Clinical Trials /

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

NCT01783756

Description:

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

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: TRIO-US B09
  • SECONDARY ID: NCI-2013-00082
  • SECONDARY ID: 12-001358
  • NCT ID: NCT01783756

Conditions

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

Interventions

DrugSynonymsArms
lapatinib ditosylateGSK572016, GW-572016, GW2016, Lapatinib, TykerbTreatment (lapatinib ditosylate, everolimus, capecitabine)
everolimus42-O-(2-hydroxy)ethyl rapamycin, Afinitor, RAD001Treatment (lapatinib ditosylate, everolimus, capecitabine)
capecitabineCAPE, Ro 09-1978/000, XelodaTreatment (lapatinib ditosylate, everolimus, capecitabine)

Purpose

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

Detailed Description

      PRIMARY OBJECTIVES:

      I. 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:

      I. 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).

      V. 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (lapatinib ditosylate, everolimus, capecitabine)ExperimentalPatients 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.
  • lapatinib ditosylate
  • everolimus
  • capecitabine

Eligibility Criteria

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

Primary Outcome Measures

Measure: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
Time Frame:12 weeks
Safety Issue:
Description: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

Measure: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
Time Frame:Up to 12 months
Safety Issue:
Description:
Measure:Progression-free survival (PFS) by the RECIST v1.1
Time Frame:Interval between the date of study enrollment and the earliest date of disease progression, assessed up to 1 year after end of treatment
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:Interval between the date of study enrollment and the date of death, assessed up to 12 months after end of treatment
Safety Issue:
Description: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.
Measure:Extra CNS response according to RECIST1.1
Time Frame:12 weeks
Safety Issue:
Description:Will be analyzed similarly to CNS objective response rate.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Jonsson Comprehensive Cancer Center

Last Updated

March 21, 2017