A Phase II Study of Cabozantinib Alone or in Combination With Trastuzumab in Breast Cancer Patients With Brain Metastases
Overview
- Phase
- Phase 2
- Intervention
- Cabozantinib
- Conditions
- Breast Cancer
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 36
- Locations
- 2
- Primary Endpoint
- CNS Objective Response Rate (ORR)
- Status
- Completed
- Last Updated
- 4 years ago
Overview
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)
Investigators
Sara Tolaney
Principal Investigator
Dana-Farber Cancer Institute
Eligibility Criteria
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.
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.
Arms & Interventions
Cohort 1 - Cabozantinib, Trastuzumab for HER2+
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.
Intervention: Cabozantinib
Cohort 1 - Cabozantinib, Trastuzumab for HER2+
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.
Intervention: Trastuzumab
Cohort 2 - Cabozantinib for ER+ and/or PR+
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.
Intervention: Cabozantinib
Cohort 3 - Cabozantinib for ER-, PR-, HER2-
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.
Intervention: Cabozantinib
Outcomes
Primary Outcomes
CNS Objective Response Rate (ORR)
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.
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 Outcomes
- 12-Week Clinical Benefit Rate(Evaluate at 12 weeks.)
- 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 .)
- 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.)
- 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.)
- 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.)
- Overall Survival (OS)(Off-treatment patients followed every 6 months until death. Follow-up time is up to 25 months.)
- 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.)