GlioblastomaPhase 1NCT00977431

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

A Phase 1 study testing Temozolomide, Radiotherapy and BIBW2992 in people with Glioblastoma, run by Boehringer Ingelheim at 5 sites in United Kingdom.

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 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… Read more about this study

Who is it for?: Ages 18 to 69 years
Conditions the study is for: Glioblastoma
What is being tested?: Temozolomide, Radiotherapy and BIBW2992
Type of treatment: Surgery or procedure
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 36 participants
Where: 5 sitesUnited Kingdom
Study dates: 17 Sep 2009to 12 Sep 2017
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

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 to 69 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Histologically-confirmed WHO Grade IV newly diagnosed malignant glioma.
Proven MGMT gene promoter methylation status
Available early postoperative Gd-enhanced MRI (within 72 hours after initial surgery). In case a patient did not perform a Gd-enhanced MRI within 72 hours post surgery, a Gd-MRI is to be performed prior to start of study treatment.
Age more or equal to 18 years and less than 70 years at entry
Karnofsky Performance Scale (KPS) more or equal to 70%
Patients receiving corticosteroids have to receive a stable or decreasing dose for at least 14 days before start of treatment.
Written informed consent that is consistent with local law and ICH- Good Clinical Practice (GCP) guidelines.

Who cannot join

Less than two weeks from surgical resection or other major surgical procedure at start of treatment.
Planned surgery for other diseases
Placement of Gliadel® wafer at surgery.
Prior or planned radiotherapy of the cranium including brachytherapy and/or radiosurgery for GBM.
Treatment with other investigational drugs; participation in another clinical study including exposure to the investigational product within the past 4 weeks before start of therapy or concomitantly with this study.
Active infectious disease requiring intravenous therapy.

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Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.
Gastrointestinal disorders that may interfere with the absorption of the study drug or chronic diarrhoea.
Patients with known pre-existing interstitial lung disease
Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol.
Patient is less than 3 years free of another primary malignancy except: if the other primary malignancy is either not currently clinically significant or does not require active intervention (such as a basal cell skin cancer or a cervical carcinoma in situ). Existence of any other malignant disease is not allowed.
Cardiac left ventricular function with resting ejection fraction less than 50%.
Absolute neutrophil count (ANC) less than 1500/mm3.
Platelet count less than 100,000/mm3.
Bilirubin greater than 1.5 x upper limit of institutional norm.
Aspartate amino transferase (AST) greater than 3 x upper limit of institutional norm.
Serum creatinine greater than 1.5 x upper limit of institutional norm.
Patients who are sexually active and unwilling to use a medically acceptable method of contraception.
Pregnancy or breast-feeding.
Patients unable to comply with the protocol.
Known or suspected active drug or alcohol abuse.
Known hypersensitivity to BIBW 2992 or the excipients of any of the trial drugs.

Trial locations and contacts

5 sites in 1 country.

City, postcode or hospital

5 sites in 1 country

United Kingdom5 sites

Addenbrooke's Hospital
Cambridge, CB2 0QQ
Ninewells Hospital & Medical School
Dundee, DD1 9SY
Beatson West of Scotland Cancer Centre
Glasgow, G12 0YN
The Christie Hospital
Manchester, M20 4BX
The Royal Marsden Hospital
Sutton, SM2 5PT

Other trials in United Kingdom

About this study

Official title: Phase I, Open Label Trial to Explore Safety of Combining BIBW 2992 and Radiotherapy With or Without Temozolomide in Newly Diagnosed GBM

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).

Conditions: Glioblastoma
Being tested: Temozolomide, Radiotherapy, BIBW2992
Medical subject headings: Glioblastoma

What participants receive

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

TemozolomideDrug
During RT: 75 mg/m2 daily , 4 weeks after RT: given days 1 to 5 of 28 day cycles (150 mg/m2 in cycle 1, 200 mg/m2 in cycle 2 up to cycle 6)
RadiotherapyProcedure or surgery
Day 1 to day 42
BIBW2992Drug
Escalating dose cohorts during Radiotherapy(RT) period, fixed dose after RT
RadiotherapyProcedure or surgery
Day 1 to day 42
BIBW2992Drug
Escalating dose cohorts during Radiotherapy(RT) period , fixed dose after RT

Study groups in NCT00977431
Study group	Role	What they receive
Regimen U	Experimental	BIBW2992 + Radiotherapy Receives: Procedure: Radiotherapy; Drug: BIBW2992
Regimen M	Experimental	BIBW2992 + Temozolomide + Radiotherapy Receives: Drug: Temozolomide; Drug: BIBW2992; Procedure: Radiotherapy

What is being measured

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

Number of Patients With Investigator Defined Dose Limiting Toxicities (DLT) During the RT Phase
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.
Measured: 6 weeks
Maximum Tolerated Dose (MTD) of Afatinib
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).
Measured: 6 weeks

Secondary outcomes (3)

Incidence and Intensity of Adverse Events (AE) According to Common Terminology Criteria of Adverse Events (CTCAE v.3.0)
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).
Measured: From the first administration of trial medication until 4 weeks after the last administration of trial medication, up to approximately 338 weeks
The Objective Tumour Response According to the Macdonald Criteria
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.
Measured: From the first administration of trial medication until 4 weeks after the last administration of trial medication, up to approximately 338 weeks
Concentration of Afatinib in Plasma at Steady State Pre-dose on Days 8, 15 and 29
Concentration of afatinib in plasma at steady state pre-dose (Cpre,ss) on days 8, 15 and 29.
Measured: 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

Timeline

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

17 Sep 200912 Sep 2017

First posted15 Sep 2009 (estimated)
Study start17 Sep 2009
Primary completion12 Sep 2017
Study completion12 Sep 2017

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for GlioblastomaStudies of the same condition, open and under way.
More trials run by Boehringer IngelheimThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

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: 36 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00977431
Sponsor's protocol ID: 1200.38
Other IDs: 2008-007284-17, 2008
Status last verified: Feb 2019
First submitted: 14 Sep 2009
Last updated: 18 Feb 2019
Results posted: Yes, on ClinicalTrials.gov

Publications

Saran F, Welsh L, James A, McBain C, Gattamaneni R, Jefferies S, Harris F, Pemberton K, Schaible J, Bender S, Cseh A, Brada M. Afatinib and radiotherapy, with or without temozolomide, in patients with newly diagnosed glioblastoma: results of a phase I trial. J Neurooncol. 2021 Dec;155(3):307-317. doi: 10.1007/s11060-021-03877-6. Epub 2021 Nov 17.
PubMed 34787778

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Glioblastoma trials

Study at a glance

From the registry record, last updated by the sponsor on 18 Feb 2019. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Phase I, Open Label Trial to Explore Safety of Combining BIBW 2992 and Radiotherapy With or Without Temozolomide in Newly Diagnosed GBM
ClinicalTrials.gov ID: NCT00977431
Acronym / sponsor ID: 1200.38
Conditions: Glioblastoma
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 36 participants (actual)
Lead sponsor: Boehringer IngelheimIndustry (pharma, biotech, devices)
Study start: 17 Sep 2009 (actual)
Primary completion: 12 Sep 2017 (actual)
Study completion: 12 Sep 2017 (actual)
First posted: 15 Sep 2009 (estimated)
Results: Posted 18 Feb 2019

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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).

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
Regimen U	Experimental	Procedure: Radiotherapy, Drug: BIBW2992BIBW2992 + Radiotherapy
Regimen M	Experimental	Drug: Temozolomide, Drug: BIBW2992, Procedure: RadiotherapyBIBW2992 + Temozolomide + Radiotherapy

Who may qualify

Ages: 18 to 69 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (7 listed)

Histologically-confirmed WHO Grade IV newly diagnosed malignant glioma.
Proven MGMT gene promoter methylation status
Available early postoperative Gd-enhanced MRI (within 72 hours after initial surgery). In case a patient did not perform a Gd-enhanced MRI within 72 hours post surgery, a Gd-MRI is to be performed prior to start of study treatment.
Age more or equal to 18 years and less than 70 years at entry
Karnofsky Performance Scale (KPS) more or equal to 70%

Key exclusion criteria (22 listed)

Less than two weeks from surgical resection or other major surgical procedure at start of treatment.
Planned surgery for other diseases
Placement of Gliadel® wafer at surgery.
Prior or planned radiotherapy of the cranium including brachytherapy and/or radiosurgery for GBM.
Treatment with other investigational drugs; participation in another clinical study including exposure to the investigational product within the past 4 weeks before start of therapy or concomitantly with this study.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
TemozolomideDuring RT: 75 mg/m2 daily , 4 weeks after RT: given days 1 to 5 of 28 day cycles (150 mg/m2 in cycle 1, 200 mg/m2 in cycle 2 up to cycle 6)	Drug	Regimen M
RadiotherapyDay 1 to day 42	Procedure or surgery	Regimen U
BIBW2992Escalating dose cohorts during Radiotherapy(RT) period, fixed dose after RT	Drug	Regimen M
RadiotherapyDay 1 to day 42	Procedure or surgery	Regimen M
BIBW2992Escalating dose cohorts during Radiotherapy(RT) period , fixed dose after RT	Drug	Regimen U

Primary outcome

Number of Patients With Investigator Defined Dose Limiting Toxicities (DLT) During the RT Phase
Time frame: 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
Time frame: 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).

3 secondary outcomes

Incidence and Intensity of Adverse Events (AE) According to Common Terminology Criteria of Adverse Events (CTCAE v.3.0)
Time frame: From the first administration of trial medication until 4 weeks after the last administration of trial medication, up to approximately 338 weeks
The Objective Tumour Response According to the Macdonald Criteria
Time frame: From the first administration of trial medication until 4 weeks after the last administration of trial medication, up to approximately 338 weeks
Concentration of Afatinib in Plasma at Steady State Pre-dose on Days 8, 15 and 29
Time frame: 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

Results and safety

Results posted to the registry on 18 Feb 2019, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Afatinib 20 Milligram, Radiotherapy + Temozolomide - Regimen M	7	0
Afatinib 30 mg, Radiotherapy + Temozolomide - Regimen M	6	0
Afatinib 40 mg, Radiotherapy + Temozolomide - Regimen M	7	0
Afatinib 20 mg, Radiotherapy - Regimen U	3	0
Afatinib 40 mg, Radiotherapy - Regimen U	13	0

Primary outcome: Number of Patients With Investigator Defined Dose Limiting Toxicities (DLT) During the RT Phase

Time frame: 6 weeks. Number. Unit: Participants

Measure	Afatinib 20 Milligram, Radiotherapy + Temozolomide - Regimen M n = 6	Afatinib 30 mg, Radiotherapy + Temozolomide - Regimen M n = 6	Afatinib 40 mg, Radiotherapy + Temozolomide - Regimen M n = 5	Afatinib 20 mg, Radiotherapy - Regimen U n = 3	Afatinib 40 mg, Radiotherapy - Regimen U n = 6
Value	1	0	2	0	1

Population analysed: Treated Set (TS); 3 patients were not evaluable for the determination of the maximum tolerated dose replaced in regimen M. 7 patients were excluded from the Afatinib 40 mg arm regimen U count as these were part of the expansion phase after the Maximum Tolerated Dose (MTD) had been determined.

Primary outcome: Maximum Tolerated Dose (MTD) of Afatinib

Time frame: 6 weeks. Number. Unit: Milligram (mg)

Measure	Total - Regimen M n = 17	Total - Regimen U n = 9
Value	30	40

3 secondary outcomes are reported in the full results.

Adverse events

Time frame: From the first administration of trial medication until 4 weeks after the last administration of trial medication, up to approximately 338 weeks. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Afatinib 20 Milligram, Radiotherapy + Temozolomide - Regimen M	4 of 7 (57.1%)	7 of 7 (100%)	0 of 7
Afatinib 30 mg, Radiotherapy + Temozolomide - Regimen M	5 of 6 (83.3%)	6 of 6 (100%)	0 of 6
Afatinib 40 mg, Radiotherapy + Temozolomide - Regimen M	3 of 7 (42.9%)	6 of 7 (85.7%)	0 of 7
Total - Regimen M	12 of 20 (60%)	19 of 20 (95%)	0 of 20
Afatinib 20 mg, Radiotherapy - Regimen U	2 of 3 (66.7%)	3 of 3 (100%)	0 of 3
Afatinib 40 mg, Radiotherapy - Regimen U	10 of 13 (76.9%)	13 of 13 (100%)	3 of 13
Total - Regimen U	12 of 16 (75%)	16 of 16 (100%)	3 of 16

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 18 Feb 2019.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 34787778Saran F, Welsh L, James A, McBain C, Gattamaneni R, Jefferies S, Harris F, Pemberton K, Schaible J, Bender S, Cseh A, Brada M. Afatinib and radiotherapy, with or without temozolomide, in patients with newly diagnosed glioblastoma: results of a phase I trial. J Neurooncol. 2021 Dec;155(3):307-317. doi: 10.1007/s11060-021-03877-6. Epub 2021 Nov 17.

Related trials for Glioblastoma

Active, not recruitingPhase 3
EF-41/KEYNOTE D58: Phase 3 Study of Optune Concomitant With Temozolomide Plus Pembrolizumab in Newly Diagnosed Glioblastoma
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Testing the Addition of an Anti-cancer Drug, Selinexor, to the Usual Chemotherapy Treatment (Temozolomide) for Brain Tumors That Have Returned After Previous Treatment
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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Boehringer Ingelheim study chair

Boehringer Ingelheim

5 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Temozolomide, Radiotherapy and BIBW2992 in people with Glioblastoma, run by Boehringer Ingelheim at 5 sites in United Kingdom.

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 7 inclusion and 22 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 18 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in United Kingdom. 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?

Yes. Results are posted in the registry (first posted 18 Feb 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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?

Number of Patients With Investigator Defined Dose Limiting Toxicities (DLT) During the RT Phase (time frame: 6 weeks). 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 NCT00977431, which also lists 1 linked publication.

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 18 Feb 2019.