Cabozantinib +/- Trastuzumab In Breast Cancer Patients w/ Brain Metastases

Study Overview
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Brief Summary
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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
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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)

Official Title
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A Phase II Study of Cabozantinib Alone or in Combination With Trastuzumab in Breast Cancer Patients With Brain Metastases

Conditions
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Breast Cancer, Brain Tumor - Metastatic

Intervention / Treatment
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* Drug: Cabozantinib
* Drug: Trastuzumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - Cabozantinib, Trastuzumab for HER2+<br>HER2-positive Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Trastuzumab- IV administered once per cycle, 8 mg/kg IV loading dose followed by 6 mg/kg IV Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons. | Drug: Cabozantinib<br> <br> * Other names: Cometriq®;Drug: Trastuzumab<br> <br> * Other names: Herceptin;|
| Experimental: Cohort 2 - Cabozantinib for ER+ and/or PR+<br>Hormone receptor-positive (ER+ and/or PR+) - Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons. | Drug: Cabozantinib<br> <br> * Other names: Cometriq®;|
| Experimental: Cohort 3 - Cabozantinib for ER-, PR-, HER2-<br>Triple negative (ER-, PR-, HER2-) - Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons. | Drug: Cabozantinib<br> <br> * Other names: Cometriq®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 . | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | Evaluate at 12 weeks. | 
| First Progression Site | Site that a patient has his/her first tumor progression (CNS vs Non-CNS) | 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. | 
| 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. | Off-treatment patients followed every 6 months until death. Follow-up time is up to 25 months. | 
| 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. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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