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Intermittent High-Dose Lapatinib in Tandem With Capecitabine for HER2 Overexpressed/Amplified Metastatic Breast Cancer With Central Nervous System (CNS) Metastases

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02650752
Recruitment Status : Active, not recruiting
First Posted : January 8, 2016
Last Update Posted : April 11, 2019
Queens Cancer Center of Queens Hospital
University of Michigan
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Brief Summary:
The purpose of this study is to see if capecitabine can be taken safely with different doses of lapatinib in patients with HER-2 positive breast cancer involving brain (brain metastases) and/or in spinal fluid (leptomeningeal disease).

Condition or disease Intervention/treatment Phase
Metastatic Breast Cancer Central Nervous System (CNS) Metastases Drug: Lapatinib in Tandem With Capecitabine Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Intermittent High-Dose Lapatinib in Tandem With Capecitabine for HER2 Overexpressed/Amplified Metastatic Breast Cancer With Central Nervous System (CNS) Metastases
Study Start Date : January 6, 2016
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : January 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Lapatinib in Tandem With Capecitabine
A minimum of one patient at each dose level will be enrolled. Patients will receive a 4 week treatment cycle consisting of lapatinib 3 day on/11 day off in tandem with capecitabine 7 day on/7 day off with lapatinib. Both drugs will be administered orally as outpatient. Safety, toxicity, and DLT will be assessed weekly during the cycle 1 (first 4 weeks). Each patient will be monitored during cycle 1 prior to enrolling the next patient to the next higher dose level. Dose escalation will take place if no DLT or less than two occurrences of grade 2 toxicity (except those listed below) is observed within a given patient. In the event that a second instance of separate grade 2 toxicity (except those listed below) is noted, the cohort will be expanded to 3 patients at the same dose level and the study will revert to the standard 3+3 design with 3 patients per cohort. There will be no intra-patient dose escalation.
Drug: Lapatinib in Tandem With Capecitabine

Primary Outcome Measures :
  1. maximum tolerated dose (MTD) [ Time Frame: first 28-day cycle ]

    During the standard 3+3, the probability that dose escalation will occur at any stage during MTD determination is a function of the underlying DLT rate at the current dose level. This probability can be calculated as the sum of the binomial probabilities of the following two outcomes that would permit escalation to occur:

    1. No DLT observed in the first three patients.
    2. One DLT is observed in the first three patients followed by no DLT observed in three additional patients at the same dose level.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Age ≥18 years
  • Histologically-confirmed metastatic adenocarcinoma of the breast with either invasive primary tumor or metastatic tissue confirmation of HER2+ status as defined by immunohistochemistry (IHC) with score of 3+, or, if 2+ with confirmatory fluorescence in situ hybridization (FISH) ratio of ≥ 2.0
  • Received prior trastuzumab or chemotherapy for metastatic breast cancer except if patient has CNS as only site of metastatic disease.
  • Radiologic evidence of new and/or progressive parenchymal brain metastasis, spinal cord metastases ( intramedullary) or leptomeningeal disease (LMD) by magnetic resonance (MR) imaging of the brain and/or spine, or CSF cytology evidence of new LMD.
  • Life expectancy of >12 weeks.
  • ECOG Performance of 0 to 2
  • Non-escalating corticosteroid dose (not exceeding more than 16 mg daily of dexamethasone oral) for ≥ 5 days.
  • Prior therapy:

    • No limit to prior therapies with last anti-cancer treatment ≥ 2 weeks from initiation of protocol-based therapy provided all toxicities (other than alopecia) have resolved to ≤Grade 1 or baseline. For lapatinib and IV trastuzumab and/or pertuzumab, no washout is required.
    • Patients with prior whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) are eligible, provided that there are new lesions not previously treated by SRS and ≥4 weeks have passed since radiation
    • Patients with prior cranial surgery are eligible, provided that there is evidence of residual disease and/or progression of disease and ≥4 weeks have passed since surgery.
    • Prior hormonal therapy for locally advanced or metastatic disease is allowed and can be continued. If everolimus is used in a combination with hormonal therapy, then, everolimus must be discontinued but hormonal therapy can be continued.
    • Continuation of intravenous (IV) trastuzumab is allowed for those patients already on IV trastuzumab therapy. Patients previously treated with intrathecal (IT) trastuzumab are allowed if there is evidence of progression as determined by treating physician and last dose administered is ≥ 4 weeks.
    • Prior capecitabine therapy is allowed, provided ≥6 months have passed since the last dose of capecitabine.
  • Cardiac ejection fraction at or above the lower limit of normal as measured by multigated radionuclide angiography (MUGA) scans or echocardiogram documented ≤ 3 months prior to registration.
  • Adequate bone marrow, liver, and renal function as assessed by the following:

    • Granulocyte count ≥ 1,000/μL for lapatinib and > 1,500/uL for capecitabine , platelet count ≥ 100,000/μL, and hemoglobin ≥ 8 g/dL
    • Serum bilirubin ≤ 1.5 mg/dL; AST, ALT, and alkaline phosphatase ≤ 2.5 × ULN except for: Patients with hepatic metastases: ALT and AST ≤ 5 × ULN; patients with hepatic and/or bone metastases: alkaline phosphatase ≤ 5 × ULN and patients with Gilbert's disease: serum bilirubin < 5 mg/dL
    • Serum creatinine ≤ 1.5 mg/dL or creatinine clearance of ≥ 60 mL/min based on a 24-hour urine collection
  • Women of childbearing potential must have a negative serum pregnancy test performed within 14 days prior to enrollment. Women of childbearing potential and men must agree to use adequate contraception prior to enrollment and for the duration of study participation.
  • Patients must be able to swallow and retain oral medication.

Exclusion Criteria:

  • Contraindications or history of allergic reaction to lapatinib or to capecitabine, known dihydropyrimidine dehydrogenase deficiency, or known hypersensitivity of 5-fluorouracil.
  • Craniotomy or any other major surgery, open biopsy, or significant traumatic injury within 4 weeks of enrollment.
  • Serious, non-healing wound, infection, ulcer, bone fracture, or uncontrolled seizures
  • Significant gastrointestinal disorder with diarrhea as a major symptom (example Crohn's disease, ulcerative colitis) or Grade ≥ 2 diarrhea of any etiology at baseline. Active hepatobiliary disease with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease as determined by investigator's assessment.
  • Significant medical co-morbidities as described below:

    • Cardiac disease:
    • Congestive heart failure >class II New York Heart Association (NYHA) or
    • Unstable angina (anginal symptoms at rest), or new-onset angina (begun within the last 3 months), or myocardial infarction within the 6 months prior to enrollment, or
    • Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
    • Known history of QTc prolongation or Torsades de Pointes
  • Grade 3 hypertension (SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg despite maximal medical therapy)
  • Thrombotic, embolic, venous, or arterial events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
  • Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C
  • Previous or concurrent cancer that is distinct in primary site or histology from breast cancer within 5 years prior to enrollment EXCEPT cervical cancer in situ, treated non-melanoma skin cancers, superficial bladder tumors [Ta and Tis].
  • Concurrent medication:

    • Rivaroxaban and vitamin-K antagonists (e.g., warfarin), but enoxaparin is allowed.
    • No concurrent use of strong CYP3A4 inhibitor (e.g., ketoconazole, voriconazole, grapefruit) or inducers (e.g., phenytoin, carbamazepine, phenobarbital, St. John's Wort [Hypericum perforatum], dexamethasone at a dose of greater than 16 mg daily, or rifampin [rifampicin], and/or rifabutin). 2 week washout period before enrollment required if any of strong inducer or inhibitors used (except for dexamethasone, dose needs to be 16mg or less daily). (Appendix H)
    • Use of concurrent cytochrome P450 enzyme-inducing anti-epileptic drugs (such as phenytoin, carbamazepine, or phenobarbital) is not allowed. (Anti-epileptic levetiracetam is allowed).
  • Concurrent anti-cancer therapy (chemotherapy, hormonal therapy, radiation therapy, surgery, immunotherapy, tumor embolization, or biologic therapy including pertuzumab, but except IV trastuzumab or hormonal therapy, if patient is already being treated with either of the two agents.)
  • Use of any investigational drug within 28 days or 5 half-lives, whichever is longer, preceding enrollment.
  • Women who are pregnant or breast-feeding.
  • Inability to comply with protocol and /or not willing or not available for follow-up assessments or any condition which in the investigator's opinion makes the patient unsuitable for the study participation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02650752

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United States, Michigan
University of Michigan Health System
Ann Arbor, Michigan, United States, 48109
United States, New Jersey
Memoral Sloan Kettering Cancer Center
Basking Ridge, New Jersey, United States
Memorial Sloan Kettering Monmouth
Middletown, New Jersey, United States, 07748
United States, New York
Memorial Sloan Kettering Cancer Center @ Suffolk
Commack, New York, United States, 11725
Memorial Sloan Kettering Westchester
Harrison, New York, United States, 10604
Queens Cancer Center of Queens Hospital
Jamaica, New York, United States, 11432
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Memorial Sloan Kettering at Mercy Medical Center
Rockville Centre, New York, United States
Memorial Sloan Kettering Nassau
Uniondale, New York, United States, 11553
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Queens Cancer Center of Queens Hospital
University of Michigan
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Principal Investigator: Andrew Seidman, MD Memorial Sloan Kettering Cancer Center

Additional Information:
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Responsible Party: Memorial Sloan Kettering Cancer Center Identifier: NCT02650752     History of Changes
Other Study ID Numbers: 15-278
First Posted: January 8, 2016    Key Record Dates
Last Update Posted: April 11, 2019
Last Verified: April 2019

Keywords provided by Memorial Sloan Kettering Cancer Center:

Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasm Metastasis
Neoplasms by Site
Breast Diseases
Skin Diseases
Neoplastic Processes
Pathologic Processes
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors