Investigation of the efficacy of lapatinib plus temozolomide combination, in recurrent brain tumors. A phase I/II study.
Patients with recurrent high grade gliomas treated with lapatinib plus temozolomide combination to investigate the safety and efficacy of the combination
Hellenic Cooperative Oncology Group
66 participants
Jan 12, 2009
Interventional
Conditions
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.
Eligibility
Inclusion Criteria1
- 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.
Exclusion Criteria9
- Pregnant or lactating women
- Clinically significant non-controlled cardiovascular disease
- Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to enrolment
- Prior treatment with Epidermal Growth Factor Receptors (EGFR) inhibitors will not be allowed
- Known hypersensitivity to drugs chemically related to lapatinib
- 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
- Treatment with Enzyme-Inducing Anti-Epileptic Drugs (EIAEDs) will be excluded, use of valproate will be permitted.
- Patients will be excluded if unable to swallow tablets.
- Active infection.
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Interventions
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.
Locations(1)
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ACTRN12611000418976