Brain Tumor - Metastatic, Breast Cancer
Conditions
Keywords
Metastatic breast cancer and brain metastases, HER-2 Positive Breast Cancer, ER-Positive PR-Positive HER-2 Negative Breast Cancer, ER-Negative PR-Negative HER2-Negative Breast Cancer
Brief summary
This research study is evaluating the effectiveness of the drug called cabozantinib (alone or in combination with trastuzumab) as a possible treatment for advanced breast cancer in which the cancer has spread to the brain.
Detailed description
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. Investigational means that the intervention is being studied. The FDA (the U.S. Food and Drug Administration) has not approved cabozantinib for your specific disease but it has been approved for other uses. Few treatments exist for brain metastases from breast cancer. Radiation and surgery are generally included as a possible standard of care treatments for this diagnosis. In this research study, the investigator are looking at how well cabozantinib works in treating breast cancer that has spread to the brain. Cabozantinib has been used in some phase I studies and information from those other research studies suggests that cabozantinib may help to shrink or stabilize the participant's breast cancer. In addition, information from these studies has shown that cabozantinib may pass through the blood brain barrier (a protective layer that prevents most large molecules and cells found in the blood from entering the brain tissue) and may be an effective treatment for brain metastases. If the participant has HER2-positive breast cancer, they will receive trastuzumab in addition to cabozantinib. Trastuzumab is an FDA approved drug for the treatment of HER2-positive metastatic breast cancer. However, the combination of cabozantinib and trastuzumab has not yet been tested. Trastuzumab may help to shrink or stabilize breast cancer in combination with cabozantinib. If the participant's breast cancer is HER2-negative, they will not receive trastuzumab as part of this clinical trial. The names of the study interventions involved in this study are: * Cabozantinib (XL184) * Trastuzumab (herceptin) (participants with HER2-positive disease only)
Interventions
DRUGCabozantinib
DRUGTrastuzumab
Sponsors
Exelixis
Genentech, Inc.
Dana-Farber Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically or cytologically confirmed invasive breast cancer, with stage IV disease. * New or progressive CNS lesions, as assessed by the patient's treating physician. * For patients who have received prior cranial radiation, no increase in corticosteroid dose in the week prior to the baseline brain MRI * Discontinued prior therapy (with the exception of trastuzumab for patients with HER2+ breast cancer) * Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy; * The subject has an ECOG performance status of 0 or 1 * Patients must have normal organ and marrow function and laboratory values as follows within 14 days before the first dose of cabozantinib * Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s) * Subjects of childbearing potential must not be pregnant at screening. * Patients on bisphosphonates may continue receiving bisphosphonate therapy during study. Patients wanting to initiate bisphosphonate therapy may do so. * The subject has had an assessment of all known disease sites eg, by computerized tomography (CT) scan, magnetic resonance imaging (MRI), bone scan as appropriate, within 28 days before the first dose of cabozantinib
Exclusion criteria
* The subject has received cabozantinib or another c-Met inhibitor (please note ARQ 197 is not considered a MET inhibitor for purposes of this study given data to suggest it inhibits tubulin) * The subject has uncontrolled, significant intercurrent or recent illness * Leptomeningeal disease as the only site of CNS involvement * Known contraindication to MRI with gadolinium contrast, such as cardiac pacemaker, shrapnel, or ocular foreign body * More than 2 seizures over the last 4 weeks prior to study entry * Grade 1 or higher CNS hemorrhage on baseline brain MRI, or history of grade 2 or higher CNS hemorrhage within 12 months * Has experienced clinically-significant GI bleeding within 6 months before first dose of cabozantinib; hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the first dose of cabozantinib; any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of cabozantinib * The subject has tumor in contact with, invading or encasing any major blood vessels * The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib * The subject requires