Phase 1b/2 Trial Using Lapatinib, Everolimus and Capecitabine for Treatment of HER-2 Positive Breast Cancer With CNS Metastasis

Sponsor

Jonsson Comprehensive Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT01783756

Collaborator

(none)

Enrollment

Location

Arm

70.4

Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a phase 1b/2 study to evaluate the safety and clinical activity of the combination of lapatinib, everolimus and capecitabine for the treatment of participants with HER2+ breast cancer with metastases in the brain who have progressed on trastuzumab.

The combination of 2 drugs able to reach the brain (lapatinib and everolimus) that target different parts of the HER2 signaling pathway plus chemotherapy (capecitabine) that has proven benefits in metastatic breast cancer may lead to improved clinical outcomes for participants with CNS metastasis.

Participants will undergo brain MRIs and CT scans of the chest and abdomen to evaluate response to the treatment, regular laboratory tests and echocardiogram or Multi Gated Acquisition Scan (MUGA) to assess cardiac activity

Condition or Disease	Intervention/Treatment	Phase
Central Nervous System Metastases HER2-positive Breast Cancer Male Breast Cancer Recurrent Breast Cancer Stage IV Breast Cancer	Drug: lapatinib ditosylate Drug: everolimus Drug: capecitabine Other: laboratory biomarker analysis	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

Central nervous system (CNS) objective response rate at 12 weeks: defined as either a complete response or partial response provided there is no progression of extra-CNS disease, increasing steroid requirements, or worsening of neurologic signs and symptoms (NSS)^34 Lesions will be measured using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

SECONDARY OBJECTIVES:

Safety and tolerability. II. Median progression free survival. III. Median overall survival. IV. CNS objective response rate and clinical benefit rate (complete response, partial response and stable disease lasting at least 6 months).
Extra-CNS objective response rate according to RECIST1.1.

OUTLINE:

Patients receive lapatinib ditosylate orally (PO) once daily (QD) and everolimus PO QD on days 1-21, and capecitabine PO twice daily (BID) on days 1-14. Treatment repeats every 21 days for 17 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment or treatment discontinuation, patients will complete 2 follow up visits within 7 days and at 30 days and then will be followed for survival every 3 months for up to 12 months.

Study Design

Study Type:

Interventional

Actual Enrollment :

9 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase 1b/2 Single-arm Trial Evaluating the Combination of Lapatinib, Everolimus and Capecitabine for the Treatment of Patients With HER2-positive Metastatic Breast Cancer With CNS Progression After Trastuzumab

Study Start Date :

Jun 26, 2013

Actual Primary Completion Date :

May 10, 2019

Actual Study Completion Date :

May 10, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (lapatinib ditosylate, everolimus, capecitabine) Patients receive lapatinib ditosylate PO QD and everolimus PO QD on days 1-21, and capecitabine PO BID on days 1-14. Treatment repeats every 21 days for 17 courses in the absence of disease progression or unacceptable toxicity.	Drug: lapatinib ditosylate Given PO Other Names: GSK572016 GW-572016 GW2016 Lapatinib Tykerb Drug: everolimus Given PO Other Names: 42-O-(2-hydroxy)ethyl rapamycin Afinitor RAD001 Drug: capecitabine Given PO Other Names: CAPE Ro 09-1978/000 Xeloda Other: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Treatment (lapatinib ditosylate, everolimus, capecitabine)

Patients receive lapatinib ditosylate PO QD and everolimus PO QD on days 1-21, and capecitabine PO BID on days 1-14. Treatment repeats every 21 days for 17 courses in the absence of disease progression or unacceptable toxicity.

Drug: lapatinib ditosylate

Given PO

Other Names:

GSK572016

GW-572016

GW2016

Lapatinib

Tykerb

Drug: everolimus

Given PO

Other Names:

42-O-(2-hydroxy)ethyl rapamycin

Afinitor

RAD001

Drug: capecitabine

Given PO

Other Names:

CAPE

Ro 09-1978/000

Xeloda

Other: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

CNS objective response rate defined as either a complete response or partial response provided there is no progression of extra-CNS disease, increasing steroid requirements, or worsening of NSS measured using RECIST v1.1 [12 weeks]
Estimated with a 95% confidence interval. Chi-square test will be used evaluate if the CNS response rate at week 12 is significantly higher than 20%.

