Clinical Trials /

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

NCT02101905

Description:

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.

Related Conditions:
  • Glioblastoma
  • Glioma
  • Gliosarcoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Lapatinib Ditosylate Before Surgery in Treating Patients With Recurrent High-Grade Glioma
  • Official Title: Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified Recurrent High-Grade Glioma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2014-00634
  • SECONDARY ID: NCI-2014-00634
  • SECONDARY ID: ABTC-1302
  • SECONDARY ID: ABTC-1302
  • SECONDARY ID: U01CA137443
  • SECONDARY ID: UM1CA137443
  • NCT ID: NCT02101905

Conditions

  • Anaplastic Astrocytoma
  • Anaplastic Ependymoma
  • Anaplastic Oligodendroglioma
  • Gliosarcoma
  • Mixed Glioma
  • Recurrent Adult Brain Neoplasm
  • Recurrent Glioblastoma

Interventions

DrugSynonymsArms
LapatinibGSK572016, GW 2016, GW2016, GW572016Group A (lapatinib ditosylate, surgery)
Lapatinib DitosylateTykerbGroup A (lapatinib ditosylate, surgery)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Group A (lapatinib ditosylate, surgery)ExperimentalPatients 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.
  • Lapatinib
  • Lapatinib Ditosylate
Reference Group (surgery, lapatinib ditosylate)Active ComparatorPatients 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.
  • Lapatinib
  • Lapatinib Ditosylate

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

Primary Outcome Measures

Measure:Lapatinib ditosylate intratumoral concentration (pharmacokinetics)
Time Frame:Baseline and day of surgery
Safety Issue:
Description: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

Measure:Incidence of adverse events (AEs)
Time Frame:Up to day 30
Safety Issue:
Description: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.
Measure:Inhibition of tumor cell proliferation (KI-67)
Time Frame:Day of surgery
Safety Issue:
Description:Descriptive statistics will be used for summarizes results and Box plots could be used to present the difference between the treated and untreated groups.
Measure:Ex-vivo sensitivity of tumor sphere cultures to lapatinib ditosylate
Time Frame:Day of surgery
Safety Issue:
Description: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.
Measure:Objective response rate
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated along with 95% confidence intervals using the exact binomial method.
Measure:Overall survival
Time Frame:From the date of treatment start to the date of death, assessed up to 2 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate overall survival probability and median time of survival along with a 95% confidence interval.
Measure:Progression-free survival
Time Frame:Start of treatment up to 6 months
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate progression-free survival probability and median time of survival along with a 95% confidence interval.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

January 22, 2021