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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

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ClinicalTrials.gov Identifier: NCT00977431
Recruitment Status : Completed
First Posted : September 15, 2009
Results First Posted : February 18, 2019
Last Update Posted : February 18, 2019
Sponsor:
Information provided by (Responsible Party):
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).

Condition or disease Intervention/treatment Phase
Glioblastoma Drug: Temozolomide Procedure: Radiotherapy Drug: BIBW2992 Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I, Open Label Trial to Explore Safety of Combining BIBW 2992 and Radiotherapy With or Without Temozolomide in Newly Diagnosed GBM
Actual Study Start Date : September 17, 2009
Actual Primary Completion Date : September 12, 2017
Actual Study Completion Date : September 12, 2017


Arm Intervention/treatment
Experimental: Regimen U
BIBW2992 + Radiotherapy
Procedure: Radiotherapy
Day 1 to day 42

Drug: BIBW2992
Escalating dose cohorts during Radiotherapy(RT) period , fixed dose after RT

Experimental: Regimen M
BIBW2992 + Temozolomide + Radiotherapy
Drug: Temozolomide
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)

Drug: BIBW2992
Escalating dose cohorts during Radiotherapy(RT) period, fixed dose after RT

Procedure: Radiotherapy
Day 1 to day 42




Primary Outcome Measures :
  1. 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.


  2. 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).


Secondary Outcome Measures :
  1. 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 ]
    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).

  2. 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 ]
    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.

  3. 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 ]
    Concentration of afatinib in plasma at steady state pre-dose (Cpre,ss) on days 8, 15 and 29.



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Ages Eligible for Study:   18 Years to 69 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  1. Histologically-confirmed WHO Grade IV newly diagnosed malignant glioma.
  2. Proven MGMT gene promoter methylation status
  3. 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.
  4. Age more or equal to 18 years and less than 70 years at entry
  5. Karnofsky Performance Scale (KPS) more or equal to 70%
  6. Patients receiving corticosteroids have to receive a stable or decreasing dose for at least 14 days before start of treatment.
  7. Written informed consent that is consistent with local law and ICH- Good Clinical Practice (GCP) guidelines.

Exclusion criteria:

  1. Less than two weeks from surgical resection or other major surgical procedure at start of treatment.
  2. Planned surgery for other diseases
  3. Placement of Gliadel® wafer at surgery.
  4. Prior or planned radiotherapy of the cranium including brachytherapy and/or radiosurgery for GBM.
  5. 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.
  6. Active infectious disease requiring intravenous therapy.
  7. Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.
  8. Gastrointestinal disorders that may interfere with the absorption of the study drug or chronic diarrhoea.
  9. Patients with known pre-existing interstitial lung disease
  10. Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol.
  11. 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.
  12. Cardiac left ventricular function with resting ejection fraction less than 50%.
  13. Absolute neutrophil count (ANC) less than 1500/mm3.
  14. Platelet count less than 100,000/mm3.
  15. Bilirubin greater than 1.5 x upper limit of institutional norm.
  16. Aspartate amino transferase (AST) greater than 3 x upper limit of institutional norm.
  17. Serum creatinine greater than 1.5 x upper limit of institutional norm.
  18. Patients who are sexually active and unwilling to use a medically acceptable method of contraception.
  19. Pregnancy or breast-feeding.
  20. Patients unable to comply with the protocol.
  21. Known or suspected active drug or alcohol abuse.
  22. Known hypersensitivity to BIBW 2992 or the excipients of any of the trial drugs.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00977431


Locations
United Kingdom
Addenbrooke's Hospital
Cambridge, United Kingdom, CB2 0QQ
Ninewells Hospital & Medical School
Dundee, United Kingdom, DD1 9SY
Beatson West of Scotland Cancer Centre
Glasgow, United Kingdom, G12 0YN
The Christie Hospital
Manchester, United Kingdom, M20 4BX
The Royal Marsden Hospital
Sutton, United Kingdom, SM2 5PT
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  Study Documents (Full-Text)

Documents provided by Boehringer Ingelheim:
Study Protocol  [PDF] May 24, 2017
Statistical Analysis Plan  [PDF] December 1, 2011


Additional Information:
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00977431     History of Changes
Other Study ID Numbers: 1200.38
2008-007284-17 ( EudraCT Number )
First Posted: September 15, 2009    Key Record Dates
Results First Posted: February 18, 2019
Last Update Posted: February 18, 2019
Last Verified: February 2019

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents