A Study Of Everolimus, Trastuzumab And Vinorelbine In HER... | NCT01305941

NCT01305941

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

ID	Type	Description	Link
11-0242	Other Identifier	UNC IRB assigned protocol number

Status Module

Sponsor/Collaborators Module

Name	Class
Novartis Pharmaceuticals	INDUSTRY

Oversight Module

Description Module

Detailed Description

STUDY OBJECTIVES Primary Objective -To determine the intracranial objective response rate of mTOR inhibition (everolimus) in combination with vinorelbine and trastuzumab in the treatment of HER2-positive, progressive breast cancer brain metastases as defined via modified RECIST criteria.

Secondary Objectives

To determine the intracranial objective response rate of mechanistic target of rapamycin (mTOR) inhibition (everolimus) in combination with vinorelbine and trastuzumab in the treatment of HER2-positive, progressive breast cancer brain metastases as defined by MacDonald criteria.
To evaluate the safety and tolerability of everolimus in combination with trastuzumab and vinorelbine as assessed via the NCI CTCAE version 4.0
To evaluate time to intracranial progression after administration of everolimus in combination with trastuzumab and vinorelbine as defined via modified RECIST criteria
To evaluate the extracranial objective response rate as determined by RECIST 1.1 criteria after administration of everolimus in combination with trastuzumab and vinorelbine.
To evaluate the extracranial time to progression as determined by RECIST 1.1 criteria after administration of everolimus in combination with trastuzumab and vinorelbine.
To evaluate progression free survival (PFS) and overall survival (OS) after administration of everolimus in combination with trastuzumab and vinorelbine.
To evaluate the impact of everolimus in combination with trastuzumab and vinorelbine on quality of life as measured by the Functional Assessment of Cancer Therapy Breast (FACT-B) and Functional Assessment of Cancer Therapy Brain (FACT-Br) questionnaires.

Exploratory Objective

-To evaluate biomarkers in archival tumor tissue samples and correlate with therapeutic response to everolimus in combination with vinorelbine and trastuzumab.

Following Hepatitis B antiviral prophylaxis if required, or following screening and informed consent if antiviral therapy is not needed, treatment will be initiated with everolimus PO daily in combination with weekly intravenous (IV) vinorelbine and trastuzumab (Days 1, 8, and 15)

A cycle is defined as 3 weeks (21 days). Cycles of therapy will be repeated until documented disease progression, unacceptable toxicity, or patient withdrawal from study for other reasons, including death.

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Everolimus +Vinorelbine + trastuzumab	Experimental	daily everolimus plus weekly (Days 1, 8, and 15) vinorelbine and trastuzumab	Drug: Everolimus Drug: Vinorelbine Drug: Trastuzumab

Name	Type	Description	Arm Group Labels	Other Names
Everolimus	Drug	everolimus 5 mg PO daily as two 2.5-mg tablets	Everolimus +Vinorelbine + trastuzumab

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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

Measure	Description	Time Frame
Intracranial Response Rate- MacDonald Criteria	Intracranial tumor lesions were evaluated via gadolinium-enhanced brain MRI using the MacDonald criteria. Measurable disease is defined as at least 1 measurable brain lesion accurately measured in at least 2 dimensions (longest diameter) as ≥5.0 mm. Tumor size is the product of the 2 longest bi-dimensional lines. Complete Response (CR)- Disappearance of all tumor on consecutive CT or MRI scans at least 1 month apart, off steroids for treatment of neurological symptoms, and neurologically stable or improved. Partial Response (PR)- ≥50% reduction in size of tumor on consecutive CT or MRI scans at least 1 month part, steroids stable or reduced, and neurologically stable or improved. Progressive Disease (PD)- ≥25% increase in size of tumor or any new tumor on CT or MRI scans, or neurologically worse, and steroids stable or increased due to neurologic symptoms. Stable Disease (SD)- all other situations Overall Response Rate (ORR) is the sum of partial responses (PRs) and CRs.

Eligibility Module

Eligibility Criteria

Inclusion Criteria

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.
Patients must have adequate organ function as evidenced by:
Absolute neutrophil count ≥1.5/µL
Platelet count ≥100,000/µL
Hg ≥9 g/dL
Bilirubin ≤1.5 x upper limit of normal (ULN)
aspartate aminotransferase (AST) or Alanine transaminase (ALT) ≤2.5 x ULN (≤5 x ULN if liver metastases are present)
Serum creatinine ≤1.5 x ULN
Archived, paraffin-embedded tissue block (primary or metastatic) available for genomic studies is required.
Signed, institutional review board (IRB)-approved written informed consent.

Exclusion Criteria

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;
- Symptomatic pericarditis
History of cardiac dysfunction including any one of the following:
- Myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular (LV) function;
- History of documented congestive heart failure (New York Heart Association functional classification III-IV);
- Documented cardiomyopathy
Patients who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia), or patients that may require major surgery during the course of the study.
Patients should not receive immunization with attenuated live vaccines within 1 week of study entry or during study period. Close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Guérin (BCG), yellow fever, varicella, and Typhoid Vaccine Live Oral (TY21a) typhoid vaccines.
Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
- severely impaired lung function, defined as spirometry and diffusion lung capacity for carbon monoxide (DLCO) that is 50% of the normal predicted value and/or 02 saturation that is ≤88% at rest on room air
- uncontrolled diabetes, defined as fasting serum glucose >1.5 x ULN (Note: Optimal glycemic control should be achieved before starting trial therapy)
- active (acute or chronic) or uncontrolled severe infections
- liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).

Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. Hepatitis B Virus (HBV) DNA and hepatitis C Virus (HCV) RNA polymerase chain reaction (PCR) testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection.

A known history of HIV seropositivity.
Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
Patients with an active, bleeding diathesis or on oral anti-vitamin K medication (except low-dose warfarin and aspirin or equivalent, as long as the INR ≤2.0).
Unable or unwilling to discontinue use of prohibited fruit (or its juices) and prohibited medications listed in Appendices II and III for at least 14 days or 5 half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study.
Female patients who are pregnant or breastfeeding, or adults of reproductive potential who are not using effective birth control methods. Adequate contraception must be used throughout the trial and for 8 weeks after the last dose of study drug, by both sexes. Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test within 7 days prior to everolimus initiation.
Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment
Contraindication to gadolinium-enhanced MRI imaging.
Inability to comply with study and/or follow-up procedures.
History of noncompliance to medical regimens.

Contacts/Locations Module

Name	Affiliation	Role
Carey K Anders, MD	UNC Lineberger Comprehensive Cancer Center	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
University Of Alabama at Birmingham		Birmingham	Alabama	35294	United States
UNC Lineberger Comprehensive Cancer Center

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
29938395	Derived	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.

Label	URL
Lineberger Comprehensive Cancer Center	View source

IPD Sharing Statement Module

No data available

No data is available for this block.

A total of 41 patients were consented to this study. Of these, 6 patients were found ineligible, 2 withdrew prior to treatment, and 1 patient has disease progression prior to protocol therapy. Therefore only 32 patients were enrolled and participated in the trial.

Arm/Group Information

ID	Title	Description
FG000	Everolimus +Vinorelbine + Trastuzumab	daily everolimus plus weekly (Days 1, 8, and 15) vinorelbine and trastuzumab Everolimus: everolimus 5 mg PO daily as two 2.5-mg tablets Vinorelbine: vinorelbine 25 mg/m2 will be administered via IV infusion over 6-10 minutes weekly. Trastuzumab: 2 mg/kg IV administered over 30 minutes weekly

Periods

Title

Milestones

Reasons Not Completed

Overall Study

Type	Comment	Milestone Data
STARTED		FG00032 subjects
COMPLETED		FG00022 subjects
NOT COMPLETED		FG00010 subjects

Type	Comment	Reasons
Adverse Event		FG0006 subjects
Clinical decline		FG0002 subjects
Withdrawal by Subject		FG0001 subjects

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Everolimus +Vinorelbine + Trastuzumab	daily everolimus plus weekly (Days 1, 8, and 15) vinorelbine and trastuzumab Everolimus: everolimus 5 mg PO daily as two 2.5-mg tablets Vinorelbine: vinorelbine 25 mg/m2 will be administered via IV infusion over 6-10 minutes weekly. Trastuzumab: 2 mg/kg IV administered over 30 minutes weekly

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Median

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

Six subjects were not evaluable for response because there was no follow-up disease assessment done due to poor clinical status of subjects

Posted

Count of Participants

Participants

3 years

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Everolimus +Vinorelbine + Trastuzumab	daily everolimus plus weekly (Days 1, 8, and 15) vinorelbine and trastuzumab Everolimus: everolimus 5 mg PO daily as two 2.5-mg tablets Vinorelbine: vinorelbine 25 mg/m2 will be administered via IV infusion over 6-10 minutes weekly. Trastuzumab: 2 mg/kg IV administered over 30 minutes weekly

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Adrenal Insufficiency	Endocrine disorders	CTCAE (4.0)	Non-systematic Assessment

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Abdominal pain	Gastrointestinal disorders	CTCAE (4.0)	Non-systematic Assessment

More Info Module

Certain Agreements

Title	Organization	Phone	Extension	Email
Robin V. Johnson	UNC Comprehensive Cancer Center	919-966-1125		Robin_V_Johnson@med.unc.edu

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

ID	Term
D001943	Breast Neoplasms
D001932	Brain Neoplasms

ID	Term
D009371	Neoplasms by Site
D009369	Neoplasms
D001941	Breast Diseases
D012871	Skin Diseases

Intervention Browse Module

ID	Term
D000068338	Everolimus
D000077235	Vinorelbine
D000068878	Trastuzumab

ID	Term
D020123	Sirolimus
D018942	Macrolides
D007783	Lactones
D009930	Organic Chemicals
D014748

Masking Info

EG0001 affected32 at risk

EG0002 affected32 at risk

Title	Measurements
	OG0001