Breast Cancer
Conditions
Keywords
Metastatic, Triple Negative, Stage IV
Brief summary
In this research study, we are looking at the anti-tumor effects of Cabozantinib (XL184) in metastatic breast cancer. Data suggest that MET expression and activation are important for initiation and progression of triple-negative breast cancer (TNBC). We evaluated the efficacy of cabozantinib (XL184), a novel inhibitor of multiple receptor tyrosine kinases, including MET and VEGFR2, in patients with metastatic TNBC.
Detailed description
OBJECTIVES: Primary \* To evaluate the activity of cabozantinib, as defined by objective response rate in patients with triple-negative metastatic breast cancer Secondary * To evaluate progression free survival * To evaluate c-Met and phospho c-Met expression in archival tumor tissue * To evaluate the incidence of c-Met amplified circulating tumor cells at baseline * To evaluate potential plasma biomarkers of cabozantinib DESIGN: This study uses a two-stage design enrolling 35 patients to evaluate efficacy of cabozantinib based on overall response defined as complete or partial response per RECIST1.1 criteria. The null and alternative overall response rates were 5% and 20%. If one or more patients enrolled in the stage one cohort (n=13 patients) achieve PR or better then accrual proceeds to stage two (n=22 patients).
Interventions
DRUGCabozantinib
Sponsors
Dana-Farber Cancer Institute
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
* Histologically or cytologically confirmed invasive breast cancer with stage IV disease * Primary tumor and/or metastasis must be ER-negative, PR-negative and HER2-negative * May have received 0-3 prior chemotherapeutic regimens for metastatic breast cancer. Must be off treatment for at least 21 days prior to enrollment * Must have discontinued all biologic therapy at least 14 days before enrollment * May have received prior radiation therapy in the early stage or metastatic setting, but must have completed treatment at least 14 days prior to enrollment * Must agree to use medically acceptable methods of contraception * Confirmed availability of formalin-fixed, paraffin-embedded tumor tissue * Able to swallow tablets
Exclusion criteria
* Pregnant or breastfeeding * Received another investigational agent within 14 days prior to enrollment * Received prior c-Met inhibitor * Known brain metastases that are untreated, symptomatic or require therapy to control symptoms * Psychiatric illness or social situation that could limit ability to comply with study requirements * Require concomitant treatment in therapeutic doses with anticoagulants or antiplatelet agents * Diagnosis of another malignancy requiring systemic treatment within the last two years (except non-melanoma skin cancer or in-situ carcinoma of the cervix) * Known to be positive for HIV * Active infection requiring IV antibiotics at Day 1 of cycle 1 * Uncontrolled, significant intercurrent illness * Requires chronic concomitant treatment of a strong CYP3A4 inducer * tumor in contact with, invading or encasing major blood vessels * Have experienced clinically significant gastrointestinal bleeding within 6 months, hemoptysis of more than 0.5 teaspoon of red blood within 3 months or other signs indicative of pulmonary hemorrhage within 3 months of enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Disease was evaluated radiologically at baseline, week 6 and every 9 weeks on treatment; Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of 3 cycles range (1-17). | The objective response rate (ORR) was defined as achieving complete response (CR) or partial response (PR) on treatment based on RECIST1.1 criteria. For target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. Confirmatory scans were required 3 weeks following initial documentation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Disease was evaluated radiologically at baseline, week 6 and every 9 weeks on treatment; Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of 3 cycles range (1-17). | Progression-free survival (PFS) estimated using Kaplan-Meier methods was defined as the time from registration to documented disease progression (PD) or death. Based on RECIST1.1, radiographic PD is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum since beginning therapy, the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Patients who were event-free were censored at the date of their last disease evaluation. |
Countries
United States
Participant flow
Recruitment details
Patients enrolled from January 2013 through June 2014.
Participants by arm
| Arm | Count |
|---|---|
| Cabozantinib Cabozantinib was given at a dose of 60 mg orally once per day for 21 day cycles. Treatment continued in the absence of disease progression or unacceptable toxicity. | 35 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Disease Progression | 32 |
Baseline characteristics
| Characteristic | Cabozantinib |
|---|---|
| Age, Continuous | 50 years |
| Gender Female | 35 Participants |
| Gender Male | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 32 Participants |
| Region of Enrollment United States | 35 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 34 / 35 |
| serious Total, serious adverse events | 14 / 35 |
Outcome results
Primary
Objective Response Rate
The objective response rate (ORR) was defined as achieving complete response (CR) or partial response (PR) on treatment based on RECIST1.1 criteria. For target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. Confirmatory scans were required 3 weeks following initial documentation.
Time frame: Disease was evaluated radiologically at baseline, week 6 and every 9 weeks on treatment; Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of 3 cycles range (1-17).
Population: The analysis dataset is comprised of all treated patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabozantinib | Objective Response Rate | 0.09 proportion of participants |
Secondary
Progression Free Survival
Progression-free survival (PFS) estimated using Kaplan-Meier methods was defined as the time from registration to documented disease progression (PD) or death. Based on RECIST1.1, radiographic PD is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum since beginning therapy, the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Patients who were event-free were censored at the date of their last disease evaluation.
Time frame: Disease was evaluated radiologically at baseline, week 6 and every 9 weeks on treatment; Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of 3 cycles range (1-17).
Population: The analysis dataset is comprised of all treated patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cabozantinib | Progression Free Survival | 2 months |
Post Hoc
15-Week Clinical Benefit Rate
The 15-week clinical benefit rate (CBR) was defined as absence of disease progression (PD) per RECIST1.1 criteria at the second disease assessment (week 15). Radiographic PD is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum since beginning therapy, the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Confirmatory scans for response were required 3 weeks following initial documentation.
Time frame: Disease was evaluated radiologically at baseline, week 6 and week 15 on treatment.
Population: The analysis dataset is comprised of all treated patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabozantinib | 15-Week Clinical Benefit Rate | .34 proportion of participants |