Secondary Outcome Measures

Body system, severity and relation with study treatment of adverse events graded according to the National Institute of Health (NIH)/ National Cancer Institute (NCI) Common Toxicity Criteria (CTC) v4.0 [Up to 12 months]
Progression-free survival (PFS) by the RECIST v1.1 [Interval between the date of study enrollment and the earliest date of disease progression, assessed up to 1 year after end of treatment]
The distribution of PFS and OS will be estimated using Kaplan-Meier method and survival curves for PFS and OS will be plotted. Median PFS and median OS will be obtained.
Overall survival (OS) [Interval between the date of study enrollment and the date of death, assessed up to 12 months after end of treatment]
The distribution of PFS and OS will be estimated using Kaplan-Meier method and survival curves for PFS and OS will be plotted. Median PFS and median OS will be obtained.
Extra CNS response according to RECIST1.1 [12 weeks]
Will be analyzed similarly to CNS objective response rate.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients with HER2+ (immunohistochemistry [IHC] 3+ or fluorescence in situ hybridization [FISH]+ R/G > 2.0 or silver-enhanced in situ hybridization [SISH]+ HER2/chromosome 17 centromere [CEP17] > 2.0) breast cancer with documented central nervous system (CNS) recurrence or progression
Must have received trastuzumab (neoadjuvant, adjuvant or metastatic setting)
At least one measurable lesion in the brain (>= 10 mm on T1-weighted, gadolinium-enhanced magnetic resonance imaging [MRI]); (prior neurosurgical resection, whole brain radiation or stereotactic radiation therapy is allowed provided the patient has a measurable CNS progression [at least one new and/or progressive measurable brain metastasis]; measurable or non-measurable extracranial metastases allowed)
Concurrent steroids allowed (up to equivalent of prednisone 20 mg daily, on taper or stable dose for at least 2 weeks)
Life expectancy of >= 12 weeks
Previous treatment with other HER2 targeted agents allowed; (previous treatment with HER2 inhibitors and investigational drugs to be discontinued prior to starting study treatment [at least 21 days for trastuzumab and other antibodies; at least 14 days for lapatinib; at least 5 half-lives for other agents])
Previous chemotherapy (adjuvant and metastatic regimens) and hormonal therapy allowed, but chemotherapy must have been discontinued at least 21 days prior to starting study treatment and hormonal therapy at least 7 days prior to starting study treatment; patients must have recovered from acute Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 grade >= 2 side effects of previous treatments
At least 2 weeks since prior radiotherapy or stereotactic radiosurgery, and 4 weeks since prior major surgery at time of study enrollment
Eastern Cooperative Oncology Group (ECOG) performance status =< 2
Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
Platelets >= 100 x 10^9/L
Hemoglobin (Hb) >= 9 g/dL
Serum bilirubin =< 1.5 x upper limit of normal (ULN) (=< 3.0 if Gilbert's syndrome)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5 x ULN in patients with liver metastases)
International normalized ratio (INR) =< 1.5
Adequate renal function: serum creatinine =< 1.5 x ULN
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
Signed informed consent
Age >= 18 years

Exclusion Criteria:

Patients who have never received trastuzumab
Prior treatment with an mammalian target of rapamycin (MTOR) inhibitor (including everolimus, sirolimus, temsirolimus)
Leptomeningeal carcinomatosis as only site of CNS disease
Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
Patients with clinically significant interstitial lung disease or history of cardiac disease
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
Prior treatment with any investigational drug within the preceding 4 weeks prior to starting study drug
Patients receiving chronic, systemic treatment with corticosteroids (more than 20 mg/day prednisone equivalent, see inclusion criteria) or another immunosuppressive agent; topical or inhaled corticosteroids are allowed
Patients should not receive immunization with attenuated live vaccines within one week of starting study drug 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 (TY)21a 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:
Symptomatic congestive heart failure of New York heart Association class III or IV
Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia, left ventricular ejection fraction (LVEF) < 50% or any other clinically significant cardiac disease
Severely impaired lung function as defined as spirometry and diffusion capacity of the lung of carbon monoxide (DLCO) that is 50% of the normal predicted value and/or oxygen (02) saturation that is 88% or less at rest on room air
Uncontrolled diabetes as defined by 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) deoxyribonucleic acid (DNA) and hepatitis C ribonucleic acid polymerase chain reaction (HCV RNA 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; patients with positive results for HBV/HCV infection will be allowed in this study provided monitoring and prophylactic treatment are followed
A known history of human immunodeficiency virus (HIV) seropositivity
Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus/lapatinib (lapatinib ditosylate) (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
Patients with an active, bleeding diathesis
Patients on warfarin (patients on injectable blood thinners, such as Lovenox, are able to continue those)
Female patients who are pregnant or breast feeding, 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 must have a negative urine or serum pregnancy test within 7 days prior to administration of study drug)
Male patient whose sexual partner(s) are women of childbearing potential (WOCBP) who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment
Patients with a known hypersensitivity to everolimus or other rapamycins (e.g., sirolimus, temsirolimus) or to its excipients
History of noncompliance to medical regimens
Patients unwilling to or unable to comply with the protocol