Metastatic Breast Cancer
Conditions
Keywords
metastatic, breast, cancer
Brief summary
Ixabepilone adds significantly to the antitumor effectiveness of capecitabine in both ER+ and triple negative breast cancer. Ixabepilone has substantial antitumor activity in taxane-refractory patients and novel combinations are needed in this poor prognosis population. Carboplatin in combination with gemcitabine or paclitaxel has activity in metastatic breast cancer (MBC); there is also demonstrated activity of the gemcitabine/carboplatin combination in the ER+ versus triple negative subsets. A Phase I study of ixabepilone plus carboplatin in solid tumor patients demonstrated the safety of this combination at the doses and schedule proposed for this Phase II trial (BMS data on file).
Detailed description
This is a Phase II, open label, nonrandomized, parallel, noncomparative, study of 2 groups (as stratified below). All patients will receive ixabepilone 20 mg/m2 on Days 1 and 8 and carboplatin AUC=2.5 on Days 1 and 8 of each 21-day cycle. Patients will be stratified by either hormone receptor positive \[ER+/PR+/HER2-, ER+/PR-/HER2-, ER-/PR+/HER2-\]- (n=50) or triples negative ER-/PR-/HER2- (n=53). If one group fulfills their accrual goal first, registration into that strata will be stopped and only patients meeting stratification requirements for the other group will be registered.
Interventions
DRUGIxabepilone
20 mg/m2 on Days 1 and 8
DRUGCarboplatin
carboplatin AUC=2.5 on Days 1 and 8
Sponsors
Bristol-Myers Squibb
US Oncology Research
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Male or female patients will be eligible for inclusion in this study if they meet all of the following criteria: 1. Has measurable metastatic and or locally unresectable breast cancer with documented HER2 negative (-) disease 2. Has at least 1 measurable lesion per RECIST criteria (lesions that can be accurately measured in at least 1 dimension (longest diameter (LD) to be recorded) as ≥20 mm with conventional techniques (CT, MRI, X-ray) or as ≥10 mm with spiral CT scan). Irradiated lesions cannot be used to assess response but can be used to assess progression. 3. Has received up to 2 (0 to 2) prior chemotherapy regimens for metastatic disease with the following conditions: •Has had no prior treatment with ixabepilone or platinum agents 4. Has had no adjuvant chemotherapy within the 6 months prior to study, but may have received prior anthracyclines and/or taxanes as adjuvant chemotherapy 5. 3 weeks or more have elapsed since last chemotherapy treatment and any related toxicities have resolved to \<Grade 1; at least 30 days must have passed since any investigational product has been administered and associated toxicities must have resolved to \<Grade 1 (if applicable). 6. Has an ECOG Performance Status (PS) 0-2 7. Is ≥18 years of age 8. Has a life expectancy of at least 12 weeks 9. Has laboratory values of: White blood cell (WBC) count ≥3000 x 106/L Absolute neutrophil count (ANC) ≥1500 x 106/L Hemoglobin ≥9 g/dL Total bilirubin ≤1x upper limit of normal (ULN) AST and ALT ≤2.5 x ULN Alkaline phosphatase ≤2.5 x ULN; up to 5xULN if elevation is due to bone disease Serum creatinine ≤1.5 mg/dL Calculated creatinine clearance \>50 mL/min (based on Cockroft and Gault method \[Appendix III\]) Platelet count ≥100,000 x 106/L 10. If patient has had radiation therapy, it has been completed \>3 weeks prior to the start of study treatment. NOTE: Previously irradiated lesions will not be evaluable. However, these patients will still be eligible. 11. Has a negative serum pregnancy test within 7 calendar days prior to registration (female patients of childbearing potential \[not surgically sterilized and between menarche and 1 year postmenopause 12. If fertile, patient (male or female) has agreed to use an acceptable method of birth control to avoid pregnancy for the duration of the study and for a period of 3 months thereafter 13. Has signed the most recent Patient Informed Consent Form 14. Has signed a Patient Authorization Form Note: Having tissue available is not an inclusion criterion in this study; however, available tissue will be collected (see Section 8) if possible.
