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

NCT02650752 | Completed Phase 1

• 1 other identifier: 15-278
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 9

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).

Conditions

Metastatic Breast Cancer; Central Nervous System (CNS) Metastases

Keywords

Lapatinib; Capecitabine; HER2; 15-278

Outcome Measures

Primary Outcomes (1)

• maximum tolerated dose (MTD)

  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.

  first 28-day cycle

Study Arms (1)

Lapatinib in Tandem With Capecitabine

EXPERIMENTAL

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

Interventions

Lapatinib in Tandem With Capecitabine DRUG

Lapatinib in Tandem With Capecitabine

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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:

Sponsors & Collaborators

• Memorial Sloan Kettering Cancer Center: lead
• Queens Cancer Center of Queens Hospital: collaborator
• University of Michigan: collaborator

Study Sites (9)

University of Michigan Health System

Ann Arbor, Michigan, 48109, United States

Location

Memoral Sloan Kettering Cancer Center

Basking Ridge, New Jersey, United States

Location

Memorial Sloan Kettering Monmouth

Middletown, New Jersey, 07748, United States

Location

Memorial Sloan Kettering Cancer Center @ Suffolk

Commack, New York, 11725, United States

Location

Memorial Sloan Kettering Westchester

Harrison, New York, 10604, United States

Location

Queens Cancer Center of Queens Hospital

Jamaica, New York, 11432, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Memorial Sloan Kettering at Mercy Medical Center

Rockville Centre, New York, United States

Location

Memorial Sloan Kettering Nassau

Uniondale, New York, 11553, United States

Location

Related Publications (1)

• Morikawa A, de Stanchina E, Pentsova E, Kemeny MM, Li BT, Tang K, Patil S, Fleisher M, Van Poznak C, Norton L, Seidman AD. Phase I Study of Intermittent High-Dose Lapatinib Alternating with Capecitabine for HER2-Positive Breast Cancer Patients with Central Nervous System Metastases. Clin Cancer Res. 2019 Jul 1;25(13):3784-3792. doi: 10.1158/1078-0432.CCR-18-3502. Epub 2019 Apr 15.

  PMID: 30988080 DERIVED

Related Links

• Memorial Sloan Kettering Cancer Center

MeSH Terms

Conditions

Breast Neoplasms; Neoplasm Metastasis

Interventions

Lapatinib; TANDEM (quinoxaline); Capecitabine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

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

Study Officials

• Andrew Seidman, MD

  Memorial Sloan Kettering 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 6, 2016
• First Posted: January 8, 2016
• Study Start: January 6, 2016
• Primary Completion: January 22, 2021
• Study Completion: January 22, 2021
• Last Updated: January 26, 2021

Record last verified: 2021-01

Locations

US (9)