques; If the only measurable lesion is a lymph node, it must measure at least 20 mm in LD. If a single lesion is identified as the target lesion, a cytological or histological confirmation of breast carcinoma is required. * Patients must have had prior treatment with an anthracycline and a taxane (either sequential or in combination) and may have had prior treatment with other agents as well. * Patients must have progressed within six months of the last dose of chemotherapy, or experienced disease progression while receiving chemotherapy for advanced/metastatic disease. * Resolution of all chemotherapy or radiation-related toxicities to less than grade 1 severity * Age ≥ 18 years * Eastern Cooperative Oncology Group (ECOG) Performance Status (APPENDIX 4) of 0 or 1 * Life expectancy of ≥ 3 months * Adequate renal function as evidenced by serum creatinine ≤ 1.5 mg/dL or calculated creatinine clearance ≥ 50 mL/minute (min) per the Cockcroft and Gault formula * Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L, hemoglobin ≥ 10.0 g/dL (a hemoglobin \<10.0 g/dL would be acceptable if it can be corrected by growth factor or transfusion), and platelet count ≥ 100 x 10\^9/L * Adequate liver function as evidenced by bilirubin ≤ 1.5 mg/dL and alkaline phosphatase, alanine transaminase (ALT), and aspartate transaminase (AST) ≤ 3 times the upper limits of normal (ULN) (in the case of liver metastases ≤ 5 x ULN) * Patients willing and able to complete the FACT-B questionnaire, Analgesic Diary, Pain VAS, and the tumor-related symptomatic assessment * Patients willing and able to comply with the study protocol for the duration of the study * A sample from the diagnostic biopsy (paraffin block) must be available * Written informed consent prior to any study-specific screening procedures with the understanding that the patient may withdraw consent at any time without prejudice
Exclusion criteria
* Patients who have received chemotherapy, radiation, hormonal therapy, or Herceptin within 2 weeks of E7389 treatment start * Radiation therapy encompassing \> 10% of marrow * Failure to recover from any chemotherapy related or other therapy related toxicity at study entry that is deemed to be clinically significant by the study investigator * Prior treatment with Mitomycin C or nitrosoureas * Prior high dose chemotherapy with hematopoietic stem cell rescue in the past two years * Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen * Active symptomatic brain metastasis; Patients with central Nervous System (CNS) metastasis are considered eligible if they have completed local therapy and discontinued from corticosteroids for at least two weeks before starting treatment with E7389 * Patients with meningeal carcinomatosis * Patients who require therapeutic anti-coagulant therapy with Warfarin or related compounds; Mini dose warfarin for catheter related thrombosis prophylaxis is permitted * Women who are pregnant or breast-feeding; Women of childbearing potential with either a positive pregnancy test at Screening or no pregnancy test. Women of childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception in the opinion of the Investigator. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. * Severe /uncontrolled intercurrent illness/infection * Significant cardiovascular impairment (history of congestive heart failure \> NYHA grade II, unstable angina or myocardial infarction within the past six months, or serious cardiac arrhythmia) * Patients with organ allografts * Patients with known positive HIV status * Patients who have had a prior malignancy, other than carcinoma in situ of the cervix, or non-melanoma skin cancer, unless the prior malignancy was diagnosed and definitively treated ≥ 5 years previously with no subsequent evidence of recurrence * Patients with pre-existing neuropathy \> Grade 1 * Patients with a hypersensitivity to halichondrin B and/or halichondrin B chemical derivative * Patients who participated in a prior E7389 clinical trial * Patients with other significant disease or disorders that, in the Investigator's opinion, would exclude the patient from the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Confirmed 4 to 8 weeks after first observed | Defined as the percentage of subjects with CR or PR from the start of treatment until disease progression or recurrence. Lesions measured by computed tomography (CT) scan and magnetic resonance imaging (MRI). Objective response rate: complete response (CR-disappearance of all lesions)+ partial response (PR-30% decrease in lesion diameter), Progressive Disease (PD-20% increase in lesion diameter), stable disease (SD-neither shrinkage nor increase of lesions). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | From CR or partial response PR (whichever recorded first) to date of recurrent or progressive disease | Measured from the time measurement criteria were met for complete response (CR) or partial response (PR) (whichever was first recorded) until the first date that recurrent progressive disease was objectively documented (taking as a reference for progressive disease the smallest measurements recorded since the treatment started). |
| Progression Free Survival | From start of study drug administration to progressive disease or death | Defined as the time from start of study drug administration until progressive disease or death from any cause during the study period in the absence of disease progression. |
| Overall Survival | From start of study drug administration to death | Defined as the time from the start of study drug administration until death from any cause |
| Change From Baseline to Study Termination in Quality of Life Measures Using Functional Assessment of Cancer Therapy-Breast (FACT-B) Scores | At Screening, Day 1 of each cycle, and 30 days after last dose of study drug | The FACT-B questionnaire consists of 36 questions each scored from 0-4. The total score is calculated by summing these scores. The total possible range is from 0 to 144. The higher scores indicate a better health-related quality of life. This measures emotional, functional, physical, and social well being as well as concerns specific to patients with breast cancer. |
Countries
United States
Participant flow
Recruitment details
This study was recruited at 23 centers in U.S. during the period of Nov 2004 to Nov 2006.
