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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Drug Distribution and Pharmacodynamic Study of Pulsatile Lapatinib in Surgically Accessible EGFR-Amplified Recurrent High-Grade Glioma

Brief Summary: This pilot 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 Summary:

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 OBJECTIVES:

I. To evaluate the safety profile of pulsatile lapatinib in pre-operative patients with EGFR amplified recurrent high-grade glioma. (Group A and Reference Group) II. To evaluate acute and late toxicities associated with pulsatile lapatinib. (Group A and Reference Group) III. To determine the effect of lapatinib on tumor cell proliferation (marker of proliferation Ki-67 [KI-67] staining). (Group A compared to Reference Group) IV. To determine the ex-vivo sensitivity of tumor sphere cultures to lapatinib. (Group A and Reference Group) V. To assess tumor objective response rate (ORR). (Group A and Reference Group) VI. To estimate overall survival (OS). (Group A and Reference Group) VII. 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. Courses repeat every 28 d
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

  • Lapatinib ditosylate intratumoral concentration (pharmacokinetics) [ Time Frame: Baseline and day of surgery ]
  • 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%).


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • 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.
  • Incidence of adverse events (AEs) [ Time Frame: Up to day 30 ]
    All treatment or surgically related AEs will be reported descriptively. A proportion of toxicity grade >=3 will be estimated using binomial distribution.
  • 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.
  • Objective response rate [ Time Frame: Up to 2 years ]
    Will be estimated along with 95% confidence intervals using the exact binomial method.
  • OS [ 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.
  • 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.


Original Secondary Outcome:

  • Incidence of adverse events (AEs) [ Time Frame: Up to day 30 ]
    All treatment or surgically related AEs will be reported descriptively. A proportion of toxicity grade >=3 will be estimated using binomial distribution.
  • 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.
  • 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.


Information By: National Cancer Institute (NCI)

Dates:
Date Received: March 28, 2014
Date Started: March 2014
Date Completion:
Last Updated: May 23, 2017
Last Verified: May 2017