concomitant treatment, in therapeutic doses, with anticoagulants. Low dose aspirin (≤ 81 mg/day), low-dose warfarin ( ≤1 mg/day), and prophylactic LMWH are permitted. * The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥1.3 × the laboratory ULN within 7 days before the first dose of cabozantinib. * Inability to swallow intact tablets * Pregnant or lactating females * Diagnosis of another malignancy within 2 years before the first dose of cabozantinib, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy * Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible * The subject is known to be positive for the human immunodeficiency virus (HIV) * Subjects with clinically relevant ongoing complications from prior surgery are not eligible * QTcF \> 500 msec on average of screening EKGs performed within 28 days of first dose of cabozantinib. Three EKGs must be performed at screening. If the average of these three consecutive results for QTcF is \> 500 msec, the subject is ineligible. * Active infection requiring IV antibiotics at Day 1 of cycle 1 * No prior lapatinib within 7 days prior to initiation of protocol treatment * Receive concurrent investigational agents while on study * Receive any concurrent chemotherapy, radiotherapy, or hormonal therapy while on study * Previously identified allergy or hypersensitivity to components of the cabozantinib formulations * The subject requires chronic concomitant treatment with strong CYP3A4 inducers
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CNS Objective Response Rate (ORR) | Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months. | The central nervous system (CNS) ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria in the evaluation CNS lesions on treatment: 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Non-CNS Objective Response Rate (ORR) | Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months. | The non-central nervous system (CNS) ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria in the evaluation non-CNS lesions on treatment: 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. |
| Median Progression-Free Survival (PFS) | Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. Follow-up time is up to 25 months. | Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. |
| 12-Week Clinical Benefit Rate | Evaluate at 12 weeks. | Clinical benefit rate (CBR) was defined as the percentage of patients achieving complete response (CR), partial response (PR), or stable disease (SD) based on RECIST 1.1 criteria by 12 weeks. Per RECIST 1.1 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. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria. |
| CNS Volumetric Objective Response Rate (ORR) | Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months . | CNS volumetric ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) defined as: CR * Complete resolution of all measurable (≥ 1 cm diameter) and non-measurable brain metastases * No new CNS lesions (new lesion defined as ≥ 6 mm diameter) PR * ≥ 50% reduction in the volumetric sum of all measurable (≥ 1 cm diameter) brain metastases compared to baseline * No progression of non-measurable lesions * No new lesions (new lesion defined as ≥ 6 mm) ORR also requires: * Stable or decreasing steroid dose * No new/progressive tumor-related neurologic signs or symptoms |
| Overall Survival (OS) | Off-treatment patients followed every 6 months until death. Follow-up time is up to 25 months. | OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive. |
| Incidence of Grade 4 Treatment-Related Toxicity | Participants should be re-evaluated for response every 6 weeks. Patients with stable or responsive disease after completion of 6 cycles may have the frequency of scans reduced to once every 3 cycles, and in long-term follow-up every 6 months until death. | All grade 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 4 AE of any type during the time of observation. |
| First Progression Site | Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. Follow-up time is up to 25 months. | Site that a patient has his/her first tumor progression (CNS vs Non-CNS) |
Countries
United States
Participant flow
Recruitment details
36 patients were enrolled between November 2014 and June 2018
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 - Cabozantinib, Trastuzumab for HER2+ HER2-positive
* Cabozantinib- orally administered daily per treatment cycle
* Trastuzumab- IV administered once per cycle
* MRI- Baseline, Cycle 2 Day 1, and every 2 cycles
* Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.
