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Anaplastic AstrocytomaPhase 1NCT02101905

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

A Phase 1 study testing Laboratory Biomarker Analysis, Lapatinib and Lapatinib Ditosylate in people with Anaplastic Astrocytoma and Anaplastic Ependymoma, run by National Cancer Institute (NCI) at 12 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Laboratory Biomarker Analysis, Lapatinib and Lapatinib Ditosylate
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
29 participants
Where
12 sitesUnited States
Study dates
7 Nov 2016to 30 Oct 2024
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

12 sites in 1 country.

12 sites in 1 country

United States12 sites

  • Johns Hopkins University/Sidney Kimmel Cancer Center

    Baltimore, Maryland, 21287

  • Memorial Sloan Kettering Basking Ridge

    Basking Ridge, New Jersey, 07920

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • Cleveland Clinic Foundation

    Cleveland, Ohio, 44195

  • Memorial Sloan Kettering Commack

    Commack, New York, 11725

  • Henry Ford Hospital

    Detroit, Michigan, 48202

  • Memorial Sloan Kettering Westchester

    Harrison, New York, 10604

  • UCLA / Jonsson Comprehensive Cancer Center

    Los Angeles, California, 90095

  • Memorial Sloan Kettering Monmouth

    Middletown, New Jersey, 07748

  • Memorial Sloan Kettering Cancer Center

    New York, New York, 10065

  • University of Pittsburgh Cancer Institute (UPCI)

    Pittsburgh, Pennsylvania, 15232

  • Wake Forest University Health Sciences

    Winston-Salem, North Carolina, 27157

Other trials in United States

About this study

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

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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.

Being tested
Laboratory Biomarker Analysis, Lapatinib, Lapatinib Ditosylate, Pharmacological Study, Therapeutic Conventional Surgery
Medical subject headings
Astrocytoma, Ependymoma, Oligodendroglioma, Gliosarcoma, Glioma, Brain Neoplasms, Glioblastoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • LapatinibDrug

    Also called GSK572016, GW 2016, GW 572016, GW-572016

    Given PO

  • Lapatinib DitosylateDrug

    Also called Tykerb

    Given PO

  • Pharmacological StudyOther

    Correlative studies

  • Therapeutic Conventional SurgeryProcedure or surgery

    Undergo surgical resection of tumor

Study groups in NCT02101905
Study groupRoleWhat they receive
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.
Receives: Other: Laboratory Biomarker Analysis; Drug: Lapatinib; Drug: Lapatinib Ditosylate; Other: Pharmacological Study; Procedure: Therapeutic Conventional Surgery
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.
Receives: Other: Laboratory Biomarker Analysis; Drug: Lapatinib; Drug: Lapatinib Ditosylate; Other: Pharmacological Study; Procedure: Therapeutic Conventional Surgery

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Baseline and day of surgery

  2. 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%).

    Measured: Day of surgery

Secondary outcomes (6)

  1. 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.

    Measured: Up to day 30

  2. 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.

    Measured: Inhibition of Tumor Cell Proliferation (KI-67)

  3. 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.

    Measured: Day of surgery

  4. Objective Response Rate

    Will be estimated along with 95% confidence intervals using the exact binomial method.

    Measured: Up to 2 years

  5. 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.

    Measured: From the date of treatment start to the date of death, assessed up to 2 years

  6. 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.

    Measured: Start of treatment up to 6 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Apr 2014 (estimated)
  2. Study start7 Nov 2016
  3. Primary completion19 Oct 2021
  4. Study completion30 Oct 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
29 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02101905
Sponsor's protocol ID
NCI-2014-00634
Other IDs
NCI-2014-00634, ABTC-1302, ABTC-1302, U01CA137443, UM1CA137443
Status last verified
Nov 2024
First submitted
28 Mar 2014
Last updated
6 Nov 2024
Results posted
No
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Laboratory Biomarker Analysis, Lapatinib and Lapatinib Ditosylate in people with Anaplastic Astrocytoma and Anaplastic Ependymoma, run by National Cancer Institute (NCI) at 12 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 28 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 12 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

To Determine the Lapatinib Ditosylate Intratumoral Concentration (Pharmacokinetics) (time frame: Baseline and day of surgery). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02101905.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Nov 2024.

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