Clinical Trials /

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

NCT02260531

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cabozantinib +/- Trastuzumab In Breast Cancer Patients w/ Brain Metastases
  • Official Title: A Phase II Study of Cabozantinib Alone or in Combination With Trastuzumab in Breast Cancer Patients With Brain Metastases

Clinical Trial IDs

  • ORG STUDY ID: 14-359
  • NCT ID: NCT02260531

Conditions

  • Breast Cancer
  • Brain Tumor - Metastatic

Interventions

DrugSynonymsArms
CabozantinibCometriq®Cohort 1 - Cabozantinib, Trastuzumab for HER2+
TrastuzumabHerceptinCohort 1 - Cabozantinib, Trastuzumab for HER2+

Purpose

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)
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1 - Cabozantinib, Trastuzumab for HER2+ExperimentalHER2-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.
  • Cabozantinib
  • Trastuzumab
Cohort 2 - Cabozantinib for ER+ and/or PR+ExperimentalHormone 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.
  • Cabozantinib
Cohort 3 - Cabozantinib for ER-, PR-, HER2-ExperimentalTriple 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.
  • Cabozantinib

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.

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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.
Safety Issue:
Description: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 Outcome Measures

Measure:CNS Volumetric 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 .
Safety Issue:
Description: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
Measure:Non-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.
Safety Issue:
Description: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.
Measure:Median Progression-Free Survival (PFS)
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.
Safety Issue:
Description: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.
Measure:12-Week Clinical Benefit Rate
Time Frame:Evaluate at 12 weeks.
Safety Issue:
Description: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.
Measure:First Progression Site
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.
Safety Issue:
Description:Site that a patient has his/her first tumor progression (CNS vs Non-CNS)
Measure:Overall Survival (OS)
Time Frame:Off-treatment patients followed every 6 months until death. Follow-up time is up to 25 months.
Safety Issue:
Description:OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.
Measure:Incidence of Grade 4 Treatment-Related Toxicity
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.
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Dana-Farber Cancer Institute

Trial 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

Last Updated

May 20, 2021