Exclusion criteria
A patient will be excluded from this study if he or she meets any of the following criteria: 1. Had prior treatment with ixabepilone or other epothilones 2. Had prior radiation to ≥30% of major bone marrow containing areas (pelvis, lumbar spine) 3. Has ER+ and/or PR+ disease that has not progressed on hormone therapy, unless the patient has life-threatening or rapidly progressing visceral disease 4. Has HER2+ disease (IHC staining of 3+ \[uniform, intense membrane staining of \>30% of invasive tumor cells\]), a FISH result of more than 6 HER2 gene copies per nucleus or a FISH ratio (HER2 gene signals to chromosome 17 signals of \>2.2) 5. Has only lytic bone disease or nonmeasurable disease only 6. Has a known, prior, severe (NCI CTCAE Grade 3-4) history of hypersensitivity reaction to a drug formulated in Cremophor®EL (polyoxyethylated castor oil) or has history of severe allergic reactions to cisplatin or other platinum-containing compounds 7. Has been treated previously with a platinum-containing agent 8. Is receiving concurrent immunotherapy, hormonal therapy, or radiation therapy. Washout periods for these prior therapies are specified in Section 5. 9. Is receiving concurrent investigational therapy or has received such therapy within the 30 days prior to dosing Day 1 10. Has neuropathy (motor or sensory) \>Grade 1 11. Has evidence of CNS involvement requiring radiation or steroid treatment. Patients with stable brain metastases who are off steroids at least 2 weeks are eligible. 12. Has a serious uncontrolled intercurrent medical or psychiatric illness, including serious infection 13. Has clinically relevant coagulopathy either secondary to hepatic dysfunction or an underlying condition requiring therapeutic anticoagulation (specifically, A-fib, history of DVT). A daily aspirin or Plavix for CAD are permitted. 14. Has a history of other malignancy within the last 5 years (except cured basal cell carcinoma of skin and carcinoma in situ of uterine cervix), which could affect the diagnosis or assessment of any of the study drugs 15. Is a pregnant or breast feeding woman 16. Is unable to comply with the requirements of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 24 months | Evaluate the objective response rate calculated as CR+ PR in the population evaluable for response, as well as the 2 subgroups (hormone receptor positive \[ER+/PR+/HER2-, ER+/PR-/HER2-, ER-/PR+/HER2-\]) and ER-/PR-HER2-, separately). 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate (CBR) | 24 months | Clinical benefit rate (CBR) defined as objective response rate (ORR, CR + PR) + SD \>= 6 months |
| Progression-free Survival (PFS) | 24 months | PFS is measured from the date of randomization to the date of first documented disease progression or date of death, whichever comes first. If a patient neither progresses nor dies, this patient will be censored at last contact date. 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 |
| Overall Survival (OS) | 24 months | OS is measured from the date of randomization to the date of death for a dead patient. If a patient is still alive or is lost to follow up, the patient will be censored at the last contact date. |
| Time to Response | 24 months | For patients who achieve a major objective response (CR or PR) the time to response will be assessed as the date of registration to the date of response. |
| Duration of Response | 30 months | The duration of response is measured from the time measurement criteria are first met for CR/PR until the first date that recurrent or progressive disease is objectively documented. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Triple Negative ER-/PR-/HER2- patients who received receive Ixabepilone 20 mg/m2 on Days 1 and 8 and Carboplatin AUC=2.5 on Days 1 and 8 of each 21-day cycle. | 49 |
| HR Positive ER+/PR+/HER2-, or ER+/PR-/HER2-, or ER-/PR+/HER2- patients who received receive Ixabepilone 20 mg/m2 on Days 1 and 8 and Carboplatin AUC=2.5 on Days 1 and 8 of each 21-day cycle. | 54 |
| Total | 103 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 15 | 18 |
| Overall Study | Disease Progression | 25 | 29 |
| Overall Study | Investigator Request | 2 | 1 |
| Overall Study | Other | 3 | 1 |
| Overall Study | Patient Request | 4 | 4 |
Baseline characteristics
| Characteristic | Total | HR Positive | Triple Negative |
|---|---|---|---|
| Age, Continuous | 55.9 years STANDARD_DEVIATION 9.9 | 56.7 years STANDARD_DEVIATION 10.6 | 55.0 years STANDARD_DEVIATION 9 |
| Race/Ethnicity, Customized Asian | 2 participants | 2 participants | 0 participants |
| Race/Ethnicity, Customized Black | 24 participants | 10 participants | 14 participants |
| Race/Ethnicity, Customized Caucasian | 72 participants | 39 participants | 33 participants |
| Race/Ethnicity, Customized Hawaiian | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Hispanic | 4 participants | 2 participants | 2 participants |
| Region of Enrollment United States | 103 participants | 54 participants | 49 participants |
| Sex: Female, Male Female | 103 Participants | 54 Participants | 49 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 | 44 / 48 | 52 / 53 |
| serious Total, serious adverse events | 10 / 48 | 5 / 53 |
Outcome results
Primary
Objective Response Rate (ORR)
Evaluate the objective response rate calculated as CR+ PR in the population evaluable for response, as well as the 2 subgroups (hormone receptor positive \[ER+/PR+/HER2-, ER+/PR-/HER2-, ER-/PR+/HER2-\]) and ER-/PR-HER2-, separately). 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: 24 months
Population: Evaluable population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Triple Negative | Objective Response Rate (ORR) | 30.4 percentage of participants |
| HR Positive | Objective Response Rate (ORR) | 34 percentage of participants |
Secondary
Clinical Benefit Rate (CBR)
Clinical benefit rate (CBR) defined as objective response rate (ORR, CR + PR) + SD \>= 6 months
Time frame: 24 months
Population: Evaluable population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Triple Negative | Clinical Benefit Rate (CBR) | 41.3 percentage of participants |
| HR Positive | Clinical Benefit Rate (CBR) | 56.6 percentage of participants |
Secondary
Duration of Response
The duration of response is measured from the time measurement criteria are first met for CR/PR until the first date that recurrent or progressive disease is objectively documented.
Time frame: 30 months
Population: Patients who achieved CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Triple Negative | Duration of Response | 6.68 months |
| HR Positive | Duration of Response | 5.92 months |
Secondary
Overall Survival (OS)
OS is measured from the date of randomization to the date of death for a dead patient. If a patient is still alive or is lost to follow up, the patient will be censored at the last contact date.
Time frame: 24 months
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Triple Negative | Overall Survival (OS) | 12.5 months |
| HR Positive | Overall Survival (OS) | 17.9 months |
Secondary
Progression-free Survival (PFS)
PFS is measured from the date of randomization to the date of first documented disease progression or date of death, whichever comes first. If a patient neither progresses nor dies, this patient will be censored at last contact date. 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
Time frame: 24 months
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Triple Negative | Progression-free Survival (PFS) | 7.6 months |
| HR Positive | Progression-free Survival (PFS) | 7.6 months |
Secondary
Time to Response
For patients who achieve a major objective response (CR or PR) the time to response will be assessed as the date of registration to the date of response.
Time frame: 24 months
Population: Patients who achieve a major objective response (CR or PR).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Triple Negative | Time to Response | 1.27 months |
| HR Positive | Time to Response | 1.60 months |