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

NCT00977431 | Completed Phase 1 Results

• 2 other identifiers: 1200.382008-007284-17
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 5

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).

Conditions

Glioblastoma

Outcome Measures

Primary Outcomes (2)

• 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.

  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).

  6 weeks

Secondary Outcomes (3)

• 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

• 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

• 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

Study Arms (2)

Regimen U

EXPERIMENTAL

BIBW2992 + Radiotherapy

Procedure: Radiotherapy; Drug: BIBW2992

Regimen M

EXPERIMENTAL

BIBW2992 + Temozolomide + Radiotherapy

Drug: Temozolomide; Drug: BIBW2992; Procedure: Radiotherapy

Interventions

Temozolomide DRUG

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)

Regimen M

Radiotherapy PROCEDURE

Day 1 to day 42

Regimen U

BIBW2992 DRUG

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

Regimen M

Eligibility Criteria

• Age: 18 Years - 69 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Boehringer Ingelheim: lead

Study Sites (5)

Addenbrooke's Hospital

Cambridge, CB2 0QQ, United Kingdom

Location

Ninewells Hospital & Medical School

Dundee, DD1 9SY, United Kingdom

Location

Beatson West of Scotland Cancer Centre

Glasgow, G12 0YN, United Kingdom

Location

The Christie Hospital

Manchester, M20 4BX, United Kingdom

Location

The Royal Marsden Hospital

Sutton, SM2 5PT, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 34787778 DERIVED

MeSH Terms

Conditions

Glioblastoma

Interventions

Temozolomide; Radiotherapy; Afatinib

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics; Amides; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Boehringer Ingelheim, Call Center
• Organization: Boehringer Ingelheim

clintriage.rdg@boehringer-ingelheim.com

1-800-243-0127

Study Officials

• Boehringer Ingelheim

  Boehringer Ingelheim

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 14, 2009
• First Posted: September 15, 2009
• Study Start: September 17, 2009
• Primary Completion: September 12, 2017
• Study Completion: September 12, 2017
• Last Updated: February 18, 2019
• Results First Posted: February 18, 2019

Record last verified: 2019-02

Locations

GB (5)