Participants by arm
| Arm | Count |
|---|---|
| E7389 28 Day Schedule E7389 1.4 mg/m\^2 intravenous bolus on Days 1, 8 and 15 of a 28 day cycle. | 70 |
| E7389 21 Day Schedule E7389 1.4 mg/m\^2 intravenous bolus on Days 1 and 8 of a 21 day cycle. | 33 |
| Total | 103 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 1 |
| Overall Study | Physician Decision | 1 | 3 |
| Overall Study | Progressive Disease | 55 | 27 |
| Overall Study | Reason not given | 1 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 1 |
Baseline characteristics
| Characteristic | E7389 28 Day Schedule | Total | E7389 21 Day Schedule |
|---|---|---|---|
| Age Continuous | 55.9 years STANDARD_DEVIATION 10.7 | 55.4 years STANDARD_DEVIATION 10.76 | 54.5 years STANDARD_DEVIATION 10.99 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 3 participants | 5 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 5 participants | 11 participants | 6 participants |
| Race/Ethnicity, Customized Hispanic/Latino | 9 participants | 12 participants | 3 participants |
| Race/Ethnicity, Customized More than one race | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 2 participants | 3 participants | 1 participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized White | 51 participants | 72 participants | 21 participants |
| Sex: Female, Male Female | 70 Participants | 103 Participants | 33 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 | 69 / 70 | 33 / 33 |
| serious Total, serious adverse events | 23 / 70 | 18 / 33 |
Outcome results
Primary
Overall Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST)
Defined as the percentage of subjects with CR or PR from the start of treatment until disease progression or recurrence. Lesions measured by computed tomography (CT) scan and magnetic resonance imaging (MRI). Objective response rate: complete response (CR-disappearance of all lesions)+ partial response (PR-30% decrease in lesion diameter), Progressive Disease (PD-20% increase in lesion diameter), stable disease (SD-neither shrinkage nor increase of lesions).
Time frame: Confirmed 4 to 8 weeks after first observed
Population: Per Protocol Population (Independent Reviewer Assessment)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E7389 28 Day Schedule | Overall Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Complete Response: | 0 percentage of participants |
| E7389 28 Day Schedule | Overall Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Partial Response | 10.2 percentage of participants |
| E7389 21 Day Schedule | Overall Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Complete Response: | 0 percentage of participants |
| E7389 21 Day Schedule | Overall Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Partial Response | 14.3 percentage of participants |
Secondary
Change From Baseline to Study Termination in Quality of Life Measures Using Functional Assessment of Cancer Therapy-Breast (FACT-B) Scores
The FACT-B questionnaire consists of 36 questions each scored from 0-4. The total score is calculated by summing these scores. The total possible range is from 0 to 144. The higher scores indicate a better health-related quality of life. This measures emotional, functional, physical, and social well being as well as concerns specific to patients with breast cancer.
Time frame: At Screening, Day 1 of each cycle, and 30 days after last dose of study drug
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| E7389 28 Day Schedule | Change From Baseline to Study Termination in Quality of Life Measures Using Functional Assessment of Cancer Therapy-Breast (FACT-B) Scores | Change From Baseline | -2.2 units on a scale |
| E7389 28 Day Schedule | Change From Baseline to Study Termination in Quality of Life Measures Using Functional Assessment of Cancer Therapy-Breast (FACT-B) Scores | Baseline Score | 102.0 units on a scale |
| E7389 28 Day Schedule | Change From Baseline to Study Termination in Quality of Life Measures Using Functional Assessment of Cancer Therapy-Breast (FACT-B) Scores | Study Termination Score | 104.3 units on a scale |
| E7389 21 Day Schedule | Change From Baseline to Study Termination in Quality of Life Measures Using Functional Assessment of Cancer Therapy-Breast (FACT-B) Scores | Change From Baseline | 0 units on a scale |
| E7389 21 Day Schedule | Change From Baseline to Study Termination in Quality of Life Measures Using Functional Assessment of Cancer Therapy-Breast (FACT-B) Scores | Baseline Score | 101.0 units on a scale |
| E7389 21 Day Schedule | Change From Baseline to Study Termination in Quality of Life Measures Using Functional Assessment of Cancer Therapy-Breast (FACT-B) Scores | Study Termination Score | 98.4 units on a scale |
Secondary
Duration of Response
Measured from the time measurement criteria were met for complete response (CR) or partial response (PR) (whichever was first recorded) until the first date that recurrent progressive disease was objectively documented (taking as a reference for progressive disease the smallest measurements recorded since the treatment started).
Time frame: From CR or partial response PR (whichever recorded first) to date of recurrent or progressive disease
Population: Intent to Treat/Safety Population (Investigator Assessment)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| E7389 28 Day Schedule | Duration of Response | 204 days |
| E7389 21 Day Schedule | Duration of Response | 121 days |
Secondary
Overall Survival
Defined as the time from the start of study drug administration until death from any cause
Time frame: From start of study drug administration to death
Population: Per Protocol Population (Investigator Assessment)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| E7389 28 Day Schedule | Overall Survival | 239 days |
| E7389 21 Day Schedule | Overall Survival | NA days |
Secondary
Progression Free Survival
Defined as the time from start of study drug administration until progressive disease or death from any cause during the study period in the absence of disease progression.
Time frame: From start of study drug administration to progressive disease or death
Population: Per Protocol Population (Investigator Assessment)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| E7389 28 Day Schedule | Progression Free Survival | 57 days |
| E7389 21 Day Schedule | Progression Free Survival | 86 days |