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Trial registered on ANZCTR


Registration number
ACTRN12611000418976
Ethics application status
Approved
Date submitted
15/04/2011
Date registered
21/04/2011
Date last updated
14/12/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
Investigation of the efficacy of lapatinib plus temozolomide combination, in recurrent brain tumors. A phase I/II study.
Scientific title
Patients with recurrent high grade gliomas treated with lapatinib plus temozolomide combination to investigate the safety and efficacy of the combination
Secondary ID [1] 260012 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
patients with recurrent or refractory gliomas 265674 0
Condition category
Condition code
Cancer 265807 265807 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Phase I: In the phase I study patients will be enrolled in cohorts of 3. They will receive fixed dose temozolomide [200 mg/m2 orally (po) once daily for 5 days] in cycles of 28 days and escalating doses of lapatinib. The starting dose of lapatinib will be 1000 mg administered orally (po) once daily (OD) every day of the 28 day cycle. Three dose levels of lapatinib will be explored (1000, 1250 and 1500 mg). Patients will receive lapatinib/ temozolomide combination until disease progression or unacceptable toxicity. Cohorts of 3 patients will receive escalating doses of lapatinib until the maximum tolerated dose is determined (MTD) as recorded in week 4 of treatment. Phase II: Temozolomide 200 mg/m2 orally (po) once daily for 5 days will be used along with Lapatinib 1000 mg orally (po) once daily (dose as defined from phase I). The cycle duration is 28 days. The treatment will continue until disease progression, unacceptable toxicity or consent withdrawal.
Intervention code [1] 264430 0
Treatment: Drugs
Comparator / control treatment
N/A
Control group
Uncontrolled

Outcomes
Primary outcome [1] 266559 0
Phase I
Determine the maximum tolerated dose and recommended phase II dose of lapatinib when given in combination with temozolomide in patients with recurrent or refractory glioblastoma multiforme.
Timepoint [1] 266559 0
Three dose levels of lapatinib will be explored (1000, 1250 and 1500 mg). Patients will receive lapatinib/ temozolomide combination until disease progression or unacceptable toxicity. Cohorts of 3 patients will receive escalating doses of lapatinib until the maximum tolerated dose (MTD) is determined as recorded in week 4 of treatment.
Primary outcome [2] 266560 0
Phase I
Determine the safety and tolerability (toxicity profile) of this regimen in these patients.
Timepoint [2] 266560 0
Adverse Events (AEs) (hematological and non-hematological toxicities) of all participants will be recorded and assessed upon signature of the informed consent form until 30 days after the last administration of study treatment
Primary outcome [3] 266565 0
Phase II

Efficacy
Timepoint [3] 266565 0
MRI scans carried out at baseline, at the end of week 8, and every 8 weeks thereafter until progression, unacceptable toxicity or consent withdrawal.
Secondary outcome [1] 276029 0
-Determine Time to disease progression (TTP)
Timepoint [1] 276029 0
- TTP will be calculated from date of treatment initiation until objective tumor progression
Secondary outcome [2] 276030 0
-Determine Overall Survival (OS)
Timepoint [2] 276030 0
OS will be calculated from the date of treatment initiation to the date of death or last contact
Secondary outcome [3] 276031 0
- Evaluate toxicity
Timepoint [3] 276031 0
Adverse Events (AEs) (e.g. hematological and non-hematological toxicities) of all participants will be recorded and assessed upon signature of the informed consent form until 30 days after the last administration of study treatment
Toxicity is assessed by laboratory evaluation of hematology and biochemistry, physical examination etc.

