Open Label Trial to Explore Safety of Combining Afatinib (BIBW 2992) and Radiotherapy With or Without Temozolomide in Newly Diagnosed Glioblastoma Multiform

Phase 1

Completed

• Conditions: Glioblastoma
• Interventions: Procedure: Radiotherapy; Drug: Temozolomide; Drug: BIBW2992

• Registration Number: NCT00977431
• Lead Sponsor: Boehringer Ingelheim

Brief Summary

This study is a phase I, open label trial to determine the Maximum Tolerated Dose (MTD), safety, pharmacokinetics, and efficacy of BIBW 2992 (an epidermal growth factor receptor(EGFR)inhibitor) to be used in combination with:

* radiotherapy alone (in patients with an unmethylated (functioning) MGMT gene regulator) or

* radiotherapy and Temozolomide (in patients with a methylated (silenced) O6-methylguanine-DNA methyltransferase gene (MGMT) to treat newly diagnosed patients with Grade IV Glioblastoma (primary brain cancer).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2009-09-14
• Study First Submitted QC: 2009-09-14
• Study First Posted: 2009-09-15
• Study Start: 2009-09-17
• Primary Completion: 2017-09-12
• Study Completion: 2017-09-12
• Results First Submitted: 2018-09-04
• Status Verified: 2019-02
• Results First Submitted QC: 2019-02-11
• Last Update Submitted: 2019-02-11
• Results First Posted: 2019-02-18
• Last Update Posted: 2019-02-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 36

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Regimen U	Radiotherapy	BIBW2992 + Radiotherapy
Regimen M	Temozolomide	BIBW2992 + Temozolomide + Radiotherapy
Regimen M	BIBW2992	BIBW2992 + Temozolomide + Radiotherapy
Regimen M	Radiotherapy	BIBW2992 + Temozolomide + Radiotherapy
Regimen U	BIBW2992	BIBW2992 + Radiotherapy

Primary Outcome Measures

Name	Time	Method
Number of Patients With Investigator Defined Dose Limiting Toxicities (DLT) During the RT Phase	6 weeks	Adverse event (AE) related to afatinib with any one criteria; Hematological: Common terminology criteria for adverse events (CTCAE) Grade 4 neutropenia (Absolute neutrophil count, including bands \<500/cubic millimeter (mm³)) for \>7 days, CTCAE Grade 3 or 4 neutropenia of any duration associated with fever \>38.3 Celsius, CTCAE Grade 3 thrombocytopenia (platelet count \<50000 - 25000/mm³), All other toxicities of CTCAE Grade ≥3 leading interruption of treatment \> 14 days.; Non-hematological: CTCAE Grade ≥3 nausea or vomiting despite appropriate use of standard anti-emetics for ≥3 days, CTCAE Grade ≥3 diarrhea despite appropriate use of standard anti-diarrheal therapy for ≥3 days, CTCAE Grade ≥3 rash despite standard medical management and lasting \>7 days, CTCAE Grade ≥2 cardiac left ventricular function, CTCAE Grade ≥2 worsening of renal function as measured by serum creatinine, newly developed proteinuria or decrease in glomerular filtration rate, All other toxicities of CTCAE Grade ≥3.
Maximum Tolerated Dose (MTD) of Afatinib	6 weeks	The MTD was defined as the highest afatinib dose level, at which no more than 1 out of 6 patients experienced drug-related DLT, i.e. the highest afatinib dose with a DLT incidence ≤17%. A separate MTD was determined for afatinib and RT (Regimen U), and for afatinib, TMZ, and RT (Regimen M).

Secondary Outcome Measures

Name	Time	Method
The Objective Tumour Response According to the Macdonald Criteria	From the first administration of trial medication until 4 weeks after the last administration of trial medication, up to approximately 338 weeks	Objective response was defined as a best overall response of complete response (CR) or partial response (PR). The best overall response was the best overall response to trial medication according to the Macdonald criteria recorded since the first administration of trial medication and until the earliest of disease progression, death, or start of further anti-cancer treatment. Tumour response was assessed based on local radiological image evaluation by the investigators according to the Macdonald criteria: Complete Response (CR): Disappearance of all enhancing tumour on consecutive Magnetic resonance imaging (MRI) scans at least 28 days apart, off steroids, and neurologically stable or improved. Partial Response (PR): At least 50% reduction in size of enhancing tumour on consecutive MRI scans at least 28 days apart, steroids stable or reduced, and neurologically stable or improved.
Concentration of Afatinib in Plasma at Steady State Pre-dose on Days 8, 15 and 29	Pharmacokinetic blood sample were taken at 5 minutes before drug on days 8, 15 and 29 and 1, 3 and 6 hours after drug administration on day 15	Concentration of afatinib in plasma at steady state pre-dose (Cpre,ss) on days 8, 15 and 29.
Incidence and Intensity of Adverse Events (AE) According to Common Terminology Criteria of Adverse Events (CTCAE v.3.0)	From the first administration of trial medication until 4 weeks after the last administration of trial medication, up to approximately 338 weeks	Incidence and intensity of adverse events (AE) according to Common Terminology Criteria of Adverse Events (CTCAE v.3.0). The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).

Trial Locations

Locations (5)

The Royal Marsden Hospital; 🇬🇧 Sutton, United Kingdom

Addenbrooke's Hospital; 🇬🇧 Cambridge, United Kingdom

The Christie Hospital; 🇬🇧 Manchester, United Kingdom

Ninewells Hospital & Medical School; 🇬🇧 Dundee, United Kingdom

Beatson West of Scotland Cancer Centre; 🇬🇧 Glasgow, United Kingdom