A Study Of Everolimus, Trastuzumab And Vinorelbine In HER2-Positive Breast Cancer Brain Metastases

NCT01305941 | Completed Phase 2 Results DMC

• 2 other identifiers: LCCC 102511-0242
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 4

Brief Summary

Purpose: This study is a single-arm, open-label phase II clinical trial testing the hypothesis that daily everolimus plus weekly vinorelbine and trastuzumab will be effective, safe, and tolerable among patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases. Once enrolled, patients will receive everolimus PO daily in combination with weekly intravenous (IV) vinorelbine and trastuzumab. Cycles will be repeated every 3 weeks (21 days). At the time of progression, patients will come off study. Participants: Up to 35 adults over 21 with HER-2 positive breast cancer that has metastasized to the brain.

Conditions

HER-2 Positive Breast Cancer

Keywords

everolimus; trastuzumab; vinorelbine; RAD001; Breast Cancer; Herceptin; Navelbine; Lineberger Comprehensive Cancer Center; Brain Metastases

Outcome Measures

Primary Outcomes (1)

• Intracranial Objective Response Rate- Modified RECIST Criteria

  response will be evaluated via gadolinium-enhanced brain MRI using modified RECIST criteria. Complete Response (CR) - Disappearance of all target and nontarget lesions Partial Response (PR) - at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum longest diameter AND an absolute decrease of at least 5mm in at least one target lesion. Stable Disease (SD) - neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of the longest diameter since the treatment started. Progressive Disease (PD) - at least a 20% increase in the sum LD of target lesions, taking as reference the smallest sum of the longest diameter recorded since the treatment started AND an absolute increase in size of at least 5 mm in at least one target lesion OR the appearance of one or more new lesions of at least 6 mm in size.

  3 years

Secondary Outcomes (8)

• Intracranial Response Rate- MacDonald Criteria

  3 years

• Toxicity

  24 weeks

• Time to Intracranial Progression.

  3 years

• Extracranial Response

  3 years

• Extracranial Time to Progression

  3 years

Study Arms (1)

Everolimus +Vinorelbine + trastuzumab

EXPERIMENTAL

daily everolimus plus weekly (Days 1, 8, and 15) vinorelbine and trastuzumab

Drug: Everolimus; Drug: Vinorelbine; Drug: Trastuzumab

Interventions

Everolimus DRUG

everolimus 5 mg PO daily as two 2.5-mg tablets

Also known as: RAD001

Everolimus +Vinorelbine + trastuzumab

Vinorelbine DRUG

vinorelbine 25 mg/m2 will be administered via IV infusion over 6-10 minutes weekly.

Also known as: Navelbine

Everolimus +Vinorelbine + trastuzumab

Trastuzumab DRUG

2 mg/kg IV administered over 30 minutes weekly

Also known as: Herceptin

Everolimus +Vinorelbine + trastuzumab

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically-confirmed HER2-positive (IHC 3+ or fluorescence in situ hybridization (FISH) amplified; by clinical assay on either primary or metastatic tumor) adenocarcinoma of the breast with at least one progressive and/or new metastatic brain lesion (\>/=5 mm on radiographic imaging) after receipt of intracranial radiation therapy (whole brain radiation therapy, stereotactic radiosurgery, gamma knife, or equivalent). Patients in whom brain metastases (BM) are asymptomatic and detected during routine brain MRI screening per institutional protocols are eligible.
• Prior intracranial radiation therapy (whole brain radiation therapy, stereotactic radiosurgery, gamma knife or equivalent) is allowed but not required.
• Patients with no prior treatment with intracranial Response (ICR) may be included unless ICR is emergently indicated (in consultation with a local therapist, ie neurosurgeon or radiation oncologist)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Life expectancy \>12 weeks.
• At least 21 years of age.
• No prior mTOR inhibitors
• Prior navelbine allowed provided navelbine therapy discontinued \>/= 12 months from Day 1 of treatment under this protocol.
• Last anti-cancer treatment (including any investigational drug) \>/= 2 weeks from initiation of protocol based therapy, provided all adverse events (AEs) (other than alopecia) have resolved to ≤grade 1 at baseline.
• No active serious infection or other comorbid illness which would impair ability to participate in the trial.
• Left ventricular ejection fraction assessment (echocardiogram or multigated acquisition scan (MUGA) scan) performed within 4 weeks prior to study initiation, showing a Left ventricular ejection fraction (LVEF) value ≥ lower limit of normal (LLN).
• If patient is on dexamethasone, must be on stable or decreasing dose of dexamethasone for ≥7 days. If patient is on different glucocorticoid e.g., prednisone, must be converted to dexamethasone prior to enrollment. Refer to dose modification of everolimus for patients taking dexamethasone.
• Interval ≥4 weeks between open brain biopsy and initiation of protocol-based therapy.
• international normalized ratio (INR) ≤2.0. Anticoagulation is allowed if target INR ≤2.0 on a stable dose of warfarin or if patient on a stable dose of Low-molecular-weight (LMW) heparin for \>1 weeks at time of enrollment.
• Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤2.5 x ULN. Note: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.

You may not qualify if:

• Patients who have received prior treatment with an mTOR inhibitor (e.g., sirolimus, temsirolimus, everolimus); patients who have received prior treatment with navelbine within prior 12 months.
• patients with a known hypersensitivity to everolimus or other rapamycins (e.g. sirolimus, temsirolimus) or to its excipients.
• Patients requiring treatment with any other systemic glucocorticoid. Note: This restriction regarding choice of glucocorticoid does not apply should patient need \<2 week course of glucocorticoid for treatment of non-infectious pneumonitis during study (see section 4.5.2).
• Patients with a known hypersensitivity to vinorelbine or to its excipients.
• Prior allergic reaction to trastuzumab for the treatment of metastatic breast cancer.
• Concurrent or planned radiation, hormonal, chemotherapeutic, experimental or targeted biologic therapy.
• Peripheral neuropathy ≥grade 3.
• Evidence of frank hemorrhage or impending herniation on baseline brain imaging. Note: asymptomatic micro-hemorrhage is allowed.
• Evidence of diffuse leptomeningeal disease on brain MRI or by previously documented Cerebrospinal fluid (CSF) cytology. Note: discrete dural metastases are permitted.
• Active cardiac disease including any of the following:
• Angina pectoris that requires the use of anti-anginal medication;
• Ventricular arrhythmias except for benign premature ventricular contractions;
• Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication;
• Conduction abnormality requiring a pacemaker;
• Valvular disease with documented compromise in cardiac function;

Sponsors & Collaborators

• UNC Lineberger Comprehensive Cancer Center: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (4)

University Of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

UNC Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, 27599, United States

Location

Carolinas Healthcare System

Charlotte, North Carolina, 28203, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37212, United States

Location

Related Publications (1)

• Van Swearingen AED, Siegel MB, Deal AM, Sambade MJ, Hoyle A, Hayes DN, Jo H, Little P, Dees EC, Muss H, Jolly T, Zagar TM, Patel N, Miller CR, Parker JS, Smith JK, Fisher J, Shah N, Nabell L, Nanda R, Dillon P, Abramson V, Carey LA, Anders CK. LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases. Breast Cancer Res Treat. 2018 Oct;171(3):637-648. doi: 10.1007/s10549-018-4852-5. Epub 2018 Jun 25.

  PMID: 29938395 DERIVED

Related Links

• Lineberger Comprehensive Cancer Center

MeSH Terms

Conditions

Breast Neoplasms; Brain Neoplasms

Interventions

Everolimus; Vinorelbine; Trastuzumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Robin V. Johnson
• Organization: UNC Comprehensive Cancer Center

Robin_V_Johnson@med.unc.edu

919-966-1125

Study Officials

• Carey K Anders, MD

  UNC Lineberger Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 25, 2011
• First Posted: March 1, 2011
• Study Start: September 1, 2011
• Primary Completion: August 1, 2016
• Study Completion: October 16, 2017
• Last Updated: December 17, 2018
• Results First Posted: October 17, 2017

Record last verified: 2018-12

Locations

US (4)