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Lapatinib Ditosylate Before Surgery in Treating Patients With Recurrent High-Grade Glioma

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.
 
ClinicalTrials.gov Identifier: NCT02101905
Recruitment Status : Active, not recruiting
First Posted : April 2, 2014
Last Update Posted : February 5, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This pilot phase I clinical trial studies how well lapatinib ditosylate before surgery works in treating patients with high-grade glioma that has come back after a period of time during which the tumor could not be detected. Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Anaplastic Astrocytoma Anaplastic Ependymoma Anaplastic Oligodendroglioma Gliosarcoma Mixed Glioma Recurrent Adult Brain Neoplasm Recurrent Glioblastoma Other: Laboratory Biomarker Analysis Drug: Lapatinib Drug: Lapatinib Ditosylate Other: Pharmacological Study Procedure: Therapeutic Conventional Surgery Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To achieve an intratumoral lapatinib (lapatinib ditosylate) concentration of at least 1.5 uM in at least 70% of patients 3 hours after the last dose of pulsatile lapatinib. (Group A) II. To determine the pharmacodynamic (PD) effect of pulsatile lapatinib (at pulsatile maximum tolerated dose [MTD]) on epidermal growth factor receptor (EGFR) phosphorylation (using Mesoscale Discovery enzyme-linked immunosorbent assay [ELISA] assay for total and phospho-EGFR). (Group A and Reference Group)

SECONDARY/EXPLORATORY OBJECTIVES:

Ia. To evaluate the safety profile of pulsatile lapatinib in pre-operative patients with EGFR amplified recurrent high-grade glioma. (Group A and Reference Group) Ib. To evaluate acute and late toxicities associated with pulsatile lapatinib. (Group A and Reference Group) II. To determine the effect of lapatinib on tumor cell proliferation (marker of proliferation Ki-67 [KI-67] staining). (Group A compared to Reference Group) III. To determine the ex-vivo sensitivity of tumor sphere cultures to lapatinib. (Group A and Reference Group) IV. To assess tumor objective response rate (ORR). (Group A and Reference Group) V. To estimate overall survival (OS). (Group A and Reference Group) VI. To estimate progression-free survival. (Group A and Reference Group)

OUTLINE: Patients are assigned to 1 of 2 treatment groups.

GROUP A: Patients receive lapatinib ditosylate orally (PO) twice daily (BID) on days -2 to 0. Within 3-5 hours after last dose of lapatinib ditosylate, patients undergo surgical resection of tumor on day 0. Within 30 days of surgical resection of tumor, patients receive lapatinib ditosylate BID for 2 days every 7 days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

REFERENCE GROUP: Patients undergo surgical resection of tumor on day 0. Within 30 days of surgical resection of tumor, patients receive lapatinib ditosylate BID for 2 days every 7 days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at 30 days, every 2 months for 2 years, and every 6 months thereafter.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 29 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified Recurrent High-Grade Glioma
Actual Study Start Date : March 13, 2014
Actual Primary Completion Date : December 31, 2019


Arm Intervention/treatment
Experimental: Group A (lapatinib ditosylate, surgery)
Patients receive lapatinib ditosylate PO BID on days -2 to 0. Within 3-5 hours after last dose of lapatinib ditosylate, patients undergo surgical resection of tumor on day 0. Within 30 days of surgical resection of tumor, patients receive lapatinib ditosylate BID for 2 days every 7 days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Lapatinib
Given PO
Other Names:
  • GSK572016
  • GW 2016
  • GW2016
  • GW572016

Drug: Lapatinib Ditosylate
Given PO
Other Name: Tykerb

Other: Pharmacological Study
Correlative studies

Procedure: Therapeutic Conventional Surgery
Undergo surgical resection of tumor

Active Comparator: Reference Group (surgery, lapatinib ditosylate)
Patients undergo surgery on day 0. Within 30 days of surgical resection of tumor, patients receive lapatinib ditosylate BID for 2 days every 7 days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Lapatinib
Given PO
Other Names:
  • GSK572016
  • GW 2016
  • GW2016
  • GW572016

Drug: Lapatinib Ditosylate
Given PO
Other Name: Tykerb

Other: Pharmacological Study
Correlative studies

Procedure: Therapeutic Conventional Surgery
Undergo surgical resection of tumor




Primary Outcome Measures :
  1. Lapatinib ditosylate intratumoral concentration (pharmacokinetics) [ Time Frame: Baseline and day of surgery ]
  2. Ratio of phosphorylated (p)EGFR/total EGFR (PD) in tumor tissue [ Time Frame: Day of surgery ]
    A ratio of pEGFR/total EGFR at 80% reduction from a median value from the untreated reference group will be considered as the putative threshold to qualify a near complete inhibition of EGFR (at 80%).


Secondary Outcome Measures :
  1. Incidence of adverse events (AEs) [ Time Frame: Up to day 30 ]
    Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events 4.0 (version 5.0 beginning April 1, 2018). All treatment or surgically related AEs will be reported descriptively. A proportion of toxicity grade >=3 will be estimated using binomial distribution.

  2. Inhibition of tumor cell proliferation (KI-67) [ Time Frame: Day of surgery ]
    Descriptive statistics will be used for summarizes results and Box plots could be used to present the difference between the treated and untreated groups.

  3. Ex-vivo sensitivity of tumor sphere cultures to lapatinib ditosylate [ Time Frame: Day of surgery ]
    The ex-vivo sensitivity of tumor sphere cultures established from surgical specimens to pulsatile lapatinib ditosylate is defined by a minimum of 20% reduction in cell proliferation as measured by cell titer glow in the pulsatile lapatinib ditosylate group compared to the untreated group. Fisher's exact test will be used for testing a difference in the proportion between the two groups.

  4. Objective response rate [ Time Frame: Up to 2 years ]
    Will be estimated along with 95% confidence intervals using the exact binomial method.

  5. Overall survival [ Time Frame: From the date of treatment start to the date of death, assessed up to 2 years ]
    The Kaplan-Meier method will be used to estimate overall survival probability and median time of survival along with a 95% confidence interval.

  6. Progression-free survival [ Time Frame: Start of treatment up to 6 months ]
    The Kaplan-Meier method will be used to estimate progression-free survival probability and median time of survival along with a 95% confidence interval.



Information from the National Library of Medicine

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

Inclusion Criteria:

  • Patients must have histologically proven World Health Organization (WHO) grade IV glioblastoma/ gliosarcoma or WHO grade III glioma (anaplastic astrocytoma, anaplastic oligodendroglioma, mixed anaplastic oligoastrocytoma, anaplastic ependymoma) which is progressive or recurrent following radiation therapy +/- chemotherapy
  • Patients must have measurable, supratentorial contrast-enhancing progressive or recurrent high-grade glioma by magnetic resonance imaging (MRI) imaging within 21 days of starting treatment; patient must be able to tolerate MRIs
  • Patients may have an unlimited number of prior therapy regimens
  • Patients must have recovered from severe toxicity of prior therapy; the following intervals from previous treatments are required to be eligible:

    • 12 weeks from the completion of radiation
    • 6 weeks from a nitrosourea chemotherapy
    • 3 weeks from a non-nitrosourea chemotherapy
    • 4 weeks from any investigational (not Food and Drug Administration [FDA]-approved) agents
    • 4 weeks from the last treatment with bevacizumab
    • 2 weeks from administration of a non-cytotoxic, FDA-approved agent other than bevacizumab (e.g., hydroxychloroquine, etc.)
  • Patients must be undergoing surgery that is clinically indicated as determined by their care providers; patients must be eligible for surgical resection according to the following criteria:

    • Expectation that the surgeon is able to resect at least 500 mg of tumor from enhancing tumor and 100 mg from non-enhancing tumor with low risk of inducing neurological injury
  • Patient tumor sample must have evidence of EGFR gene amplification by fluorescence in situ hybridization (FISH) using a Clinical Laboratory Improvement Act (CLIA)-certified laboratory assay
  • Paraffin embedded tissue must be available from initial surgical resection at diagnosis (prior to any treatment)
  • Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be able to care for himself/herself with occasional help from others)
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 9 g/dL
  • Total bilirubin =< institutional upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal
  • Creatinine =< institutional upper limit of normal OR creatinine clearance >= 60 ml/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Activated partial thromboplastin time (APTT)/partial thromboplastin time (PTT) =< 1.5 x institutional upper limit of normal
  • Patients must have left ventricular ejection fraction (LVEF) within normal institutional limits within 21 days of starting treatment
  • Patients must have a 12-lead electrocardiogram performed within 2 weeks of treatment start with corrected (QTC) =< 470 msec
  • Patients must be able to provide written informed consent
  • Women of childbearing potential must have a negative serum pregnancy test prior to study entry; women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 4 months after completion of lapatinib administration
  • Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder; patients with prior malignancies must be disease-free for >= five years
  • Patients must be able to swallow medication by mouth, either tablets or dispersed tablets in solution

Exclusion Criteria:

  • Patients may not be receiving any other investigational agents
  • Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to lapatinib are ineligible
  • Patients with prior therapy with EGFR inhibitors are ineligible because treatment with EGFR kinase inhibitors or other EGFR-targeted agents has the potential to deplete the tumor of EGFR-amplified or EGFR mutant cell populations and confound the evaluation of lapatinib effects on EGFR phosphorylation; patients with prior EGFRvIII vaccine are eligible if recurrent tumor is positive for EGFR gene amplification
  • Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for treatment on this protocol; patients may be on non-enzyme inducing anti-epileptic drugs or not be taking any anti-epileptic drugs; patients previously treated with EIAED may be enrolled if they have been off the EIAED for 10 days or more prior to the first dose of lapatinib
  • Patients must not have evidence of significant hematologic, renal, or hepatic dysfunction
  • Patients must not have evidence of significant intracranial hemorrhage
  • Patients with uncontrolled intercurrent illness including, but not limited to, hypertension, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible
  • Pregnant women are excluded from this study because lapatinib has potential for teratogenic or abortifacients effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with lapatinib, breastfeeding should be discontinued if the mother is treated with lapatinib
  • Human immunodeficiency virus (HIV)-positive patients on strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers or inhibitors are ineligible
  • Patients who have acute or currently active/requiring anti-viral therapy hepatic or biliary disease are ineligible (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases from the primary brain tumor, or stable chronic liver disease per investigator assessment)
  • Patients receiving P-glycoprotein (P-gp) inhibitors are ineligible
  • Patients who are receiving a drug that has a risk of QTc prolongation if QTc is >= 460 msec. are ineligible

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 ClinicalTrials.gov identifier (NCT number): NCT02101905


Locations
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United States, California
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, United States, 90095
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Michigan
Henry Ford Hospital
Detroit, Michigan, United States, 48202
United States, New Jersey
Memorial Sloan Kettering Basking Ridge
Basking Ridge, New Jersey, United States, 07920
Memorial Sloan Kettering Monmouth
Middletown, New Jersey, United States, 07748
United States, New York
Memorial Sloan Kettering Commack
Commack, New York, United States, 11725
Memorial Sloan Kettering Westchester
Harrison, New York, United States, 10604
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, North Carolina
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Timothy F Cloughesy National Cancer Institute (NCI)

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02101905    
Other Study ID Numbers: NCI-2014-00634
NCI-2014-00634 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ABTC-1302 ( Other Identifier: Adult Brain Tumor Consortium )
ABTC-1302 ( Other Identifier: CTEP )
U01CA137443 ( U.S. NIH Grant/Contract )
UM1CA137443 ( U.S. NIH Grant/Contract )
First Posted: April 2, 2014    Key Record Dates
Last Update Posted: February 5, 2020
Last Verified: January 2020
Additional relevant MeSH terms:
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Glioblastoma
Glioma
Astrocytoma
Ependymoma
Gliosarcoma
Oligodendroglioma
Brain Neoplasms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Lapatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action