E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-small cell lung cancer patients who developed acquired resistance to Epidermal Growth Factor Receptor - Tyrosine Kinase Inhibitor (EGFR-TKI) following prior treatment with erlotinib or gefitinib or BIBW 2992 |
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E.1.1.1 | Medical condition in easily understood language |
Non-small cell lung cancer patients who derived clinical benefit and then failed Epidermal Growth Factor Receptor (EGFR) targeted therapy with erlotinib or gefitinib or BIBW 2992 |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To establish the maximum tolerated dose (MTD) and recommended Phase II doses and evaluate the safety and preliminary anti-tumor activity for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib, gefitinib or BIBW 2992. |
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E.2.2 | Secondary objectives of the trial |
Overall safety, pharmacokinetics and anti-tumor activity will be evaluated as secondary objectives.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Pathologically or cytologically confirmed Stage IIIB/IV disease or recurrent disease following locoregional treatment
2. Either or both of the following:
• A tumor which harbors an EGFR-mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) from previous tumor biopsy or surgery. A tumor which harbors exon 20 insertion or de novo T790M mutation is eligible for the treatment in the sequential arm
• Objective clinical benefit from treatment with an EGFR TKI as defined by either
1) Documented partial or complete response (RECIST), or
2) Stable disease ≥6 months as defined by RECIST in absence of radiographic progression after initiation of gefitinib or erlotinib; or stable disease/PR/CR ≥ 12 weeks as defined by RECIST after initiation of BIBW 2992
3. Systemic progression of disease (RECIST v1.1) while on continuous treatment with erlotinib or gefitinib or BIBW 2992 within the last 30 days. Patients whose disease progresses only in the central nervous system (CNS) are not eligible
4. No intervening systemic therapy between cessation of gefitinib or erlotinib or BIBW 2992 and initiation of the treatment in the study
5. Adequate tumor-derived material such as fresh or archived tumor tissue or pleural fluid from malignant pleural effusion after disease progression on erlotinib/gefitinib/BIBW 2992 must be made available for EGFR mutation analyses
6. Patients aged 18 years or older
7. Life expectancy of at least three (3) months
8. Eastern Cooperative Oncology Group (ECOG) performance score 0-2
9. Written informed consent that is consistent with ICH-GCP guidelines
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E.4 | Principal exclusion criteria |
1. Prior treatment with EGFR targeting antibodies
2. Prior severe infusion reaction to a monoclonal antibody
3. Major surgery within 28 days or minor surgery within 14 days of the start of the study treatment
4. Radiotherapy less than two weeks prior to the start of the study treatment
5. Systemic chemotherapy, hormonal therapy, immunotherapy, or experimental or approved proteins/antibodies (except erlotinib/gefitinib/BIBW 2992) <=30 days before study treatment
6. Less than three days from prior treatment with gefitinib or erlotinib. Patients with adverse events related to gefitinib or erlotinb must recover to CTC AE grade 1 or less to be eligible. No need to stop BIBW 2992 before start of the study treatment for patient who progressed on BIBW 2992 from a seperate clinical trial/treatment setting
7. Brain metastases, which are symptomatic. 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. Anticonvulsant therapy will be allowed if patient is stable on anticonvulsant treatment without adjustments of the latter
8. Other malignancies diagnosed within the past five (5) years (other than non melanomatous skin cancer, ductal carcinoma in situ and in situ cervical cancer), unless treated with curative intent. Patients with inactive malignancy may be eligible upon discussion and agreement between investigator and sponsor
9. Known pre-existing interstitial lung disease
10. Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn’s disease, malabsorption, or CTCAE grade >2 diarrhea of any etiology
11. History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure, New York Heart Association (NYHA) functional classification of 3, unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 month prior to the study entry
12. Cardiac left ventricular function with resting ejection fraction of less than 50%
13. Any other concomitant serious 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 and anti-tumor activity of the test drug
14. Absolute neutrophil count (ANC) <1000/mm3
15. Platelet count <75,000/mm3
16. Bilirubin >1.5 times upper limit of normal. Aspartate amino transferase (AST) or alanine amino transferase (ALT) >three times the upper limit of normal (if related to liver metastases >five times the upper limit of normal)
17. Serum creatinine >1.5 times of the upper normal limit or calculated/measured creatinine clearance <60 ml/min
18. Known hepatitis B infection, active hepatitis C infection or known HIV carrier
19. Women of childbearing potential (WOCBP), or men who are able to father a child, unwilling to use a medically acceptable method of contraception during the trial.
20. Pregnancy or breast-feeding
21. Patients unable to comply with the protocol
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the occurrence of dose limiting toxicity (DLT) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The first 28 days of starting the combination therapy during dose-finding phase. DLT occurred at a later timepoint will be assessed separately. |
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E.5.2 | Secondary end point(s) |
1) Safety of BIBW 2992 when administered together with cetuximab as indicated by intensity and incidence of adverse events, graded according to NCI CTCAE Version 3.0
2) Pharmacokinetic parameters of BIBW 2992 and cetuximab in the applied treatment setting
3) Objective tumor response (Complete Response [CR] and Partial Response [PR]) determined by RECIST v1.1
4) Disease control (CR, PR and Stable Disease [SD] determined by RECIST v1.1
5) Progression-free survival (PFS)
6) Duration of disease control
7) Duration of objective response
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Patients will continue to be assessed until disease progression or start of new treatment |
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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 | No |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
First administration of the combination of two drugs in human |
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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 | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
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 | 2 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Netherlands |
United States |
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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
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The clinical trial will be considered completed as soon as the last patient has completed the follow-up assessment. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |