| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients diagnosed with EGFR/HER2-positive solid tumour cancers with and without brain metastases, and patients with recurrent glioblastoma. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10018336 |
| E.1.2 | Term | Glioblastoma |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006128 |
| E.1.2 | Term | Brain metastases |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
This trial aims to investigate the efficacy and safety of BIBW 2992 monotherapy in patients with EGFR/HER2-positive tumours with and without brain metastases, and in patients with recurrent glioblastoma (GBM).
This trial will evaluate
1. QTcF interval (corrected by the Fridericia formula, as described in 7.3.1.1)
2. Objective tumour response according to the Macdonald criteria for GBM
patients and for patients with brain metastases, and the RECIST criteria for other patients |
|
| E.2.2 | Secondary objectives of the trial |
1. Marked prolongation of QT
- any time-matched change from screening in QTcF of more than 30 and 60 ms
- any QTcF of more than 450, 480, and 500 ms (excluding patients with any prolonged value during screening)
2. Cardiac safety parameters
- abnormalities in PR interval and QRS intervals, Heart rate (HR), T wave and U wave morphology
3. Disease control rate ( CR, PR and SD)
4. Progression-free survival (PFS)
5. Molecular determinants of response
5.1 EGFR, HER2 and PTEN by immunohistochemistry, fluorescent in situ hybridization (FISH) for amplification of genes including EGFR, HER2 and PTEN, and mutation analysis of EGFR and K-RAS. Further biomarkers will be chosen by the investigator according to the tumour type.
6. Incidence and intensity of adverse events, graded according to NCI CTCAE Version 3.0 with special emphasis on skin reactions and GI adverse events
7. Pharmacokinetic characteristics of BIBW 2992 after single dose and at steady state |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients aged at least 18 years old.
2. Histologically or cytologically confirmed diagnosis of a solid malignant tumour, known to historically express EGFR/HER2 that is either refractory to standard therapies, or for which no standard treatment is available (including patients with brain metastases).
3. At least one tumor lesion that can accurately be measured by computed tomography (CT) or magnetic resonance imaging (MRI) in at least one dimension with longest diameter to be recorded as ≥20 mm using conventional techniques or or ≥10 mm with spiral CT scan.
4. Life expectancy of at least 3 months.
5. Written informed consent that is consistent with ICH-GCP guidelines.
6. Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score 0,1 or 2.
7. Patients must have recovered from any previous surgery.
8. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) for the duration of trial participation. Female patients with reproductive potential must have a negative serum pregnancy test within 7 days of trial enrolment. Breast feeding mothers will be excluded since these agents may be toxic to infants.
For patients with Glioma and brain metastases the following additional inclusion criteria should apply:
1. Histologically-confirmed WHO Grade IV malignant glioma at first episode of recurrence after prior combined chemo-radiotherapy. Patients with prior low-grade glioma are eligible if histological assessment demonstrates transformation to WHO Grade IV malignant glioma.
2. Bi-dimensionally measurable disease with a minimum measurement of 1 cm (10 mm) in one diameter on Gd MRI performed within 14 days prior to first treatment (Day 1). |
|
| E.4 | Principal exclusion criteria |
1. Active infectious disease
2. Patients unable to comply with the protocol.
3. Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom e.g., Crohn’s disease, malabsorption, or CTCAE Grade >2 diarrhoea of any aetiology at baseline.
4. Patients who have any other life-threatening illness or organ system dysfunction which, in the opinion of the investigator, would either compromise patient safety or interfere with the evaluation of the safety of the test drug.
5. Other malignancies diagnosed within the past five (5) years (other than non
melanomatous skin cancer and in situ cervical cancer).
6. Patients with any serious active infection (i.e., requiring an i.v. antibiotic, antifungal, or antiviral agents).
7. Patients with known HIV, active hepatitis B or active hepatitis C infection
8. Known or suspected active drug or alcohol abuse.
9. Radiotherapy within the past 2 weeks prior to treatment with the trial drug.
10. Chemo-, hormone- (other than megestrol acetate or steroids required for maintenance non-cancer therapy) or immunotherapy within the past 4 weeks before first drug administration
11. Patients not completely recovered from any therapy-related toxicities from previous chemo-, hormone-, immuno-, or radiotherapies to CTC < Grade 1. Prior chemotherapy is allowed if completed at least 4 weeks prior to first trial treatment (6 weeks for mitomycin C or nitrosoureas) and the patient has recovered from the acute toxicities of that therapy.
12. Prior treatment with EGFR targeting therapies or treatment with EGFR- or HER2
inhibiting drugs within the four weeks prior to start of therapy or concomitantly with thistrial.
13. Pregnancy or breast feeding.
14. Women of child-bearing potential or men who are able to father a child unwilling to use a medically acceptable method of contraception during the trial.
15. History of clinically significant or uncontrolled cardiac disease, including congestive
heart failure, angina, myocardial infarction, arrhythmia, including New York Heart
Association (NYHA) functional classification of 3.
16. Cardiac left ventricular function with resting ejection fraction of less than 50% measured by multigated blood pool imaging of the heart (MUGA scan) or Echocardiogram.
17. QTcF- interval > 470 ms at screening
18. PR-interval > 230 ms at screening
19. QRS-interval >120 ms at screening
20. ST-segment and T/U-wave abnormalities at screening, as will be assessed by a cardiology specialist of a central lab ( Nabios GmbH)
21. Absolute neutrophil count (ANC) less than 1,500/mm3.
22. Platelet count less than 100,000 / mm3.
23. Bilirubin greater than 1.5 mg / dl (>26 μmol / L, SI unit equivalent). Aspartate amino transferase (AST) or alanine amino transferase (ALT) > than three times the upper limit of normal (if related to liver metastases greater than five times the upper limit of normal).
24. Serum creatinine greater than 1.5 times of the upper normal limit or calculated/measured creatinine clearance ≤ 45 ml / min.
25. Patients with known Interstitial Lung Disease (ILD)
For Patients with glioma and brain metastases additional exclusion criteria apply
1. Patients with untreated or symptomatic brain metastases. Patients with treated,
asymptomatic brain metastases are eligible if there has been no change in brain disease status for at least four (4) weeks, no history of cerebral oedema or bleeding in the past four (4) weeks. Steroids will be allowed. Anti-epileptic therapy will be allowed if no changes are anticipated within the initial 14 days of treatment (QTC-evaluation).
2. Less than 4 weeks between radiotherapy and start of study treatment, unless new enhancing lesion outside of radiation field or radiologically progressive on two
consecutive MRI scans at least four weeks apart or biopsy-proven recurrence.
3. Less than two weeks from surgical resection (one week from prior stereotactic biopsy) or major surgical procedure.
4. Less than two weeks after previous chemotherapy (6 weeks from nitrosureas).
5. Less than four weeks from prior treatment with bevacizumab.
6. Treatment with other investigational drugs; participation in another clinical study within the past 2 weeks before start of therapy or concomitantly with this study.
26. Requirement for treatment with any of the prohibited concomitant medications listed in section 4.2.2 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. QTcF interval (corrected by the Fridericia formula)
2. Objective tumour response according to the Macdonald criteria for GBM patients and for patients with brain metastases, and the RECIST criteria for other patients |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
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