Trastuzumab: For HER2-Positive participants only. Administered by IV on day 1 of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops. | 21 |
| Cohort 2 - Cabozantinib for ER+ and/or PR+ Hormone receptor-positive (ER+ and/or PR+)
* Cabozantinib- orally administered daily per treatment cycle
* MRI- Baseline, Cycle 2 Day 1, and every 2 cycles
* Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops. | 7 |
| Cohort 3 - Cabozantinib for ER-, PR-, HER2- Triple negative (ER-, PR-, HER2-)
* Cabozantinib- orally administered daily per treatment cycle
* MRI- Baseline, Cycle 2 Day 1, and every 2 cycles
* Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops. | 8 |
| Total | 36 |
Baseline characteristics
| Characteristic | Cohort 3 - Cabozantinib for ER-, PR-, HER2- | Cohort 2 - Cabozantinib for ER+ and/or PR+ | Cohort 1 - Cabozantinib, Trastuzumab for HER2+ | Total |
|---|---|---|---|---|
| Age, Continuous | 48 years | 48 years | 52 years | 50 years |
| ECOG performance status 0 | 1 Participants | 3 Participants | 13 Participants | 17 Participants |
| ECOG performance status 1 | 7 Participants | 4 Participants | 8 Participants | 19 Participants |
| No Prior CNS radiation | 4 Participants | 2 Participants | 4 Participants | 10 Participants |
| Number of sites of metastases at study entry | 2 Sites | 1 Sites | 2 Sites | 2 Sites |
| Prior anti-HER2 therapy-Lapatinib | 0 Participants | 0 Participants | 10 Participants | 10 Participants |
| Prior anti-HER2 therapy-Trastuzumab | 0 Participants | 0 Participants | 21 Participants | 21 Participants |
| Prior Stereotactic radiosurgery No | 7 Participants | 3 Participants | 14 Participants | 24 Participants |
| Prior Stereotactic radiosurgery Yes | 1 Participants | 4 Participants | 7 Participants | 12 Participants |
| Prior Whole brain radiation No | 4 Participants | 2 Participants | 5 Participants | 11 Participants |
| Prior Whole brain radiation Yes | 4 Participants | 5 Participants | 16 Participants | 25 Participants |
| Race/Ethnicity, Customized Race African American | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race More than one race | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 8 Participants | 5 Participants | 19 Participants | 32 Participants |
| Region of Enrollment United States | 8 participants | 7 participants | 21 participants | 36 participants |
| Sex: Female, Male Female | 8 Participants | 7 Participants | 21 Participants | 36 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sites of metastatic disease Bone | 1 participants | 5 participants | 10 participants | 16 participants |
| Sites of metastatic disease Breast (Ipsilateral or Contralateral) or chest wall | 1 participants | 0 participants | 2 participants | 3 participants |
| Sites of metastatic disease Liver | 1 participants | 1 participants | 7 participants | 9 participants |
| Sites of metastatic disease Lung | 3 participants | 2 participants | 9 participants | 14 participants |
| Sites of metastatic disease Lymph nodes | 1 participants | 1 participants | 5 participants | 7 participants |
| Surgical resection of CNS metastasis No | 6 Participants | 6 Participants | 20 Participants | 32 Participants |
| Surgical resection of CNS metastasis Yes | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 11 / 21 | 3 / 7 | 8 / 8 |
| other Total, other adverse events | 21 / 21 | 7 / 7 | 8 / 8 |
| serious Total, serious adverse events | 6 / 21 | 4 / 7 | 6 / 8 |
Outcome results
Primary
CNS Objective Response Rate (ORR)
The central nervous system (CNS) ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria in the evaluation CNS lesions on treatment: 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.
Time frame: Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Cabozantinib, Trastuzumab for HER2+ | CNS Objective Response Rate (ORR) | 5 percentage of participants |
| Cohort 2 - Cabozantinib for ER+ and/or PR+ | CNS Objective Response Rate (ORR) | 14 percentage of participants |
| Cohort 3 - Cabozantinib for ER-, PR-, HER2- | CNS Objective Response Rate (ORR) | 0 percentage of participants |
Secondary
12-Week Clinical Benefit Rate
Clinical benefit rate (CBR) was defined as the percentage of patients achieving complete response (CR), partial response (PR), or stable disease (SD) based on RECIST 1.1 criteria by 12 weeks. Per RECIST 1.1 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. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria.
Time frame: Evaluate at 12 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Cabozantinib, Trastuzumab for HER2+ | 12-Week Clinical Benefit Rate | 43 percentage of participants |
| Cohort 2 - Cabozantinib for ER+ and/or PR+ | 12-Week Clinical Benefit Rate | 14 percentage of participants |
| Cohort 3 - Cabozantinib for ER-, PR-, HER2- | 12-Week Clinical Benefit Rate | 13 percentage of participants |
Secondary
CNS Volumetric Objective Response Rate (ORR)
CNS volumetric ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) defined as: CR * Complete resolution of all measurable (≥ 1 cm diameter) and non-measurable brain metastases * No new CNS lesions (new lesion defined as ≥ 6 mm diameter) PR * ≥ 50% reduction in the volumetric sum of all measurable (≥ 1 cm diameter) brain metastases compared to baseline * No progression of non-measurable lesions * No new lesions (new lesion defined as ≥ 6 mm) ORR also requires: * Stable or decreasing steroid dose * No new/progressive tumor-related neurologic signs or symptoms
Time frame: Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months .
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Cabozantinib, Trastuzumab for HER2+ | CNS Volumetric Objective Response Rate (ORR) | 5 percentage of participants |
| Cohort 2 - Cabozantinib for ER+ and/or PR+ | CNS Volumetric Objective Response Rate (ORR) | 0 percentage of participants |
| Cohort 3 - Cabozantinib for ER-, PR-, HER2- | CNS Volumetric Objective Response Rate (ORR) | 0 percentage of participants |
Secondary
First Progression Site
Site that a patient has his/her first tumor progression (CNS vs Non-CNS)
Time frame: Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. Follow-up time is up to 25 months.
Population: Data was not collected
Secondary
Incidence of Grade 4 Treatment-Related Toxicity
All grade 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 4 AE of any type during the time of observation.
Time frame: Participants should be re-evaluated for response every 6 weeks. Patients with stable or responsive disease after completion of 6 cycles may have the frequency of scans reduced to once every 3 cycles, and in long-term follow-up every 6 months until death.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Cabozantinib, Trastuzumab for HER2+ | Incidence of Grade 4 Treatment-Related Toxicity | 4 participants |
| Cohort 2 - Cabozantinib for ER+ and/or PR+ | Incidence of Grade 4 Treatment-Related Toxicity | 0 participants |
| Cohort 3 - Cabozantinib for ER-, PR-, HER2- | Incidence of Grade 4 Treatment-Related Toxicity | 0 participants |
Secondary
Median Progression-Free Survival (PFS)
Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
Time frame: Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. Follow-up time is up to 25 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - Cabozantinib, Trastuzumab for HER2+ | Median Progression-Free Survival (PFS) | 4.1 Months |
| Cohort 2 - Cabozantinib for ER+ and/or PR+ | Median Progression-Free Survival (PFS) | 0.8 Months |
| Cohort 3 - Cabozantinib for ER-, PR-, HER2- | Median Progression-Free Survival (PFS) | 2.4 Months |
Secondary
Non-CNS Objective Response Rate (ORR)
The non-central nervous system (CNS) ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria in the evaluation non-CNS lesions on treatment: 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.
Time frame: Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Cabozantinib, Trastuzumab for HER2+ | Non-CNS Objective Response Rate (ORR) | 0 percentage of participants |
| Cohort 2 - Cabozantinib for ER+ and/or PR+ | Non-CNS Objective Response Rate (ORR) | 0 percentage of participants |
| Cohort 3 - Cabozantinib for ER-, PR-, HER2- | Non-CNS Objective Response Rate (ORR) | 0 percentage of participants |
Secondary
Overall Survival (OS)
OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.
Time frame: Off-treatment patients followed every 6 months until death. Follow-up time is up to 25 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - Cabozantinib, Trastuzumab for HER2+ | Overall Survival (OS) | 13.8 Months |
| Cohort 2 - Cabozantinib for ER+ and/or PR+ | Overall Survival (OS) | NA Months |
| Cohort 3 - Cabozantinib for ER-, PR-, HER2- | Overall Survival (OS) | 5.1 Months |