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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
29
Correlative studies
Given PO
Given PO
Correlative studies
Undergo surgical resection of tumor
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Henry Ford Hospital
Detroit, Michigan, United States
Memorial Sloan Kettering Basking Ridge
Basking Ridge, New Jersey, United States
Memorial Sloan Kettering Monmouth
Middletown, New Jersey, United States
Memorial Sloan Kettering Commack
Commack, New York, United States
Memorial Sloan Kettering Westchester
Harrison, New York, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States
...and 2 more locations
To Determine the Lapatinib Ditosylate Intratumoral Concentration (Pharmacokinetics)
4 pk samples obtained: pretreatment, pre-surgery, post-surgery and interpolated pre-surgery each subject received 2500mg twice a day for two days.
Time frame: Baseline and day of surgery
To Determine the Ratio of Phosphorylated (p)EGFR/Total EGFR (PD) in Tumor Tissue
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%).
Time frame: Day of surgery
Incidence of Adverse Events (AEs)
Will be assessed by NCI CTCAE. All Treatment or surgically related AEs will be reported descriptively. A proportion of toxicity equal or greater than 3 will be estimated using binomial distribution.
Time frame: Up to day 30
Inhibition of tumor cell proliferation (KI-67)
Descriptive statistics will be used for summarizes results and Box plots could be used to present the difference between the treated and untreated groups. This was more an explorative measure and it was not completed.
Time frame: Inhibition of Tumor Cell Proliferation (KI-67)
Ex-vivo Sensitivity of Tumor Sphere Cultures to Lapatinib Ditosylate
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. This was more an explorative measure and it was not completed.
Time frame: Day of surgery
Objective Response Rate
Will be estimated along with 95% confidence intervals using the exact binomial method.
Time frame: Up to 2 years
Overall Survival
The Kaplan-Meier method will be used to estimate overall survival probability and median time of survival along with a 95% confidence interval.
Time frame: From the date of treatment start to the date of death, assessed up to 2 years
Progression-free Survival
The Kaplan-Meier method will be used to estimate progression-free survival probability and median time of survival along with a 95% confidence interval.
Time frame: Start of treatment up to 6 months
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