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

Primary Purpose

Glioblastoma

Status

Completed

Phase

Phase 1

Locations

United Kingdom

Study Type

Interventional

Intervention

Temozolomide

Radiotherapy

BIBW2992

Radiotherapy

BIBW2992

About this trial

This is an interventional treatment trial for Glioblastoma

Eligibility Criteria

18 Years - 69 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

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.

Exclusion criteria:

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.
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.

Sites / Locations

Addenbrooke's Hospital
Ninewells Hospital & Medical School
Beatson West of Scotland Cancer Centre
The Christie Hospital
The Royal Marsden Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Regimen U

Regimen M

Arm Description

BIBW2992 + Radiotherapy

BIBW2992 + Temozolomide + Radiotherapy

Outcomes

Primary Outcome Measures

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.

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).

Secondary Outcome Measures

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).

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.

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.

Full Information

NCT ID

NCT00977431

First Posted

September 14, 2009

Last Updated

February 11, 2019

Sponsor

Boehringer Ingelheim

1. Study Identification

Unique Protocol Identification Number

NCT00977431

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2019

Overall Recruitment Status

Completed

Study Start Date

September 17, 2009 (Actual)

Primary Completion Date

September 12, 2017 (Actual)

Study Completion Date

September 12, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Boehringer Ingelheim

4. Oversight

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Glioblastoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

36 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Regimen U

Arm Type

Experimental

Arm Description

BIBW2992 + Radiotherapy

Arm Title

Regimen M

Arm Type

Experimental

Arm Description

BIBW2992 + Temozolomide + Radiotherapy

Intervention Type

Drug

Intervention Name(s)

Temozolomide

Intervention Description

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)

Intervention Type

Procedure

Intervention Name(s)

Radiotherapy

Intervention Description

Day 1 to day 42

Intervention Type

Drug

Intervention Name(s)

BIBW2992

Intervention Description

Escalating dose cohorts during Radiotherapy(RT) period, fixed dose after RT

Intervention Type

Procedure

Intervention Name(s)

Radiotherapy

Intervention Description

Day 1 to day 42

Intervention Type

Drug

Intervention Name(s)

BIBW2992

Intervention Description

Escalating dose cohorts during Radiotherapy(RT) period , fixed dose after RT

Primary Outcome Measure Information:

Title

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

Description

Time Frame

6 weeks

Title

Maximum Tolerated Dose (MTD) of Afatinib

Description

Time Frame

6 weeks

Secondary Outcome Measure Information:

Title

Incidence and Intensity of Adverse Events (AE) According to Common Terminology Criteria of Adverse Events (CTCAE v.3.0)

Description

Time Frame

From the first administration of trial medication until 4 weeks after the last administration of trial medication, up to approximately 338 weeks

Title

The Objective Tumour Response According to the Macdonald Criteria

Description

Time Frame

From the first administration of trial medication until 4 weeks after the last administration of trial medication, up to approximately 338 weeks

Title

Concentration of Afatinib in Plasma at Steady State Pre-dose on Days 8, 15 and 29

Description

Concentration of afatinib in plasma at steady state pre-dose (Cpre,ss) 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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

69 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria: 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. Exclusion criteria: 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. 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Boehringer Ingelheim

Organizational Affiliation

Boehringer Ingelheim

Official's Role

Study Chair

Facility Information:

Facility Name

Addenbrooke's Hospital

City

Cambridge

ZIP/Postal Code

CB2 0QQ

Country

United Kingdom

Facility Name

Ninewells Hospital & Medical School

City

Dundee

ZIP/Postal Code

DD1 9SY

Country

United Kingdom

Facility Name

Beatson West of Scotland Cancer Centre

City

Glasgow

ZIP/Postal Code

G12 0YN

Country

United Kingdom

Facility Name

The Christie Hospital

City

Manchester

ZIP/Postal Code

M20 4BX

Country

United Kingdom

Facility Name

The Royal Marsden Hospital

City

Sutton

ZIP/Postal Code

SM2 5PT

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

34787778

Citation

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.

Results Reference

derived

Links:

URL

http://trials.boehringer-ingelheim.com

Description

Related Info

Learn more about this trial

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

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