Eligibility
Key inclusion criteria
1. Written informed consent 2. Age >18 years 3. Radiographic evidence of recurrent glioma (Grade IV glioblastoma multiforme or Grade III anaplastic astrocytoma). Patients should have achieved Complete Response (CR), Partial Response (PR) or Stable Disease (SD) with prior treatment with radiation (RT)/ temozolomide (adjuvant or 1st line setting). Early recurrence patients may be included in the phase I study. 4. Measurable disease at screening according to Response Evaluation Criteria In Solid Tumors (RECIST) 5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 6. Adequate haematological function (Absolute Neutrophils Count>=1.5 x 10^9/Litre (L), Platelet count>=100 x 10^9/L and Haemoglobin>=9grams per deciliter (g/dL) 7. Adequate liver and renal function (Total bilirubin <1.5 x upper limit of normal, aspartate aminotransferase (AST), Alanine transaminase (ALT) <2.5x Upper Limit of Normal (ULN) in patients (pts) without liver metastases; <5xULN in pts with liver metastases, serum creatinine <=1.25xULN or calculated creatinine clearance >=50 Millilitre per minute (mL/min) 8. Left Ventricular Ejection Fraction (LVEF) within institutional normal range 9. All patients must have archived tumour tissue available for translational research.10. Drugs and several herbal constituents (e.g. bergamontin and glabridin), which are inducers or inhibitors of Cytochrome P450 3A4 (CYP3A4) must not be taken within 10 days prior to initiation of treatment and are prohibited while the patient is being treated with lapatinib 11. If a patient requires anticoagulant therapy the patient may remain on study but should be monitored carefully.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnant or lactating women
2. Clinically significant non-controlled cardiovascular disease
3. Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to enrolment
4. Prior treatment with Epidermal Growth Factor Receptors (EGFR) inhibitors will not be allowed
5. Known hypersensitivity to drugs chemically related to lapatinib
6. Evidence of any other disease, neurological or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications
7. Treatment with Enzyme-Inducing Anti-Epileptic Drugs (EIAEDs) will be excluded, use of valproate will be permitted.
8. Patients will be excluded if unable to swallow tablets.
9. Active infection.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 3393 0
Greece
State/province [1] 3393 0

Funding & Sponsors
Funding source category [1] 264905 0
Other Collaborative groups
Name [1] 264905 0
Hellenic Cooperative Oncology Group
Address [1] 264905 0
Hatzikostandi 18, 11524, Athens
Country [1] 264905 0
Greece
Primary sponsor type
Other Collaborative groups
Name
Hellenic Cooperative Oncology Group
Address
Hatzikostandi 18, 11524, Athens
Country
Greece
Secondary sponsor category [1] 264003 0
None
Name [1] 264003 0
Address [1] 264003 0
Country [1] 264003 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294355 0
National Ethics Committee
Ethics committee address [1] 294355 0
284, Mesogeion Av., 255 62, Athens
Ethics committee country [1] 294355 0
Greece
Date submitted for ethics approval [1] 294355 0
Approval date [1] 294355 0
03/06/2008
Ethics approval number [1] 294355 0
144/07

Summary
Brief summary
This study will integrate an initial phase I dose-escalation part aimed at documenting the safety profile and recommended dose of lapatininb in combination with temozolomide in patients with recurrent refractory glioblastoma multiforme. It will be followed by a phase II open-label study to evaluate the efficacy of lapatinib /temozolomide combination in patients with recurrent high grade gliomas. Patients will be treated with the combination until disease progression, unacceptable toxicity or consent withdrawal.
Trial website
Trial related presentations / publications
J Neurol
DOI 10.1007/s00415-012-6812-z
Public notes

Contacts
Principal investigator
Name 32500 0
Prof George Fountzilas
Address 32500 0
"Papageorgiou" Hospital, Nea Efkarpia, 564 29, Thessaloniki
Country 32500 0
Greece
Phone 32500 0
+30 2313323134
Fax 32500 0
Email 32500 0
fountzil@auth.gr
Contact person for public queries
Name 15747 0
Ms Eleni Papakostaki
Address 15747 0
Hatzikostandi 18, 11524, Athens
Country 15747 0
Greece
Phone 15747 0
+ 30 2106912520
Fax 15747 0
Email 15747 0
e_papakostaki@hecog.ondsl.gr
Contact person for scientific queries
Name 6675 0
Prof Prof. George Fountzilas
Address 6675 0
"Papageorgiou" Hospital, Nea Efkarpia, 564 29, Thessaloniki
Country 6675 0
Greece
Phone 6675 0
+30 2313323134
Fax 6675 0
Email 6675 0
fountzil@auth.gr

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary