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

NCT01783756 | Completed Phase 1 DMC

• 3 other identifiers: TRIO-US B09NCI-2013-0008212-001358
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

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

Conditions

Central Nervous System Metastases; HER2-positive Breast Cancer; Male Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer

Outcome Measures

Primary Outcomes (1)

• 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

  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%.

  12 weeks

Secondary Outcomes (4)

• 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

• Overall survival (OS)

  Interval between the date of study enrollment and the date of death, assessed up to 12 months after end of treatment

• Extra CNS response according to RECIST1.1

  12 weeks

Study Arms (1)

Treatment (lapatinib ditosylate, everolimus, capecitabine)

EXPERIMENTAL

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; Drug: everolimus; Drug: capecitabine; Other: laboratory biomarker analysis

Interventions

lapatinib ditosylate DRUG

Given PO

Also known as: GSK572016, GW-572016, GW2016, Lapatinib, Tykerb

Treatment (lapatinib ditosylate, everolimus, capecitabine)

everolimus DRUG

Given PO

Also known as: 42-O-(2-hydroxy)ethyl rapamycin, Afinitor, RAD001

Treatment (lapatinib ditosylate, everolimus, capecitabine)

capecitabine DRUG

Given PO

Also known as: CAPE, Ro 09-1978/000, Xeloda

Treatment (lapatinib ditosylate, everolimus, capecitabine)

laboratory biomarker analysis OTHER

Correlative studies

Treatment (lapatinib ditosylate, everolimus, capecitabine)

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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 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

Sponsors & Collaborators

• Jonsson Comprehensive Cancer Center: lead

Study Sites (1)

Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095, United States

Location

Related Publications (1)

• Hurvitz S, Singh R, Adams B, Taguchi JA, Chan D, Dichmann RA, Castrellon A, Hu E, Berkowitz J, Mani A, DiCarlo B, Callahan R, Smalberg I, Wang X, Meglar I, Martinez D, Hobbs E, Slamon DJ. Phase Ib/II single-arm trial evaluating the combination of everolimus, lapatinib and capecitabine for the treatment of HER2-positive breast cancer with brain metastases (TRIO-US B-09). Ther Adv Med Oncol. 2018 Nov 9;10:1758835918807339. doi: 10.1177/1758835918807339. eCollection 2018.

  PMID: 30542377 DERIVED

MeSH Terms

Conditions

Breast Neoplasms, Male; Breast Neoplasms

Interventions

Lapatinib; N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl-6-(5-((methylsulfonyl)ethyl)aminomethyl)-2-furyl)-4-quinazolinamine; Everolimus; Capecitabine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Sirolimus; Macrolides; Lactones; Organic Chemicals; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Sara Hurvitz

  Jonsson Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 31, 2013
• First Posted: February 5, 2013
• Study Start: June 26, 2013
• Primary Completion: May 10, 2019
• Study Completion: May 10, 2019
• Last Updated: November 12, 2019

Record last verified: 2019-11

Locations

US (1)